Figures
Figure 1
Study flowchart.
On the left side the galcanezumab cohort, on the right side the erenumab cohort.
Figure 2
Experimental design and responder-specific main findings.
(A) Flowchart of the experimental design. At both visits, objective rating of pain intensity and unpleasantness on a numeric rating scale (NRS), session-specific questionnaire: current headache (yes/no), strength of headache (NRS), headache frequency (per week), date of last headache. Three months of total therapy duration, patients were contacted via phone and/or email to acquire their headache diaries. (B) Responder-specific decreased neuronal activity during nociception at visit 2 compared to visit 1 in subgroup analysis of migraine-phase matched patients (n=15). Data is shown at statistical threshold of p<0.001 and a minimum cluster size of 10 voxels, masked with gray and white matter study template where a higher t-value means a stronger decrease of activity after treatment for responders in comparison to non-responders.
Figure 3
Galcanezumab vs erenumab.
Erenumab (red)/galcanezumab (blue)-specific decreased neuronal activity during nociception at visit 2 compared to visit 1 in subgroup analysis of migraine-phase matched patients (n=15 vs. 17). Data is shown at statistical threshold of p<0.001 and a minimum cluster size of 10 voxels.
Figure 4
Prediction/functional connectivity changes after galcanezumab administration.
(A) Two-tailed Pearson’s correlation of visit 1 spinal trigeminal nucleus (STN) neuronal activity (before administration of galcanezumab) and response (in % change of MHD). Responder (>30% reduction) are marked in blue; non-responders (<30% reduction) are colored red. STN activation is shown in the image above the legend – visit 1 trigeminal-nociceptive activation (ammonia-air puffs) covaries with response (in percent reduction of monthly headache days [MHD]). Data is shown at statistical threshold of p<0.001 and a minimum cluster size of 10 voxels. (B) Results of the psychophysiological interaction (PPI) analysis, showing the decreased connectivity between STN (seed region [A]) and hypothalamus. Data is shown at statistical threshold of p<0.001.
Tables
Table 1
Patient characteristics.
| Patient characteristics | Galcanezumab | Erenumab |
|---|---|---|
| Number | 26 | 27 |
| Female, % (n) | 96 (25) | 81 (22) |
| Age, mean ± SD (range), in years | 37.81±12.11 (21–60) | 39.1±12.2 (22–60) |
| Disease duration, mean ± SD (range), in years | 19.77±12.43 (2–50) | 21.7±11.2 (6–43) |
| Headache frequency, mean ± SD (range), days/month EM: mean ± SD (range), days/month CM: mean ± SD (range), days/month | 16.71±8.92 (4–30) 10.28±2.94 (4–14) 25.48±6.32 (16–30) | 20.3±8.3 (8–30) 12.08±2.07 (8-14) 26.8±4.71(20–30) |
| Migraine with and without aura, n | 7 | 9 |
| Migraine without aura, n | 19 | 18 |
| Chronic migraine (ICHD-3), % (n) | 42 (11) | 56 (15) |
| Episodic migraine (ICHD-3), % (n) | 58 (15) | 44 (12) |
| Same headache state – episodic, % (n) | 40 (6) | 29 (5) |
| – chronic, % (n) | 60 (9) | 71 (12) |
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Abbreviation: ICHD-3=International Classification of Headache Disorders, 3rd edition, EM: episodic migraine, CM: chronic migraine.
Table 2
Details of the statistical results of the functional magnetic resonance imaging (fMRI) analyses comparing before and after treatment as well as responders and non-responders.
| Anatomical region | Cluster size(voxels), n | T value | MNI coordinates(x,y,z) |
|---|---|---|---|
| (A) Visit 1>visit 2, all participants (n=26, contrast [ammonia-air puffs]visit1 > [ammonia-air puffs]visit2,threshold: p<0.001 [uncorrected], T>3.45, minimum cluster extent 25 voxels, df = 25) | |||
| R hypothalamus | 49 | 4.99 | 8, –14, –7 |
| R cerebellum | 48 | 5.0 | 20, –40, –25 |
| R cerebell. vermis | 52 | 4.09 | 3, –67, –34 |
| (B) Responder (n=8)>non-responder (n=7) with same headache state on both days (contrast [ammonia-air puffs]visit1 > [ammonia-air puffs]visit2, threshold p<0.001 [uncorrected], T>3.85, minimum cluster extent 10 voxels, df = 14) | |||
| R inf. parietal lobule | 91 | 9.17 | 58, –44, 21 |
| L precentral gyrus | 26 | 5.99 | −48, –11, 11 |
| L parahippocampal gyrus | 12 | 5.06 | −18, –11, –19 |
| L superior temporal gyrus | 13 | 4.76 | –36, 15,–26 |
| L inf. parietal lobule | 17 | 4.7 | 46, –42, 22 |
| R lentiform nucleus | 16 | 4.67 | 24, –2, 4 |
| R parahippocampal gyrus | 27 | 4.63 | 27, –28, –12 |
| L insula | 26 | 4.56 | −45, –27, 19 |
| L hypothalamus | 13 | 4.47 | −6, –17, –6 |
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(A) Main findings of trigeminal pain processing alterations after administration of the CGRP-ligand monoclonal antibody galcanezumab. The contrast shows more neuronal activity on visit 1 than on visit 2, therefore decrease driven by galcanezumab and was tested with a one-way paired t-test. (B) Subgroup analysis of patients having the same migraine/headache state on both visits (ictal and ictal or interictal and interictal). Main findings specific for being responder (responder showing a higher decrease after galcanezumab than non-responder) tested with a one-way independent sample t-test. Note that left-right activation patterns in near proximity twin structures such as the hypothalamus are not necessarily side-locked (a left activation excludes a right activation) but may be due to statistical thresholding.
Table 3
Details of the statistical results of the functional magnetic resonance imaging (fMRI) analyses comparing calcitonin gene-related peptides (CGRP) receptor monoclonal antibody erenumab and CGRP ligand monoclonal antibody galcanezumab.
| Anatomical region | Cluster size(voxels), n | T value | MNI coordinates(x,y,z) |
|---|---|---|---|
| (A) Erenumab >Galcanezumab (Visit 1>visit 2, migraine-phase equal subgroup [n=15 vs. n=17], contrast [ammonia-air puffs]visit1 > [ammonia-air puffs]visit2,threshold: p<0.001 [uncorrected], T>3.39, minimum cluster extent 10 voxels, df = 30) | |||
| L operculum | 416 | 5.61 | −60, –5, 8 |
| L cerebellum | 122 | 5.59 | −16, –65, –22 |
| R cerebellum | 207 | 5.23 | 42, –51, –32 |
| R supramarginal gyrus | 37 | 5.11 | 64, –45, 23 |
| R thalamus | 67 | 5.0 | 6, –15, 11 |
| R hippocampus | 74 | 4.88 | 21, –32, –10 |
| L thalamus | 53 | 4.71 | −9, –7, 11 |
| L temporal pole/insula | 202 | 4.5 | –54, 17, –1 |
| L superior temporal gyrus | 55 | 4.42 | −55, –33, 16 |
| Locus coeruleus | 30 | 4.41 | 4, –37, –9 |
| R insula | 82 | 4.37 | 47, 14, –7 |
| R operculum | 19 | 4.15 | 62, –2, 7 |
| R middle temporal gyrus | 21 | 4.07 | 55, –6, –22 |
| R lingual gyrus | 11 | 3.9 | 16, –49, 0 |
| (B) Galcanezumab >Erenumab (Visit 1>visit 2, migraine-phase equal subgroup [n=15 vs. n=17], contrast [ammonia-air puffs]visit1 > [ammonia-air puffs]visit2,threshold: p<0.001 [uncorrected], T>3.39, minimum cluster extent 10 voxels, df = 30) | |||
| Pons | 40 | 4.09 | −1, –18, –38 |
| R substantia nigra | 13 | 4.01 | 9, –14, –10 |
| L thalamus | 13 | 3.93 | −18, –15, 0 |
| R hypothalamus | 12 | 3.89 | 4, –19, 0 |
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Main findings of trigeminal pain processing alterations driven by the administration of the CGRP receptor monoclonal antibody erenumab in contrast to the CGRP ligand monoclonal antibody galcanezumab in the migraine-phase equal subgroup. (A) Erenumab-specific decrease in neuronal activity/BOLD across the two visits. (B) Galcanezumab-specific decrease in neuronal activity/BOLD across the two visits. Both results stem from one-sided independent t-tests.
Table 4
Statistical results of the functional magnetic resonance imaging (fMRI) analyses regarding the coherence with the reduction of headache days after treatment and changes in functional connectivity.
| Anatomical region | Cluster size(voxels), n | T value | MNI coordinates(x,y,z) |
|---|---|---|---|
| (A) Covariation of monthly headache day reduction (in % reduction) in the contrast (ammonia-air puffs) visit1, all participants (n=26) threshold: p<0.001 [uncorrected], T>3.48, minimum cluster extent 25 voxels, df = 25 | |||
| R middle temporal gyrus | 110 | 4.9 | 49, –8, –14 |
| STN | 83 | 4.65 | 4, –42, –53 |
| (B) PPI analysis of STN (region of interest 4, −42,–53), all participants (n=26) in the contrast (ammonia-air puffs) visit1> [ammonia-air puffs]visit2, threshold: p<0.001 [uncorrected], T>3.45, minimum cluster extent 25 voxels, df = 25 | |||
| L superior temporal gyrus | 62 | 5.57 | −52, –47, 18 |
| R hyopthalamus | 52 | 4.24 | 10, 5, –12 |
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(A) Main findings of the covariation of the response to galcanezumab by the activation pattern of neuronal activity at visit 1 (before administration of galcanezumab). This result was gained by introducing the covariate of reduction in headache days into a one-sided, one-sample t-test. (B) Results from the psychophysiological interaction analysis of the above-mentioned STN activation.
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- https://cdn.elifesciences.org/articles/77146/elife-77146-transrepform1-v1.docx
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Reporting standard 1
STROBE Checklist.
- https://cdn.elifesciences.org/articles/77146/elife-77146-repstand1-v1.pdf
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Migraine monoclonal antibodies against CGRP change brain activity depending on ligand or receptor target – an fMRI study
eLife 11:e77146.
https://doi.org/10.7554/eLife.77146
