Background:Monoclonal antibodies (mAbs) against calcitonin gene-related peptides (CGRP) are novel treatments for migraine prevention. Based on a previous functional imaging study which investigated the CGRP receptor mAb (erenumab), we hypothesized that (i) the CGRP ligand mAb galcanezumab would alter central trigeminal pain processing; (ii) responders to galcanezumab treatment would show specific hypothalamic modulation in contrast to non-responders; and (iii) the ligand and the receptor antibody differ in brain responses.Methods:Using an established trigeminal nociceptive functional magnetic imaging paradigm, 26 migraine patients were subsequently scanned twice: before and 2–3 weeks after administration of galcanezumab.Results:We found that galcanezumab decreases hypothalamic activation in all patients and that the reduction was stronger in responders than in non-responders. Contrasting erenumab and galcanezumab showed that both antibodies activate a distinct network. We also found that pre-treatment activity of the spinal trigeminal nucleus (STN) and coupling between the STN and the hypothalamus covariates with the response to galcanezumab.Conclusions:These data suggest that despite relative impermeability of the blood-brain barrier for CGRP mAb, mAb treatment induces certain and highly specific brain effects which may be part of the mechanism of their efficacy in migraine treatment.Funding:This work was supported by the German Ministry of Education and Research (BMBF) of ERA-Net Neuron under the project code BIOMIGA (01EW2002 to AM) and by the German Research Foundation (SFB936-178316478-A5 to AM). The funding sources did not influence study conduction in any way.Clinical trial number:The basic science study was preregistered in the Open Science Framework (https://osf.io/m2rc6).

Objective:To investigate the behavioral and neuronal responses of patients with migraine to a visual stimulation of self-motion through a virtual roller coaster ride, in comparison to controls.Methods:Twenty consecutive migraine patients from a university-based hospital headache clinic and 20 controls were included. Participants underwent an experiment where a visually displayed self-motion paradigm was presented based on customized roller coaster videos during fMRI. Within each video, blocks of motion stimulation were interleaved with low speed upward motion in a random order. In the scanning intervals and after the experiment, participants rated their perceived level of vestibular symptoms and motion sickness during the videos. We hypothesized that migraine patients will perceive more motion sickness and that this correlates with a different central processing and brain responses.Results:Compared to controls, migraine patients reported more dizziness (65% versus 30% p= 0.03) and motion sickness [SSQ score 47.3 (95%CI 37.1, 57.5) versus 24.3 (95%CI 18.2, 30.4)] as well as longer symptom duration [01:19 min (95%CI 00:51, 01:48) versus 00:27 min (95%CI 00:03, 00:51)] and intensity [VAS 0-100, 22.0 (95%CI 14.8, 29.2) versus 9.9 (95%CI 4.9, 14.7)] during the virtual roller coaster ride. Neuronal activity in migraine patients were more pronounced in clusters within the superior [Contrast estimate 3.005 (90%CI 1.817, 4.194)] and inferior occipital gyrus [Contrast estimate 1.759 (90%CI 1.062, 2.456)], pontine nuclei [Contrast estimate 0.665 (90%CI 0.383, 0.946)] and within the cerebellar lobules V/VI [Contrast estimate 0.672 (90%CI 0.380, 0.964)], while decreased activity was seen in the cerebellar lobule VIIb [Contrast estimate 0.787 (90%CI 0.444, 1.130)] and in the middle frontal gyrus [Contrast estimate 0.962 (90%CI 0.557, 1.367)]. These activations correlated with migraine disability (r= -0.46, p= 0.04) and motion sickness scores (r= 0.32, p= 0.04). We further found enhanced connectivity between the pontine nuclei, cerebellar areas V/VI, interior and superior occipital gyrus with numerous cortical areas in migraine patients but not in controls.Conclusions:Migraine is related to abnormal modulation of visual motion stimuli within superior and inferior occipital gyrus, middle frontal gyrus, pontine nuclei, cerebellar lobules V, VI and VIIb. These abnormalities relate to migraine disability and motion sickness susceptibility.

The existence of a trigeminocervical complex has been suggested based on animal data, but only indirect evidence exists in humans. We investigated the functional relationship between the trigeminal and the occipital region by stimulating one region and measuring electrical pain thresholds (EPTs) of the corresponding opposite region. This study consists of 2 single-blinded, randomised protocols. Forty healthy participants were recruited in the propaedeutic protocol I. Electrical pain thresholds were measured on the V1 and the greater occipital nerve (GON) dermatome bilaterally as well as on the left forearm longitudinally before and after application of topical capsaicin. Protocol II was then online preregistered, and, additionally, the ipsilateral trigeminal dermatomes V2 and V3 were tested. Greater occipital nerve stimulation increased the EPT ipsilateral at V1 after 20 minutes (P 5 0.006) compared with baseline, whereas trigeminal stimulation increased the EPT at the ipsilateral (P 5 0.023) as well as the contralateral GON (P 5 0.001) after capsaicin application. Protocol II confirmed these results and additionally showed that GON stimulation with capsaicin increased EPTs ipsilateral at all 3 trigeminal dermatomes and that trigeminal stimulation on V1 led to an ipsilateral increase of EPTs at GON, V2, and V3. Our data suggest a strong functional interplay between the trigeminal and occipital system in humans. The fact that the stimulation of one of these dermatomes increases the EPT of the respective other nerve could be explained by segmental inhibition on the brainstem level.

Galcanezumab, a monoclonal antibody against calcitonin gene-related peptide, is an emerging migraine preventative. We hypothesized that the preventive effects are conveyed via the modulation of somatosensory processing and that certain sensory profiles may hence be associated with different clinical responses. We recruited migraine patients (n 5 26), who underwent quantitative sensory tests over the right V1 dermatome and forearm at baseline (T0), 2 to 3 weeks (T1) and 1 year (T12) after monthly galcanezumab treatment. The clinical response was defined as a reduction of $30% in headache frequency based on the headache diary. Predictors for clinical response were calculated using binary logistical regression models. After galcanezumab (T1 vs T0), the heat pain threshold (˚C, 44.9 6 3.4 vs 43.0 6 3.3, P 5 0.013) and mechanical pain threshold (log mN, 1.60 6 0.31 vs 1.45 6 0.26, P 5 0.042) were increased exclusively in the V1 dermatome but not the forearm. These changes were immediate, did not differ between responders and nonresponders, and did not last in 1 year of follow-up (T12 vs T0). However, baseline heat pain threshold (OR: 2.13, 95% CI: 1.08-4.19, P 5 0.029) on the forearm was a robust predictor for a clinical response 3 months later. In summary, our data demonstrated that galcanezumab modulates pain thresholds specifically in the V1 dermatome, but this modulation is short-lasting and irrelevant to clinical response. Instead, the clinical response may be determined by individual sensibility even before the administration of medication.