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The exact mechanism and site of action of triptans in aborting migraine attacks remain under debate. We hypothesized that the clinical efficacy of triptans lies in aborting central sensitization and focused on the question of why triptans are headache specific, that is highly effective in migraine and cluster headache and ineffective in extracephalic pain.Forty healthy participants were enrolled in this double-blinded, randomized, placebo-controlled study. The effect of sumatriptan (n = 20) versus placebo (n = 20) was investigated in a trigeminal (V1) versus an extracephalic dermatome (forearm) using a topical capsaicin sensitization model. Capsaicin-induced primary and secondary hyperalgesia were evaluated using quantitative sensory testing.After capsaicin application, primary hyperalgesia developed in both the sumatriptan and placebo groups in both dermatomes. However, sumatriptan exclusively prevented secondary hyperalgesia in the V1 dermatome but not on the forearm. Placebo exerted no effects on secondary hyperalgesia in both trigeminal and extracephalic dermatomes. Additionally, sumatriptan reduced the flare size exclusively in the V1 dermatome.Our data suggest that sumatriptan reduces central sensitization (secondary hyperalgesia) without modulating peripheral sensitization (primary hyperalgesia) in a human pain model of capsaicin-induced sensitization. Moreover, despite a systemic administration of sumatriptan, the modulatory effects are trigeminal specific, echoing the clinical effect of triptans in aborting headaches, but not extracephalic pain.Our data suggest that triptans exert their efficacy by suppressing central sensitization. By revealing a dermatome-specific modulation, our study demonstrates a previously unrecognized interaction between the pharmacodynamics of triptans and the trigeminal nociceptive system that provides new insight into how triptans may work in aborting headache attacks.

Background The vasodilatory calcitonin-gene related peptide (CGRP) is understood as pivotal mediator in migraine pathophysiology. Blocking CGRP with small molecules or monoclonal antibodies (CGRP-mAb) reduces migraine frequency. However, prescription of CGRP-mAbs is still regulated and possible predictive measures of therapeutic success would be useful. Methods Using standardized capsaicin-induced dermal blood flow model, 29 migraine patients underwent a laser speckle imaging measurement before and after administration of galcanezumab. At both sessions dermal blood flow before and after capsaicin stimulation as well as flare size were analyzed over all three trigeminal branches and the volar forearm for extracranial control. Long-term measures were repeated in 14 patients after continuous treatment ranging from 6 to 12 months. Results Resting dermal blood flow remained unchanged after administration of galcanezumab. Capsaicin-induced dermal blood flow decreased significantly after CGRP-mAb in all tested areas compared to baseline and this was consistent even after 12 months of treatment. However, following galcanezumab administration, the flare size decreased only in the three trigeminal dermatomes, not the arm and was therefore specific for the trigemino-vascular system. None of these two markers distinguished between responders and non-responders. Conclusion CGRP-mAb changed blood flow response to capsaicin stimulation profoundly and this effect did not change over a 12-month application. Neither capsaicin-induced flare nor dermal blood flow can be used as a predictor for treatment efficacy. These data suggest that the mechanism of headache development in migraine is not entirely CGRP-mediated.

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 = 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 ± 3.4 vs 43.0 ± 3.3, P = 0.013) and mechanical pain threshold (log mN, 1.60 ± 0.31 vs 1.45 ± 0.26, P = 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 = 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.

ObjectiveTo investigate the behavioral and neuronal responses of patients with migraine to a visual simulation of self-motion through a virtual roller coaster ride in comparison to controls.MethodsTwenty consecutive patients with migraine 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 patients with migraine will perceive more motion sickness and that it correlates with different central processing and brain responses.ResultsCompared to controls, patients with migraine reported more dizziness (65% vs 30%; p = 0.03) and motion sickness (Simulator Sickness Questionnaire score 47.3 [95% confidence interval (CI), 37.1, 57.5] vs 24.3 [95% CI, 18.2, 30.4]) as well as longer symptom duration (01:19 minutes [95% CI, 00:51, 01:48] vs 00:27 minutes [95% CI, 00:03, 00:51]) and intensity (visual analogue scale score 0–100, 22.0 [95% CI, 14.8, 29.2] vs 9.9 [95% CI, 4.9, 14.7]) during the virtual roller coaster ride. Neuronal activity in patients with migraine was 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 found enhanced connectivity between the pontine nuclei, cerebellar areas V/VI, and interior and superior occipital gyrus with numerous cortical areas in patients with migraine but not in controls.ConclusionsMigraine is related to abnormal modulation of visual motion stimuli within superior and inferior occipital gyrus, middle frontal gyrus, pontine nuclei, and cerebellar lobules V, VI, and VIIb. These abnormalities relate to migraine disability and motion sickness susceptibility.

Background The human in-vivo functional somatotopy of the three branches of the trigeminal (V1, V2, V3) and greater occipital nerve in brainstem and also in thalamus and insula is still not well understood. Methods After preregistration (clinicaltrials.gov: NCT03999060), we mapped the functional representations of this trigemino-cervical complex non-invasively in 87 humans using high-resolution protocols for functional magnetic resonance imaging during painful electrical stimulation in two separate experiments. The imaging protocol and analysis was optimized for the lower brainstem and upper spinal cord, to identify activation of the spinal trigeminal nuclei. The stimulation protocol involved four electrodes which were positioned on the left side according to the three branches of the trigeminal nerve and the greater occipital nerve. The stimulation site was randomized and each site was repeated 10 times per session. The participants partook in three sessions resulting in 30 trials per stimulation site. Results We show a large overlap of peripheral dermatomes on brainstem representations and a somatotopic arrangement of the three branches of the trigeminal nerve along the perioral-periauricular axis and for the greater occipital nerve in brainstem below pons, as well as in thalamus, insula and cerebellum. The co-localization of greater occipital nerve with V1 along the lower part of brainstem is of particular interest since some headache patients profit from an anesthetic block of the greater occipital nerve. Conclusion Our data provide anatomical evidence for a functional inter-inhibitory network between the trigeminal branches and greater occipital nerve in healthy humans as postulated in animal work. We further show that functional trigeminal representations intermingle perioral and periauricular facial dermatomes with individual branches of the trigeminal nerve in an onion shaped manner and overlap in a typical within-body-part somatotopic arrangement. Trial registration: clinicaltrials.gov: NCT03999060

Research on migraine usually focuses on the headache; however, accumulating evidence suggests that migraine not only changes the somatosensory system for nociception (pain), but also the other modalities of perception, such as visual, auditory or tactile sense. More importantly, the multisensory changes exist beyond the headache (ictal) phase of migraine and show cyclic changes, suggesting a central generator driving the multiple sensory changes across different migraine phases. This review summarizes the latest studies that explored the cyclic sensory changes of migraine.Considerable evidence from recent neurophysiological and functional imaging studies suggests that alterations in brain activation start at least 48 h before the migraine headache and outlast the pain itself for 24 h. Several sensory modalities are involved with cyclic changes in sensitivity that peak during the ictal phase.In many ways, migraine represents more than just vascular-mediated headaches. Migraine alters the propagation of sensory information long before the headache attack starts.

Objective Inhalation of oxygen is highly effective in cluster headache, a subtype of trigeminal autonomic cephalgias. Since oxygen has no effect on nociceptive pain, the mechanism of action is still unknown. The present study investigated whether oxygen inhalation modifies the trigeminal autonomic reflex arc in healthy volunteers. Methods 21 healthy volunteers participated in a randomized, placebo controlled, double-blind, cross-over, and within-subject study design. In a randomized order demand valve inhalation of 100% oxygen or medical air were administered. Capillary blood samples were collected to control for blood gas changes. Cranial parasympathetic output (lacrimation) was provoked using kinetic oscillation stimulation of the nasal mucosa. Standardized measurement of lacrimation between baseline and kinetic oscillation stimulation served as a measure of induced cranial autonomic output. Results There was no significant difference in parasympathetic output after oxygen inhalation when compared to inhalation of medical air. Conclusion The inhalation of 100% oxygen does not affect the parasympathetic reflex arc of the trigeminal autonomic reflex.