Discussion
RS, cerebellar RS, pain, a reduced thalamic RS, peripheral nociceptive trigeminal inputs, migraine, thalamus
BRAIN, PATHOPHYSIOLOGY, SECONDARY, MIGRAINE, CORTEX
This study confirmed the efficacy of a 12-week erenumab treatment in episodic migraine and showed that the treatment is associated to RS FC changes within clinically relevant brain networks mediating migraine manifestations. In line with previous clinical studies [Compared to placebo, patients receiving erenumab showed increased cerebellar RS FC with the precuneus, an area implicated in sensory integration and mind wandering from pain [We also found a reduced thalamic RS FC with frontal brain areas involved in nociception in migraine patients treated with erenumab. The thalamus is a central area for pain modulation, where peripheral nociceptive trigeminal inputs converge before reaching the cortex [Clinical efficacy of erenumab was also linked to functional modulation of primary and secondary visual areas. We found that responders to erenumab experienced a higher RS FC between the calcarine cortex and extrastriate visual areas, like the cuneus, compared to non-responders. The role of the visual network in migraine, regardless the presence of aura, is well established [Only one previous observational study [Brain functional modifications observed after 12 weeks of erenumab at the level of PAG reversed when treatment was stopped. This finding is in line with clinical data [The identification of patients who might benefit more of a given treatment is an important goal of the expanding scenario of migraine treatment. In this perspective, we found that a lower RS FC of the pontine network contributes to identify patients with a higher probability of responding to erenumab. The pontine area is one of the key players of migraine pathophysiology. Several pieces of evidence [The mechanisms underlying the therapeutic benefit of anti-CGRP mAbs in migraine prevention are a matter of ongoing discussion. Given the large size of mAbs targeting the CGRP pathway, the most promoted idea is that their site of action is outside the BBB and may include meningeal receptors, trigeminal sensory fibers and the trigeminal ganglion [To our knowledge, this is the first study investigating erenumab central effects after 12 weeks of treatment using a randomized, double-blind, placebo-controlled design. Another strength of this study is the inclusion of only episodic migraine patients, who were not taking other migraine preventives and who were studied outside their migraine attack. In addition, we have applied a statistical approach corrected for multiple comparisons, thus limiting the number of false positives.We are aware that a limitation of this study is the lack of a healthy control group to serve as reference for RS FC findings. Information regarding the time elapsed between the MRI and the following migraine attack was also missing. Moreover, the sample size of the migraine subgroups was quite small, increasing the risk of false positive results, and our migraine sample was heterogeneous, including both patients with and without aura. Lastly, the software we used for our voxel-wise comparisons (i.e., SPM12) does not include a full implementation of mixed models. Larger studies are needed to confirm our findings. Although a peripheral mechanism of action of erenumab seems the most likely, this study suggests that clinical benefit of erenumab could derive from combined peripheral and central mechanisms.