Peripheral CGRP engages brain-wide electrical network activity of migraine
Migraine is a disorder consisting of severe, recurrent headaches and debilitating sensory symptoms which often include affective symptoms or comorbidities such as depression, anxiety, and irritability. As such, migraine is a complex nervous system disorder that involves integration of many modalities across the brain. This makes migraine a complex systems neuroscience problem represented by the confluence of sensory, pain, cognitive, autonomic, and affect-related circuits. Thus, it is essential to understand how neuronal activity across various brain regions implicated in migraine is coordinated during migraine pathophysiology. Using a calcitonin gene-related peptide (CGRP) mouse model of migraine, we probed neural oscillatory activity in the anterior cingulate cortex, amygdala (BLA and CeA), thalamus (Po, VPM, and MDthal), and parabrachial nucleus following peripheral administration of CGRP. We identified three frequency bands in which directional signals occur in this network and found that power in these frequencies across the network was lower than vehicle within 10 minutes of peripheral CGRP exposure, which was sustained for (~40-50 min). Coherence, on the other hand, was mostly disrupted in CeA brain region pairings, and took on a shorter timecourse. Sumatriptan partially blunted or reversed these CGRP-induced network responses, especially with regard to amygdala power and coherence pairings. Early life stress, which has been shown to increase the likelihood of migraine in adulthood in humans, exacerbated CGRP-induced migraine-related behavioral phenotypes and induced corresponding network changes in LFP power in the CeA and Po and coherence in Po-related pairings. Clustering based on a changepoint analysis of coherence identified individual mice hypersusceptible to migraine. Overall, our findings demonstrate coordinated brain-wide network activity by which migraine is mediated in the brain in response to peripheral CGRP.