Longitudinal changes in functional connectivity and pain-induced brain activations in patients with migraine: a functional MRI study pre- and post- treatment with Erenumab

Abstract: Background: Migraine involves central and peripheral nervous system mechanisms. Erenumab, an anti-calcitonin gene-related peptide (CGRP) receptor monoclonal antibody with little central nervous system penetrance, is effective for migraine prevention. The objective of this study was to determine if response to erenumab is associated with alterations in brain functional connectivity and pain-induced brain activations. Methods: Adults with 6–25 migraine days per month during a 4-week headache diary run-in phase underwent pre-treatment brain functional MRI (fMRI) that included resting-state functional connectivity and BOLD measurements in response to moderately painful heat stimulation to the forearm. This was followed by two treatments with 140 mg erenumab, at baseline and 4 weeks later. Post-treatment fMRI was performed 2 weeks and 8 weeks following the first erenumab treatment. A longitudinal Sandwich estimator analysis was used to identify pre- to post-treatment changes in resting-state functional connectivity and brain activations in response to thermal pain. fMRI findings were compared between erenumab treatment-responders vs. erenumab non-responders. Results: Pre- and post-treatment longitudinal imaging data were available from 32 participants. Average age was 40.3 (+/− 13) years and 29 were female. Pre-treatment average migraine day frequency was 13.8 (+/− 4.7) / 28 days and average headache day frequency was 15.8 (+/− 4.4) / 28 days. Eighteen of 32 (56%) were erenumab responders. Compared to erenumab non-responders, erenumab responders had post-treatment differences in 1) network functional connectivity amongst pain-processing regions, including higher global efficiency, clustering coefficient, node degree, regional efficiency, and modularity, 2) region-to-region functional connectivity between several regions including temporal pole, supramarginal gyrus, and hypothalamus, and 3) pain-induced activations in the middle cingulate, posterior cingulate, and periaqueductal gray matter. Conclusions: Reductions in migraine day frequency accompanying erenumab treatment are associated with changes in resting state functional connectivity and central processing of extracranial painful stimuli that differ from erenumab non-responders. Trial registration: clinicaltrials.gov(NCT03773562).