Exploring the cortical effect of monoclonal antibodies against CGRP ligand: a pilot study of the cortical silent period in migraine

Background: Evidence from animal studies suggests that monoclonal antibodies targeting the calcitonin gene-related peptide (anti-CGRP mAbs) may only minimally penetrate the blood-brain barrier due to their high molecular weight. However, neuroimaging and electrophysiological studies revealed indirect neuromodulatory effects originating peripherally and moving toward the central nervous system. This pilot study aimed to investigate the cortical inhibitory activity by recording the cortical silent period (SP) triggered by transcranial magnetic stimulation (TMS) in migraine patients before and after anti-CGRP mAbs treatment. Methods: We prospectively recorded 8 individuals with episodic or chronic migraine who had not responded to at least three preventive migraine therapies. We applied high-intensity TMS to the primary motor cortex to evaluate the cortical SP from contracted perioral muscles. Electrophysiological data were gathered at baseline (T0), one month (T1), and two months (T2) before each anti-CGRP mAbs administration. Results: Anti-CGRP mAbs treatment diminished the average monthly headache days (MHD). The duration of SP was reduced at T1 (82.49 ms at T0 vs. 66.59 ms at T1, p<0.001) but reverted to baseline levels at T2 (82.11 ms). The percentage variations in SP length assessed at T1 and T2 relative to T0 did not correlate with the percentage decrease in MHD measured at T1. Conclusions: Our pilot study findings suggest that anti-CGRP mAbs not only have their known peripheral effects but also influence cortical inhibitory mechanisms in an indirect and transient manner. This provides a valuable foundation for further research, especially studies with larger sample sizes to confirm and expand on these preliminary results.