Whilst an intact blood–brain barrier in migraine has been demonstrated in imaging studies macroscopically [181,182,183], and it has been suggested that CGRP-targeted therapies exert their action peripherally [184], there is emerging evidence for central functional imaging effects of the large molecular size monoclonal antibodies [185] and for clinical effects of these drugs on symptoms that could only be deemed as centrally neurally driven, such as cognition and fatigue [186], and premonitory symptoms, triggers and aura [179]. This evidence concerns the gene CALCA and migraine disorder.