Atogepant modulates brain connectivity in episodic migraine: a longitudinal exploratory fMRI study
Episodic Migraine (EM) is a highly prevalent and disabling neurological disorder. Recent therapeutic advances have targeted the calcitonin gene-related peptide (CGRP), a neuropeptide implicated in the pathophysiology of migraine. Promising outcomes have been obtained with monoclonal antibodies and, more recently, with a new class of drugs consisting of small-molecule CGRP receptor antagonists, known as gepants. Atogepant, an oral agent of the gepant class, has demonstrated efficacy in migraine prevention, yet its effects on central brain activity and neurotransmitter circuits remain largely unclear. This exploratory study investigates changes in brain functional connectivity and changes related to key neurotransmitter systems, following 12 weeks of treatment with atogepant in a group of EM patients. This is an exploratory single-arm longitudinal study assessing clinical and neuroimaging changes before and after 12 weeks of atogepant treatment. We enrolled patients diagnosed with EM according to ICHD-3 criteria, without prior exposure to anti-CGRP therapies. Participants underwent clinical assessments (monthly migraine days MMD, acute drugs intake MAM) and resting-state functional MRI (rs-fMRI) before and after 12 weeks of treatment with atogepant 60 mg once daily. Longitudinal functional connectivity analyses were performed at the whole-brain level with a region-of-interest analysis. Additionally, longitudinal neurotransmitter-related functional connectivity was investigated within the serotoninergic and the dopaminergic systems. A total of 15 patients completed the evaluation. A significant group-level reduction in MMD (T = −7.09, p < 0.001) and MAM (T = −6.35, p < 0.001) following 12 weeks of atogepant treatment was observed, accompanied by a reduction of allodynia symptoms, albeit not statistically significant. Patients exhibited significant longitudinally increased functional connectivity, involving the right superior frontal gyrus, bilateral putamen, left pallidum, left anterior and bilateral posterior cingulate cortex. The greater the longitudinal increase in anterior–posterior cingulate cortices connectivity, the larger the improvement in MMD, MAM, and allodynia symptoms after treatment. Additionally, longitudinal connectivity changes were observed within the orbitofrontal cortex in the mesocorticolimbic dopaminergic system. In this exploratory cohort, significant clinical improvement after atogepant treatment was accompanied by longitudinal functional connectivity changes in EM patients. These preliminary findings may reflect either direct or indirect central modulation linked to atogepant treatment. A deeper understanding of the observed central changes may help to clarify the mechanisms underlying anti-CGRP therapies for migraine.