OC-16 | Network-level brain connectivity alterations in an animal model of migraine and the effects of olcegepant treatment

Rosaria Greco,¹ Gloria Castellazzi,¹ Miriam Francavilla,^1,2 Chiara Demartini,¹ Sara Facchetti,^1,2 Daniele Martinelli,¹ Cristina Tassorelli^1,2 | ¹Headache Science and Neurorehabilitation Unit, IRCCS Mondino Foundation, Pavia; ²Department of Brain and Behavioral Sciences, University of Pavia, Italy

Background: Migraine is a debilitating neurological disorder characterised by disrupted brain network connectivity during attacks. While CGRP-targeted therapies have demonstrated clinical efficacy, their impact on brain functional networks remains unclear. CGRP receptor antagonists that can partially penetrate the blood-brain barrier represent a novel treatment for acute migraines by blocking CGRP-mediated nociceptive signalling. In a previous study, we showed that nitroglycerin (NTG) administration in male rats induces alterations in thalamic and subcortical functional connectivity, reflecting disrupted dynamics within the pain-related brain network characteristic of a migraine-like state. Here, we aimed to investigate the effect of CGRP receptor antagonism on brain network connectivity in the animal model based on NTG administration.

Methods: Fifteen male rats were randomised into two groups: 7 received NTG followed by vehicle (NTG 10 mg/kg i.p. + vehicle), and 8 received NTG followed by olcegepant (NTG + OLC, 2 mg/kg i.p.) one hour and 30 min later. Resting-state fMRI (rs-fMRI) was acquired two hours post-NTG under isoflurane anaesthesia. Data were pre-processed and parcellated into 232 regions of interest (ROIs) using the SIGMA atlas. Functional connectivity matrices were computed via Spearman correlations between ROI time series. Graph-theoretical measures, nodal degree, clustering coefficient (CC) and global efficiency, were derived using the Brain Connectivity Toolbox in MATLAB. Group-level differences were assessed with the Wilcoxon rank-sum test. A significant threshold of p < 0.05 was considered. The rat pain matrix, including the somatosensory cortex, cingulate cortex, insula, thalamus, amygdala and brainstem, was selected for its key role in nociceptive processing and migraine-related dysfunction.

Results: Compared to NTG + vehicle, NTG + OLC rats exhibited a reduced nodal degree in the left striatum, bilateral cingulate, and insular cortex, indicating decreased hub centrality. The left amygdalo-hippocampal area showed a reduced degree, and CC, reflecting dampened limbic integration. Thalamic CC and global efficiency were significantly increased, consistent with reduced thalamocortical signaling.

Conclusion: Olcegepant significantly modulated connectivity within the pain matrix towards greater efficiency and reduced hubness in regions such as the thalamus, insula, and cingulate cortex. The study suggests that antagonism of the CGRP receptor may help to restore migraine-related impairments in connectivity.