Default Mode Network Connectivity and Nocebo Responses in Migraine: A Functional MRI Study

Abstract Background Migraine patients are prone to nocebo responses, that hinder treatment adherence. Identifying neurobiological markers of nocebo proneness could help predict and mitigate these adverse effects. Methods This prospective three-arm randomized explorative trial examined default mode network (DMN) connectivity changes during the interictal state and an anxiety-induced nocebo challenge. Forty migraine patients were recruited (October 2019- February 2023) from Aeginition Hospital Headache Clinic, National and Kapodistrian University of Athens. All underwent baseline MRI and resting-state-fMRI (rs- f MRI) before randomization to: Experiment A, intravenous saline plus a negative verbal suggestion (“you might feel numbness”); Experiment B, negative verbal suggestion only; or Experiment C, no intervention. After 30 minutes, participants reported whether they experienced numbness, followed by a second rs-fMRI scan. Nocebo-proneness (Q-No > 15), indicated susceptibility. Four participants were excluded due to motion artifacts, leaving 36 for analysis. Results Five participants (13.8%) exhibited a nocebo response (Experiment A, n  = 3; Experiment B, n  = 2). Overall, responders did not differ from non-responders in DMN connectivity. Compared with non-responders with Q-No < 15, responders exhibited decreased posterior cingulate cortex (PCC)/medial prefrontal cortex– left frontoparietal connectivity, indicating reduced integration of self-referential and attentional networks. In Experiment A, responders showed increased PCC–frontal pole connectivity, consistent with heightened anticipatory processing, whereas in Experiment B, responders showed decreased right parietal–postcentral connectivity reflected altered sensory–attentional integration associated with perceived numbness. Conclusions Findings suggest a functional connectivity basis for nocebo responses in migraine interictally, providing preliminary rs-fMRI markers of nocebo proneness requiring further validation.