Default Mode Network Connectivity and Nocebo Responses in Migraine: A Functional MRI Study
Ioanna Spanou, Efstratios Karavasilis, Foteini Christidi, Evangelia Kararizou, Georgios Velonakis, Dimos-Dimitrios Mitsikostas
Research Square July 7, 2026 preprint DOI: 10.21203/rs.3.rs-10179882/v1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial |
|---|---|
| Sample size | 36 |
| Population | Migraine patients recruited from a hospital headache clinic |
| Intervention | negative verbal suggestion only |
| Duration | 30 minutes between baseline and second scan |
| Measures | Q-No, resting-state fMRI connectivity |
| Topics | Default mode network |
| Key findings | Five of 36 analyzed migraine patients (13.8%) showed a nocebo response (numbness) after negative verbal suggestion. Responders did not differ from non-responders in overall default mode network connectivity, but responders had decreased posterior cingulate/medial prefrontal–left frontoparietal connectivity compared with non-responders scoring below 15 on the Q-No, which the authors interpret as reduced integration of self-referential and attentional networks and a possible preliminary marker of nocebo proneness. |
Abstract
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.
Comparable studies
Other randomized controlled trials on default mode network, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Healthy volunteers | 2012 | Within-subjects, placebo-controlled, task-free fMRI study | n = 30 |
| The effects of psilocybin and MDMA on between-network resting state functional connectivity in healthy volunteers | 2014 | Placebo-controlled study | |
| Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action Healthy subjects | 2012 | Randomized, placebo-controlled, double-blind, crossover rsfMRI challenge | |
| Antidepressants Normalize the Default Mode Network in Patients With Dysthymia Subjects with dysthymic disorder and healthy control participants aged 18 to 53 years | 2013 | Randomized controlled trial | n = 41 |
| Functional Connectivity Measures After Psilocybin Inform a Novel Hypothesis of Early Psychosis Healthy volunteers | 2012 | Within-subject, placebo-controlled experimental study | n = 15 |