Default Mode Network Connectivity and Nocebo Responses in Migraine: A Functional MRI Study (Does not exist)

People with migraine sometimes experience symptoms because they expect a treatment to cause side effects. This is known as the "nocebo effect". Unlike a drug side effect, a nocebo effect is triggered by negative expectations rather than by the treatment itself. Nocebo effects can reduce patients' confidence in treatment and may lead them to stop taking medications that could help control their migraine. Understanding why some people are more likely to experience nocebo effects could help healthcare professionals improve treatment discussions and support long-term treatment adherence.

The aim of this study was to investigate whether changes in brain activity are associated with nocebo responses in people with migraine. Researchers focused on the "default mode network" (DMN), a group of interconnected brain regions involved in self-reflection, emotions, memory, and expectations. Because expectations play an important role in nocebo effects, the researchers examined whether communication within this brain network changed during a nocebo challenge.

Forty adults with migraine were recruited from the Headache Clinic of Aeginition Hospital, National and Kapodistrian University of Athens, between October 2019 and February 2023. All participants underwent magnetic resonance imaging (MRI) and resting-state functional MRI (rs-fMRI), a technique that measures communication between brain regions while a person is resting. Participants were then randomly assigned to one of three groups. One group received an intravenous saline infusion together with the suggestion that they might experience numbness. A second group received only the same verbal suggestion, without the saline infusion. A third group received no intervention. Thirty minutes later, participants reported whether they had experienced numbness before undergoing a second brain scan. Participants also completed a questionnaire measuring their susceptibility to nocebo effects. Four participants were excluded because excessive movement affected the quality of their MRI scans, leaving 36 participants for the final analysis.

This study investigated whether changes in DMN connectivity were associated with the nocebo challenge and whether these changes differed between participants who did and did not report numbness. By identifying brain mechanisms involved in nocebo responses, this research may improve our understanding of why some people are more susceptible than others. Although the study was exploratory and included a relatively small number of participants, its findings may contribute to future strategies that help clinicians identify patients at greater risk of nocebo responses, communicate more effectively about treatment, and improve adherence to migraine therapies. Larger studies are needed to confirm these findings before they can be applied in routine clinical practice.

Study Overview

• Status: Completed
• Conditions: Migraine; Nocebo Effects
• Intervention / Treatment: Other: intravenous saline infusion; Behavioral: Negative verbal suggestion; Other: No intervention

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Greece
  • Athens, Greece, 11528
    • 1st Neurogy Department, Aeginition Hospital, National and Kapodistrian Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of migraine (ICHD-3)
• Age 18-55 years
• Right-handedness
• Be able to read and sign written informed consent in Greek
• Absence of migraine attack during the experiment

Exclusion Criteria:

• Diagnosis of chronic migraine
• Cognitive disorders requiring medication
• Pregnancy or breastfeeding
• Presence of any metallic objects in the eyes or central nervous system
• Implanted metallic or electronic devices (e.g. cardiac pacemaker, metallic cardiac valve, cochlear implant, orthopedic implants
• History of claustrophobia
• Use of prophylactic anti-migraine treatment during recruitment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: Enhanced nocebo challenge; An intravenous "contrast agent" (10 ml of normal saline 0.9%) was administrated, and participants were informed that they will be given an intravenous "contrast agent", needed for the second rs- fMRI scan, that may numb one side of their body	Other: intravenous saline infusion; An intravenous "contrast agent" (10 ml of normal saline 0.9%) was administrated, and participants were informed that they will be given an intravenous "contrast agent", needed for the second rs- fMRI scan, that may numb one side of their body.
Experimental: Arm 2 : Verbal nocebo challenge; Participants did not receive any "contrast agent", but were informed that during the second fMRI scan, "they may feel numbness", thus they received negative verbal suggestion only	Behavioral: Negative verbal suggestion; Participants did not receive any "contrast agent", but were informed that during the second fMRI scan, "they may feel numbness", thus they received negative verbal suggestion only.
Experimental: Arm 3 : No challenge; This group did not receive any "contrast agent" or negative verbal suggestion	Other: No intervention; This group did not receive any "contrast agent" or negative verbal suggestion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional Connectivity (FC) changes within Default Mode Network (DMN)-related regions both interictally and during an anxiety-mediated nocebo challenge	All functional and anatomical 3D high-resolution (HR)-T1-weighted images were preprocessed using the CONN toolbox and Statistical Parametric Mapping 12. The primary aim of this exploratory study was to investigate hypothesis-driven functional connectivity changes using a seed-based approach focused on specific DMN regions of interest. We examined connectivity among predefined DMN seed regions, which were defined using the default atlas implemented in the CONN toolbox. Four core DMN seeds were selected: the posterior cingulate cortex (PCC; MNI/Montreal Neurological Institute space -1, -61, 38), the medial prefrontal cortex (MPFC; MNI 1, 55, -3), the left lateral parietal cortex (LP; MNI -39, -77, 33), and the right lateral parietal cortex (LP; MNI 47, -67, 29). Each seed region was defined as a 6-mm radius sphere centered on the respective MNI coordinates, in line with standard CONN preprocessing defaults, to ensure the reproducibility of the seed-based connectivity analyses.	A 2nd resting- state functional Magnetic Resonance Imaging (rs- fMRI) scan was performed 30 minutes after the 1st rs- fMRI scan.

Collaborators and Investigators

• Sponsor: Ioanna Spanou

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2019
• Primary Completion (Actual): October 22, 2023
• Study Completion (Actual): October 22, 2023

Study Registration Dates

• First Submitted: July 12, 2026
• First Submitted That Met QC Criteria: July 17, 2026
• First Posted (Actual): July 22, 2026

Study Record Updates

• Last Update Posted (Actual): July 22, 2026
• Last Update Submitted That Met QC Criteria: July 17, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: default mode network; migraine; functional connectivity; nocebo; resting-state MRI
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Migraine Disorders
• Other Study ID Numbers: 905/05-12-2018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: study protocol patient's informed consent
• IPD Sharing Time Frame: Beginning 3 months and ending 3 years after the publication of results
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No