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

NCT07720895 | Completed DMC

• 1 other identifier: 905/05-12-2018
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Migraine; Nocebo Effects

Keywords

migraine; nocebo; functional connectivity; default mode network; resting-state MRI

Outcome Measures

Primary Outcomes (1)

• 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.

Study Arms (3)

Arm 1: Enhanced nocebo challenge

EXPERIMENTAL

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

Arm 2 : Verbal nocebo challenge

EXPERIMENTAL

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

Arm 3 : No challenge

EXPERIMENTAL

This group did not receive any "contrast agent" or negative verbal suggestion

Other: No intervention

Interventions

Negative verbal suggestion BEHAVIORAL

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.

Arm 2 : Verbal nocebo challenge

No intervention OTHER

This group did not receive any "contrast agent" or negative verbal suggestion

Arm 3 : No challenge

intravenous saline infusion OTHER

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.

Arm 1: Enhanced nocebo challenge

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Ioanna Spanou: lead

Study Sites (1)

1st Neurogy Department, Aeginition Hospital, National and Kapodistrian Hospital

Athens, 11528, Greece

Location

MeSH Terms

Conditions

Migraine Disorders

Condition Hierarchy (Ancestors)

Headache Disorders, Primary; Headache Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, M.Sc.

Study Record Dates

• First Submitted: July 12, 2026
• First Posted: July 22, 2026
• Study Start: October 22, 2019
• Primary Completion: October 22, 2023
• Study Completion: October 22, 2023
• Last Updated: July 22, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: Beginning 3 months and ending 3 years after the publication of results

Locations

GR (1)