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

July 17, 2026 updated by: Ioanna Spanou

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

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
40

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
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
Time Frame: A 2nd resting- state functional Magnetic Resonance Imaging (rs- fMRI) scan was performed 30 minutes after the 1st rs- fMRI scan.
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

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Ioanna Spanou

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 22, 2019

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
October 22, 2023

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
October 22, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 12, 2026

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 17, 2026

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 22, 2026

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 22, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 17, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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