Study of the Glymphatic System in Migraine

Discovering the Functional Role of the Glymphatic System in the Genesis of the Migraine Attack

This study aimed to investigate the role of the glymphatic system in the initiation of migraine attacks, using non-invasive magnetic resonance imaging techniques and a validated model of migraine induction by nitroglycerin administration. Secondarily, the relationship between the function of the glymphatic system during nitroglycerin-induced migraine attacks and sleep architecture and plasma levels of migraine-involved neuropeptides will be investigated.

Study Overview

• Status: Recruiting
• Conditions: Migraine
• Intervention / Treatment: Drug: Nitroglycerin 0.3 MG; Diagnostic test: MRI; Diagnostic test: Blood sampling; Device: Sleep profiler

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

• Study Contact: Name: Roberta Messina, MD, PhD; Phone Number: 00390226433944; Email: messina.roberta@hsr.it

Study Locations

• Italy
  • Milan, Italy, 20132
    • Recruiting
    • IRCCS San Raffaele Hospital
    • Contact: Roberta Messina, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Patients with a diagnosis of episodic migraine without aura, by the standard ICHD diagnostic criteria, will be prospectively recruited. Patients will be allowed to take only one migraine preventive treatment at a stable dose during the study. Healthy controls suffering from any headaches with the exception of infrequent tension-type headache will be excluded from the study.

Description

Inclusion Criteria:

For patients:

• Diagnosis of migraine, by the ICHD-3 criteria;

For both patients and healthy controls:

• Age between 18 and 60 years;
• Willing and able to comply with scheduled visits.

Exclusion criteria

For patients:

• Overuse of acute medications for headache;
• Continuous or daily headache;
• Other primary headache disorders, with the exception of infrequent tension-type headache.

For healthy controls:

• Any subject with frequent tension type headache, migraine, cluster headache, other pain syndromes or neurological conditions.

For both patients and healthy controls:

• Allergy to nitroglycerin;
• Major psychiatric disorders such as bipolar affective disorder and schizophrenia;
• Cardiovascular diseases that contraindicated the use of nitroglycerin;
• Intracranial hypertension;
• Cerebral haemorrhage;
• Cerebral trauma;
• Pulmonary toxic oedema;
• Closed angle glaucoma;
• Anaemia;
• Pregnancy and breastfeeding;
• Aortic stenosis or significant hypotension (SBP<90mmHg or <100mmHg and symptomatic) precluding nitroglycerin administration;
• Use of sildenafil;
• Any person unable to lie still within the environment of the MRI scanner for the required period to perform the study;
• Any person where MRI scanning is contraindicated (metal implants, pacemaker, claustrophobia, etc.);
• Use of illicit drugs;
• MRI head showing any brain pathology, such as space-occupying lesions;
• Any person unable to understand and follow the instructions of the investigators.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Adult patients with migraine; Diagnosis of migraine, by the ICHD-3 criteria. Age between 18 and 60 years. Female and males. Right-handed	Drug: Nitroglycerin 0.3 MG; Sublingual nitroglycerin will be used to provoke spontaneous-like migraine attacks in migraine patients. A dose of 0.9 mg of sublingual nitroglycerin will be used. The same dose will be administrated to controls.; Diagnostic test: MRI; The following brain MRI sequences will be acquired before and after nitroglycerin administration: fluid attenuated inversion recovery (FLAIR), 3D T1-weighted inversion recovery prepared gradient echo, diffusion weighted sequence and 3D susceptibility weighted images.; Diagnostic test: Blood sampling; Plasma levels of neuropeptides involed in migraine will be measured using commercially available enzyme-linked immune-sorbent assay (ELISA) kits. All ELISA will be performed by the same experienced technician who will be blinded for the clinical diagnosis.; Device: Sleep profiler; Sleep architecture will be investigated using the Sleep Profiler. Sleep Profiler is medical device with CE mark which is produced by Advanced Brain Monitoring and distributed throughout Italy exclusively by Medigas. Sleep staging will be automatically performed for 30-second epochs throughout a dedicated software and a standardized and validated procedure. Frontopolar EEG signal waveforms will be visually inspected to confirm the accuracy of the auto-staging.
Healthy controls; Age between 18 and 60 years. Female and males. Right-handed	Drug: Nitroglycerin 0.3 MG; Sublingual nitroglycerin will be used to provoke spontaneous-like migraine attacks in migraine patients. A dose of 0.9 mg of sublingual nitroglycerin will be used. The same dose will be administrated to controls.; Diagnostic test: MRI; The following brain MRI sequences will be acquired before and after nitroglycerin administration: fluid attenuated inversion recovery (FLAIR), 3D T1-weighted inversion recovery prepared gradient echo, diffusion weighted sequence and 3D susceptibility weighted images.; Diagnostic test: Blood sampling; Plasma levels of neuropeptides involed in migraine will be measured using commercially available enzyme-linked immune-sorbent assay (ELISA) kits. All ELISA will be performed by the same experienced technician who will be blinded for the clinical diagnosis.; Device: Sleep profiler; Sleep architecture will be investigated using the Sleep Profiler. Sleep Profiler is medical device with CE mark which is produced by Advanced Brain Monitoring and distributed throughout Italy exclusively by Medigas. Sleep staging will be automatically performed for 30-second epochs throughout a dedicated software and a standardized and validated procedure. Frontopolar EEG signal waveforms will be visually inspected to confirm the accuracy of the auto-staging.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline glymphatic function after nitroglycerin administration	The DTI-ALPS index will be quantified before and after nitroglycerin administration as an indirect measure of the glymphatic function	Up to 8 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline plasma levels of neuropeptides after nitroglycerin administration	ELISA kits will be used to measure the plasma level of neuropeptides involved in migraine pathophysiology before and after nitroglycerin administration	Up to 8 hours
Change from baseline sleep architecture after nitroglycerin administration	Sleep Architecture will be studied through the Sleep Profiler before and after nitroglycerin administration	Up to 8 hours

Collaborators and Investigators

• Sponsor: IRCCS San Raffaele
• Investigators: Principal Investigator: Roberta Messina, MD, PhD, IRCCS San Raffaele Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2023
• Primary Completion (Estimated): June 30, 2025
• Study Completion (Estimated): April 30, 2026

Study Registration Dates

• First Submitted: May 16, 2023
• First Submitted That Met QC Criteria: June 7, 2023
• First Posted (Actual): June 18, 2023

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: June 16, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: MRI; sleep; migraine; glymphatic system; neuropeptides
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Migraine Disorders; Vasodilator Agents; Nitroglycerin
• Other Study ID Numbers: GR-2021-12374851

Drug and device information, study documents

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