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.

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.

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.