The purpose of this study is to prospectively investigate the temporal sequence of premonitory symptoms across multiple migraine attacks.

The premonitory phase marks the transition from the interictal to the headache phase and is considered the beginning of the migraine attack. During this phase, changes in brain activity and network connectivity give rise to non-headache symptoms (premonitory symptoms) that precede pain.

Premonitory symptoms (PSs) are reported by a substantial proportion of individuals with migraine, with prevalence estimates ranging widely across studies, from approximately 29% in population-based to 66% in clinic-based settings, a variability largely dependent on the method of assessment. Although neuroimaging studies have consistently shown hypothalamic activation during the premonitory phase, activation of other areas may also be observed. However, neuroimaging studies have been mostly limited by their reliance on time-based criteria to define the premonitory phase and by insufficient temporal resolution to capture the sequential activation of brain regions within the same phase.

To date, the temporal sequence of events at migraine onset remains unknown and clinical evaluation of symptoms remains the most reliable approach to reconstructing the sequence of events underlying migraine initiation. Recent evidence supports the efficacy of treating the migraine attack during the prodrome. However, the lack of prospective data on the temporal ordering of premonitory symptoms represents a critical gap.

This study will prospectively investigate the temporal sequence of premonitory symptoms across multiple migraine attacks, addressing a critical gap in our understanding of early attack dynamics. By identifying consistent early symptoms and their progression, we aim to define clinically actionable windows for early intervention and provide indirect insight into the sequence of brain network activation underlying migraine onset.

PSs will be collected prospectively. Participants will record premonitory symptoms using a structured electronic diary across a maximum of 5 migraine attacks. They will be instructed to complete the diary at headache onset as early as possible, with timestamped entries to minimise recall bias. Data will be collected using an ad hoc electronic diary developed on the REDCap platform and a standardised case report form (CRF). The diary will collect information on the type, sequence, onset, and duration of PSs experienced before the pain phase.

Inclusion Criteria:

• Diagnosis of episodic (EM) or chronic migraine (CM) or CM with medication overuse headache (MOH) according to ICHD-III criteria;
• Age between 18 and 65 years;
• At least 2 migraine days (MMD) in the month preceding the inclusion;
• Migraine history of at least 12 months prior to inclusion
• Signed written informed consent.

Exclusion Criteria:

• History or current diagnosis of secondary headache disorders as defined by ICHD-III;
• History of other neurological comorbidities or major psychiatric disorders;
• History of migraine for < 12 months prior to the inclusion;
• Opioid overuse according to the ICHD-III criteria;
• Pregnancy or breastfeeding.

Prospective, longitudinal, multicentric study on patients with migraine attending the outpatient clinic of Italian Headache centres who will meet the inclusion and exclusion criteria.