Chronology and Sequence of Premonitory Symptoms

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.

• Time from onset of each premonitory symptom to headache onset (categorical intervals) [Time frame: up to 6 months]
• Time from onset of each premonitory symptom to headache onset (minutes) [Time frame: Up to 6 months]
• Intra-subject consistency of premonitory symptoms across attacks [Time frame: Up to 6 months]
• Evolution and persistence of premonitory symptoms during the headache phase [Time frame: Up to 6 months]
• Patient-level agreement between clinically reported and prospectively recorded presence of premonitory symptoms [Time frame: Up to 6 months]
• Symptom-level concordance between baseline-reported and attack-recorded premonitory symptoms [Time frame: Up to 6 months]
• Premonitory-phase disability and the symptom responsible [Time frame: Up to 6 months]