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.
Study Type
OBSERVATIONAL
Enrollment
500
Sapienza University of Rome, Polo Pontino, centro cefalee, ICOT
Latina, Italy, Italy
RECRUITINGFrequency of each symptom as the first premonitory symptom
Premonitory symptoms will be recorded at the beginning of each migraine attack for a maximum of 5 migraine attacks per participant. For each premonitory symptom, the percentage of recorded attacks in which it was reported as the first symptom of the premonitory phase. Symptoms are recorded at headache onset for each attack via a structured electronic diary, capturing the type, sequence, onset, and duration of symptoms preceding the pain phase. The denominator is the number of recorded attacks with a premonitory phase.
Time frame: Up to 6 months
Time from onset of each premonitory symptom to headache onset (categorical intervals)
Premonitory symptoms will be recorded at the beginning of each migraine attack for a maximum of 5 migraine attacks per participant. For each premonitory symptom, the time of onset relative to headache onset, classified into predefined intervals: simultaneous with pain onset; less than 1 hour before; 1 to 2 hours before; more than 2 to 6 hours before; more than 6 to 12 hours before. Results are reported as the distribution of attacks across intervals for each symptom (percentage of recorded attacks). Onset times are recorded at headache onset for each attack via a structured electronic diary.
Time frame: up to 6 months
Time from onset of each premonitory symptom to headache onset (minutes)
Premonitory symptoms will be recorded at the beginning of each migraine attack for a maximum of 5 migraine attacks per participant. For each premonitory symptom, the time interval in minutes between its onset and headache onset, recorded for each attack via a structured electronic diary. Results are summarised per symptom (e.g., median minutes before headache onset).
Time frame: Up to 6 months
Intra-subject consistency of premonitory symptoms across attacks
Premonitory symptoms will be recorded at the beginning of each migraine attack for a maximum of 5 migraine attacks per participant. The degree of within-subject agreement in the presence and chronology of premonitory symptoms across multiple attacks of the same participant, recorded via a structured electronic diary. Agreement is summarised per participant and reported across the sample (e.g., concordance in symptom presence and chronology).
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Time frame: Up to 6 months
Evolution and persistence of premonitory symptoms during the headache phase
Premonitory symptoms will be recorded at the beginning of each migraine attack for a maximum of 5 migraine attacks per participant. For each premonitory symptom, the evolution and persistence after headache onset, recorded via a structured electronic diary.
Time frame: Up to 6 months
Patient-level agreement between clinically reported and prospectively recorded presence of premonitory symptoms
Premonitory symptoms will be recorded at the beginning of each migraine attack for a maximum of 5 migraine attacks per participant. At the patient level, the agreement between whether participants report experiencing premonitory symptoms during clinical assessment (baseline) and whether they actually record premonitory symptoms during prospectively monitored attacks.
Time frame: Up to 6 months
Symptom-level concordance between baseline-reported and attack-recorded premonitory symptoms
Premonitory symptoms will be recorded at the beginning of each migraine attack for a maximum of 5 migraine attacks per participant. The degree of agreement between premonitory symptoms reported by the participant at baseline and those recorded prospectively at the time of the attack via a structured electronic diary.
Time frame: Up to 6 months
Premonitory-phase disability and the symptom responsible
Premonitory symptoms will be recorded at the beginning of each migraine attack for a maximum of 5 migraine attacks per participant. For each attack, (i) whether the premonitory phase caused a reduction in the participant's usual activities (presence or absence of premonitory-phase disability), and (ii) where disability was present, which premonitory symptom the participant identified as primarily responsible for it.
Time frame: Up to 6 months