Neuronal Dynamics of Menstrually Related Migraine: A Longitudinal Task-Based fMRI Study

Recent fMRI research has identified hypothalamic activation in the preictal phase of migraine, thereby suggesting that the hypothalamus plays a pivotal role in subsequent headaches. However, menstrual migraine (MM) attacks differ from nonmenstrual attacks because of prominent hormonal changes, which are suggested to be the cause of such attacks. This raises questions as to whether MM has different neuronal attack generators. We aimed to use longitudinal daily task-based fMRI to investigate the central changes before MM attacks.

Patients with pure menstrual migraine or menstrually related migraine (≤1 extramenstrual attack monthly), as per International Classification of Headache Disorders criteria, were recruited and compared with age-matched and sex-matched healthy controls. Longitudinal daily task-based fMRI was conducted, commencing 6 days before expected menstruation and continuing until spontaneous migraine onset and the menstruation, respectively. Per the task-based protocol, electrical stimulation was administered to the left forehead to activate the trigeminal nociceptive system, with the stimulus intensity tailored to the individual's daily pain threshold, ensuring minimal discomfort and absence of peripheral sensitization. Brain activation before the onset of MM was the primary outcome.

Ten patients and 13 healthy controls (mean age, 28.8 ± 4.9 vs 27.4 ± 2.7 years, all female) were recruited, with each participant undergoing daily fMRI for 7-11 consecutive days (overall 85 days and 91 days, respectively). Patients with MM exhibited a robust hypothalamic activation in the preictal phase (0-48 hours before headache onset), but not in other brain regions, compared with the interictal or ictal phase. In healthy controls, no hypothalamic activation was observed in the corresponding premenstruation period.

Because hypothalamic activation occurred exclusively in the MM cohort, but not in the healthy controls during the same menstrual period window (late luteal phase), the findings suggest that hypothalamic activation is a universal feature of migraine attacks, irrespective of menstrual status. The mechanism of MM may involve how hormonal changes exclusively lead to hypothalamic activation in patients with MM in the late luteal phase. Future studies should integrate functional neuroimaging with biosample measurement, such as serum hormones, to enhance understanding of the interplay between hormonal fluctuations and hypothalamic activation.

This study was preregistered at Open Science Framework Registries (osf.io/bwqy3) on May 23, 2022. The first patient was enrolled in August 2022.