Sleep, Stress and Migraine - an Observational and Training Study

Migraine is a widespread neurological disorder affecting more than one billion people worldwide, and is among the leading causes of disability, particularly in women. It is characterized by episodic or chronic headaches and often accompanied by nausea, photophobia, and cognitive impairment. Despite advances in pharmacological therapies - such as the advent of CGRP antagonists - a large proportion of patients remain undertreated or refractory to standard interventions. Critically, migraine is influenced by multiple behavioral and environmental triggers, among which sleep disturbances and stress are consistently among the most frequently reported and most modifiable. However, their complex and often bidirectional interactions with migraine are still not fully understood, and most available research is limited by methodological constraints, including short observation periods, retrospective data, and insufficient attention to sex and gender variables.

The Migraine Sleep Study (MiSleepS) is a prospective, two-phase clinical study aiming to investigate the role of sleep, circadian rhythm, and stress as dynamic triggers of migraine and to evaluate the effectiveness of individualized, non-pharmacological behavioral interventions. Conducted at the University Hospital Zurich, this monocentric study will combine high-resolution physiological data captured via the WHOOP 5.0 wrist-worn wearable device with real-time, ecological momentary assessments (EMA) collected through the SEMA3 smartphone app. These dual digital tools enable continuous monitoring of key variables such as sleep duration, sleep architecture, heart rate variability, perceived stress, and migraine occurrence and severity.

Participants will undergo a five-week observational phase (phase A), during which their natural sleep-stress-migraine interactions will be captured without interference. An interim analysis will be conducted to identify individual behavioral and circadian profiles, including insomnia-like patterns, sleep deprivation, social jetlag, and chronotype mismatch. Based on these results, participants will be stratified into clusters and assigned a tailored behavioral plan to address their specific profile. In the subsequent six-week intervention phase (phase B), participants will implement these behavioral strategies, supported by remote follow-ups and daily app-based tracking. The primary endpoint will be the change in monthly migraine days, while secondary endpoints include migraine severity, sleep quality, stress levels, and adherence to recommendations.

To control for observation-related confounding - such as the Hawthorne effect - a run-in cohort of the first ten participants will follow a modified protocol. While they undergo the same assessment and tracking procedures, they will not receive any behavioral recommendations in phase B. This approach allows for differentiation between improvements due to heightened self-awareness and those attributable to the targeted intervention itself.

The study further aims to examine sex- and gender-related differences in migraine pathophysiology and response to behavioral interventions, using validated tools such as the Stanford Gender-Related Variables for Health Research (GVHR) score (Nielsen et al., 2021). By integrating physiological, psychological, and gender-related dimensions, MiSleepS aspires to develop a more individualized understanding of migraine and to explore scalable, low-risk, non-pharmacological treatment strategies that can be implemented in clinical practice.

• Association between total sleep time and migraine onset [Time frame: Phase A (5 weeks).]
• Association between sleep latency and migraine onset [Time frame: Phase A (5 weeks).]
• Association between sleep-wake time variability and migraine onset [Time frame: Phase A (5 weeks).]
• Association between recovery score and migraine onset [Time frame: Phase A (5 weeks).]
• Association between perceived stress and migraine onset [Time frame: Phase A (5 weeks).]
• Difference in total sleep duration between nights with and without migraine attacks [Time frame: Phase A (5 weeks)]
• Difference in sleep quality between nights with and without migraine attacks [Time frame: Phase A (5 weeks)]
• Difference in light, deep, and REM-sleep proportion between nights with and without migraine attacks [Time frame: Phase A (5 weeks)]
• Change in subjective sleep quality from baseline to end of intervention [Time frame: From phase A (baseline) to the end of phase B (intervention, 6 weeks).]
• Change in total sleep duration from baseline to end of intervention [Time frame: From phase A (baseline) to the end of phase B (intervention, 6 weeks).]
• Change in sleep consistency score from baseline to end of intervention [Time frame: From phase A (baseline) to the end of phase B (intervention, 6 weeks).]
• Change in sleep onset variability from baseline to end of intervention [Time frame: From phase A (baseline) to the end of phase B (intervention, 6 weeks).]