Impaired glymphatic function and advanced brain age gap in chronic migraine: a multimodal MRI study

OBJECTIVES: This study investigated whether the coupling between cortical blood-oxygen-level-dependent (BOLD) signals and cerebrospinal fluid (CSF) flow, a physiologically motivated but indirect proxy related to glymphatic-associated dynamics, moderates the relationship between migraine disability (MIDAS) and brain age gap (BAG). METHODS: Patients with episodic migraine (EM), chronic migraine (CM), and healthy controls were recruited. BAG was estimated using a deep learning-based framework, and glymphatic-related hemodynamic-CSF dynamics were assessed using BOLD-CSF coupling. A moderation model, adjusted for sleep quality (PSQI) and biological covariates using HC3 robust standard errors, evaluated the statistical moderating role of BOLD-CSF coupling on the MIDAS-BAG association. RESULTS: A network-specific pattern of altered BOLD-CSF coupling was identified, with higher-order network abnormalities observed specifically in CM (p = 0.037). CM patients exhibited a significantly greater BAG than EM patients and healthy controls (p = 0.007). BOLD-CSF coupling significantly moderated the association between MIDAS and BAG (interaction β = -0.104, p = 0.035; Wald test p = 0.036). In individuals with relatively stronger coupling, MIDAS was more strongly associated with BAG (β = 0.066, p < 0.001), whereas this association was attenuated in those with weaker coupling (β = 0.035, p = 0.005). CONCLUSIONS: Altered higher-order network BOLD-CSF coupling may represent a relevant imaging feature of migraine chronification. BOLD-CSF coupling was associated with interindividual differences in the relationship between migraine-related disability and BAG, independent of sleep quality. These findings support the potential relevance of glymphatic-related physiological processes in chronic migraine.