Reduced brain entropy in migraine with partial restoration during attacks: A resting-state fMRI study

Abstract Migraine is a prevalent and disabling neurological disorder, characterized by impaired regulation of migraine burden, sensory processing, and cognitive-emotional states. Brain entropy quantifies the complexity of neural dynamics, where reduced entropy may reflect diminished neural adaptability, but its assessment with fMRI in migraine remains limited. Here, we examined alterations in brain entropy and their associations with clinical burden, migraine phase, and symptomatology. Resting-state fMRI data were acquired from adults with episodic migraine, chronic migraine, and healthy controls. Following standard preprocessing, voxel-wise sample entropy was computed, and group differences were assessed using ANCOVA with age and sex as covariates. Associations with clinical burden and symptom measures were examined within affected regions. In chronic migraine, attack timing-related changes in entropy were further explored, and the Largest Lyapunov Exponent (LLE) was estimated to characterize chaotic dynamics underlying attack-related complexity changes. Migraine patients showed reduced entropy in visual, dorsal attention, and default mode network regions compared to controls, most pronounced in chronic migraine. Lower entropy correlated with greater headache frequency and longer illness duration. In chronic migraine, entropy relatively increased during attacks in multisensory integration regions and was associated with positive and elevated LLEs, indicating partially restored complexity with weakly chaotic dynamics. Patients experiencing phonophobia and nausea also exhibited increased entropy in multisensory integration and default mode network regions. Our findings demonstrate widespread reductions in brain entropy in migraine, reflecting impaired neural adaptability, whereas attacks may transiently restore complexity partially through weakly chaotic dynamics. These results advance understanding of migraine pathophysiology and highlight potential targets for therapeutic intervention. Highlights - Migraine is associated with reduced brain entropy across visual, dorsal attention, and default mode network regions, correlating with clinical burden. - Reduced entropy reflects constrained neural adaptability within affected regions. - Migraine attacks transiently restore entropy, suggesting partial recovery of neural adaptability. - Positive and elevated largest Lyapunov exponents indicate a shift toward weakly chaotic dynamics during migraine attacks in multisensory integration regions. - Symptoms such as phonophobia and nausea are linked to increased entropy in multisensory integration and default mode regions. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study was supported by the National Institute of Neurological Disorders and Stroke (NINDS) under grant numbers K23 NS062946 and R01 NS094413, awarded to Dr. Alexandre F. DaSilva. The authors did not receive any payment or services from a third party for any other aspect of the submitted work. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board of the University of Michigan Medical School gave ethical approval for this work. 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Yes Footnotes This version has been revised to improve methodological clarity and transparency. Author affiliations have been updated. The Methods section has been expanded to better describe preprocessing, statistical analysis, and robustness checks, including additional sensitivity analyses and nonparametric validation. Minor revisions were made throughout to improve clarity and consistency. Data Availability The datasets generated and analyzed during the current study are not publicly available due to participant confidentiality and institutional regulations but are available from the corresponding author on reasonable request.