Modulation of subcortical activity along the migraine cycle during cognitive executive load

Objective To analyze cognition and brain activation during an executive task in migraine patients studied in the different phases of the migraine cycle, compared with healthy participants. Background Cognitive difficulties reported during migraine attacks remain poorly understood, despite evidence that the lateral frontoparietal network undergoes reversible disturbances and decreased activation during attacks. Recent findings in resting state functional magnetic resonance imaging suggest that brain areas involved in this network interact with subcortical regions during spontaneous migraine attacks. Methods Patients with low-frequency episodic menstrual migraine without aura were assessed with functional magnetic resonance imaging while performing a working memory task, along the four phases of natural migraine cycles, including spontaneous attacks, namely: peri-ictal (preictal, ictal, postictal) phases and interictally (in-between attacks). Healthy controls were assessed during the corresponding phases of their menstrual cycles. Results The protocol was completed by 24 female participants aged 21 to 47 years: 10 with migraine (four sessions each) and 14 controls (two sessions each). Patients and controls showed similar performance on the working memory task and displayed increased brain activity in regions linked to this function, namely the middle frontal gyrus, inferior parietal lobe, and anterior cingulate cortex, during all phases of the migraine/menstrual cycle. Migraine patients exhibited a significant decrease in hypothalamic activity during the postictal phase when compared to perimenstrual controls (p = 0.007), interictal (p = 0.002) and preictal (p = 0.034) migraine phases. Conclusion Cognitive areas were actively recruited during a working memory task in different phases of the migraine cycle. In addition, migraine patients displayed significantly lower neural activity at the subcortical level in the peri-ictal period. These findings, combined with previous research showing activation in cortical areas, suggest subcortical-cortical interaction during the peri-ictal phases, which may act as a compensatory mechanism when the individual faces a cognitively demanding task during migraine attacks. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the Portuguese Science Foundation (FCT) through grants PD/BD/141798/2018, COVID/BD/152659/2022, UIDP/0461/2020 and PTDC/EMD-EMD/29675/2017. ### 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: Ethics committee of Hospital da Luz Lisboa gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.