Aims: Resting-state functional imaging (RSFI) is increasingly used to understand how distinct brain networks modulate and respond to pain. As migraine, a common headache disorder, can be experimentally modeled by triggering cortical spreading depolarizations (CSD) in rodents, it is crucial to understand its impact on network connectivity to find imaging markers for experimental evaluation of headache and trigeminovascular activation. We used wide-field intrinsic optical-signal imaging (IOSI) to investigate the impact of CSDs on bihemispheric RSFI connectivity. Methods: C57BL6-ChR2mice underwent head bar installation and skull optical clearing with 10% EDTA solution. After habituation to the imaging setup, we performed IOSI for 8 minutes under 530nm light to observe changes in total hemoglobin (HbT) concentrationin awake mice. Next, CSD was triggered optogenetically using 450nm light and confirmed by laser speckle contrast imaging. A subset of mice received i.p.naproxen after CSD to modulate headache. IOSI were performed immediately, at 30 minutes, 60 minutes, 4 hours and 24 hours after CSD. Mouse grimace scale was scored at each time point for behavioral headache documentation. Time traces of HbT were bandpass filtered and regressed. Seeds were placed in primary somatosensory, primary motor, secondary motor, retrosplenial cortices, posterior parietal association and visual areas. Results: Intraregional, interregional and interhemispheric functional connectivity maps from IOSI signals at different frequency bands and how they are modulated by CSD is extensively studied and will be presented here. Conclusions: Our work will help identify imaging markers for migraine headache assessment in rodents and will be beneficial for elucidation of migraine pathophysiology.