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Background: The first data on influence of patent foramen ovale (PFO) with high-volume right-to-left shunt (RLS) on cerebral vasomotor reactivity (CVMR) in migraineurs are presented. In addition, immediate effect of air microbubbles (MB), injected for the bubble TCD test, on CVMR has been determined.Methods: Breath holding index (BHI, vasodilatory capacity-vdCVMR) and percent decrease during hyperventilation (vasoconstriction capacity-vcCVMR) tests were performed before and after bubble TCD test in bilateral middle and posterior cerebral arteries (MCA and PCA) in 38 migraine (19 with aura) and 18 control patients; 26 patients had large PFO while others had no RLS. Subjects with mild/moderate RLS were not enrolled.Results: Presence of PFO was related to a significant decrease of BHI recorded in MCA (1.43±0.39 vs. 1.04±0.67, p=0.032) and marginal reduction of PCA BHI (1.01±0.39 vs. 1.25±0.46, p=0.090) in migraineurs. vdCVMR reduction was more prominent in the contralateral side (to pain). PCA BHI significantly decreased after agitated saline injection in the bubble test. Decrease was greater in patients with PFO (from 1.03±0.40 to 0.78±0.38, p=0.007) compared those without PFO (from 1.15±0.42 to 0.91±0.45, p=0.014). The decrease was prominent in subjects with both migraine and PFO (from 1.01±0.40 to 0.76±0.42, p=0.023). No significant difference was seen in BHI with MCA after bubble injection. Bubble passage correlated to occurrence of headache after test. No difference was noted for the parameters of vcCVMR in subjects with/without PFO. Patients with FLAIR-determined silent ischemic lesion(s) had no difference in VMR before bubble test and VMR response to aerated bubble passage.Conclusions: The presence of PFO with high grade RLS is associated with reduced vasodilatory CVMR in migraineurs. Further decrease of vdCVMR of PCA upon MBs passage may support the mechanism of " facilitation with subclinical cerebral ischemia caused by microembolism", one of the hypotheses explaining the onset of migraine.