Objective: Migraine aura is sparsely studied due to the highly challenging task of capturing patients during aura. Cortical spreading depression (CSD) is likely the underlying phenomenon of aura. The possible correlation between the multifaceted phenomenology of aura symptoms and the effects of CSD on the brain has not been ascertained. Methods: Five migraine patients were studied during various forms of aura symptoms induced by hypoxia, sham hypoxia, or physical exercise with concurrent photostimulation. The blood oxygenation level–dependent (BOLD) functional magnetic resonance imaging (fMRI) signal response to visual stimulation was measured in retinotopic mapping–defined visual cortex areas V1 to V4. Results: We found reduced BOLD response in patients reporting scotoma and increased response in patients who only experienced positive symptoms. Furthermore, patients with bilateral visual symptoms had corresponding bihemispherical changes in BOLD response. Interpretation: These findings suggest that different aura symptoms reflect different types of cerebral dysfunction, which correspond to specific changes in BOLD signal reactivity. Furthermore, we provide evidence of bilateral CSD recorded by fMRI during bilateral aura symptoms. Ann Neurol 2017;82:925–939.