BOLD signal changes can oppose oxygen metabolism across the human cortex

Functional magnetic resonance imaging measures brain activity indirectly by monitoring changes in blood oxygenation levels, known as the blood-oxygenation-level-dependent (BOLD) signal, rather than directly measuring neuronal activity. This approach crucially relies on neurovascular coupling, the mechanism that links neuronal activity to changes in cerebral blood flow. However, it remains unclear whether this relationship is consistent for both positive and negative BOLD responses across the human cortex. Here we found that about 40% of voxels with significant BOLD signal changes during various tasks showed reversed oxygen metabolism, particularly in the default mode network. These ‘discordant’ voxels differed in baseline oxygen extraction fraction and regulated oxygen demand via oxygen extraction fraction changes, whereas ‘concordant’ voxels depended mainly on cerebral blood flow changes. Our findings challenge the canonical interpretation of the BOLD signal, indicating that quantitative functional magnetic resonance imaging provides a more reliable assessment of both absolute and relative changes in neuronal activity.