Opposing BOLD signals and oxygen metabolism largely arise from statistical uncertainty in metabolic estimates

Abstract

Recent work by Epp et al. (2025) reported widespread voxel-wise sign discordance between task-evoked blood-oxygenation-level-dependent (BOLD) responses and estimated changes in cerebral metabolic rate of oxygen ({Delta}CMRO2), raising important questions about the interpretability of BOLD functional magnetic resonance imaging. Reanalysing the dataset, we found that {Delta}CMRO2 estimates showed substantial voxel-wise variability across participants, consistent with the noise sensitivity of model-based metabolic estimates. When this variability was taken into account, 77.2% of voxels could not be robustly classified, as {Delta}CMRO2 effects lacked sufficient statistical support to determine concordance or discordance. Where classification was possible, positive BOLD responses were predominantly concordant with metabolism, whereas discordance was considerably higher for negative BOLD responses. These findings suggest that the observed BOLD-metabolism discordance reported previously largely reflects statistical uncertainty in CMRO2 estimates rather than widespread physiological sign reversal.