BOLD signal changes can oppose oxygen metabolism across the human cortex
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Abstract
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.
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The BOLD response does not always track underlying neuronal signaling faithfully and can diverge from activation-driven oxygen metabolism in some regions or conditions.
“Because the BOLD response depends on local changes in cerebral blood flow, blood volume, and oxygenation, it does not always track underlying neuronal signaling faithfully and can diverge from activation-driven oxygen metabolism in some regions or conditions (Epp et al., 2026; Logothetis & Wandell, 2004; Sirotin & Das, 2009).”
From 40 Years of diffusion MRI in the brain: From history to emerging frontiers (2026) · cites this paper as Epp et al., 2026
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- Authors
- Epp, S. M., Castrillón, G., Yuan, B., Andrews-Hanna, J., Preibisch, C., & Riedl, V.
- Affiliations
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University of California San Diego (US)
- Institut für Diagnostische und Interventionelle Neuroradiologie (DE)
- Corresponding author
- Riedl, Valentin
- Venue
- Nature Neuroscience
- Published
- 2025-12-16
- Volume
- 29
- Issue
- 5
- Pages
- 1225-1236
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC13156032
- OpenAlex
- W4417359775
- Cited by
- 41
- References
- 165
- Citations by year
- 2026: 36 · 2025: 2 · 2024: 3
- FWCI
- 21.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Neuroscience (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- Funders
- European Commission
- Friedrich-Alexander-Universität Erlangen-Nürnberg
- Deutsche Forschungsgemeinschaft (395030489)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Optical Imaging and Spectroscopy Techniques
- Keywords
- BOLD signal, neurovascular coupling, cerebral blood flow, oxygen metabolism, oxygen extraction fraction, default mode network, human cortex, neuronal activity
- MeSH terms
- Neurovascular Coupling, Adult, Brain Mapping, Cerebral Cortex, Cerebrovascular Circulation, Female, Humans, Magnetic Resonance Imaging, Male, Oxygen, Oxygen Consumption, Young Adult
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