Cited by 41Advanced MRI Techniques and ApplicationsFunctional Brain Connectivity StudiesOptical Imaging and Spectroscopy Techniques

BOLD signal changes can oppose oxygen metabolism across the human cortex

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Epp, Samira M., Castrillón, Gabriel, Yuan, Beijia, Andrews-Hanna, Jessica, Preibisch, Christine, Riedl, Valentin·2026·Nature Neuroscience

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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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  1. [94]Boxermann, J. L., Schmainda, K. M. & Weisskoff, R. M. Relative cerebral blood volume maps corrected for contrast agent extravasation significantly correlate with glioma tumor grade, whereas uncorrected maps do not. Am. J. Neuroradiol. 27, 859–867 (2006). 16611779 PMC8134002

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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
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
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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