Nonlinear coupling between cerebral blood flow, oxygen consumption, and ATP production in human visual cortex.
Open accessAbstract
The purpose of this study was to investigate activation-induced hypermetabolism and hyperemia by using a multifrequency (4, 8, and 16 Hz) reversing-checkerboard visual stimulation paradigm. Specifically, we sought to (i) quantify the relative contributions of the oxidative and nonoxidative metabolic pathways in meeting the increased energy demands [i.e., ATP production (J(ATP))] of task-induced neuronal activation and (ii) determine whether task-induced cerebral blood flow (CBF) augmentation was driven by oxidative or nonoxidative metabolic pathways. Focal increases in CBF, cerebral metabolic rate of oxygen (CMRO(2); i.e., index of aerobic metabolism), and lactate production (J(Lac); i.e., index of anaerobic metabolism) were measured by using physiologically quantitative MRI and spectroscopy methods. Task-induced increases in J(ATP) were small (12.2-16.7%) at all stimulation frequencies and were generated by aerobic metabolism (approximately 98%), with %DeltaJ(ATP) being linearly correlated with the percentage change in CMRO(2) (r = 1.00, P < 0.001). In contrast, task-induced increases in CBF were large (51.7-65.1%) and negatively correlated with the percentage change in CMRO(2) (r = -0.64, P = 0.024), but positively correlated with %DeltaJ(Lac) (r = 0.91, P < 0.001). These results indicate that (i) the energy demand of task-induced brain activation is small (approximately 15%) relative to the hyperemic response (approximately 60%), (ii) this energy demand is met through oxidative metabolism, and (iii) the CBF response is mediated by factors other than oxygen demand.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Neuronal activation is associated with a small energy demand: an 8-12% increase in ATP production with visual stimulation in awake human visual cortex and a 5% increase in metabolic rate with somatosensory stimulation in awake somatosensory cortex.
“While fractional changes in neuronal firing frequency are directly proportional to changes in energy use [53], the energy demand associated with neuronal activation appears to be small: there is only a 8–12% increase in ATP production with visual stimulation in the awake human visual cortex [54], and a 5% increase in metabolic rate with somatosensory stimulation in the awake somatosensory cortex [”
From Scaling of Brain Metabolism with a Fixed Energy Budget per Neuron: Implications for Neuronal Activity, Plasticity and Evolution (2011) · cites this paper as [54]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation.
Kwong, K. K., Belliveau, J. W., Chesler, D. A., Goldberg, I. E., Weisskoff, R. M., Poncelet, B. P., Kennedy, D. N., Hoppel, B. E., Cohen, M. S., & Turner, R. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.12.5675 · Cited by 4,212 · see citing works
Ogawa, S., Tank, D. W., Menon, R., Ellermann, J. M., Kim, S. G., Merkle, H., & Ugurbil, K. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.13.5951 · Cited by 3,681 · see citing works
Pellerin, L., & Magistretti, P. J. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.22.10625 · Cited by 2,927 · cited 1× · see citing works
“Of these, the astrocyte–neuron lactate shuttle (ANLS) hypothesis is the most conceptually evolved and widely accepted (27).”
BackgroundFox, P. T., & Raichle, M. E. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.4.1140 · Cited by 2,056 · see citing works
Self-citationOn the Regulation of the Blood‐supply of the Brain
Roy, C., & Sherrington, C. (1890) · The Journal of Physiology · doi:10.1113/jphysiol.1890.sp000321 · Cited by 1,834 · see citing works
Kety, S. S., & Schmidt, C. F. (1948) · Journal of Clinical Investigation · doi:10.1172/jci101995 · Cited by 1,827 · see citing works
Nonoxidative Glucose Consumption During Focal Physiologic Neural Activity
Fox, P. T., Raichle, M. E., Mintun, M. A., & Dence, C. (1988) · Science · doi:10.1126/science.3260686 · Cited by 1,796 · see citing works
Self-citationFrackowiak, R. S. J., Lenzi, G.-L., Jones, T., & Heather, J. D. (1980) · Journal of Computer Assisted Tomography · doi:10.1097/00004728-198012000-00001 · Cited by 1,241 · see citing works
Astrocyte-mediated control of cerebral blood flow
Takano, T., Tian, G.-F., Peng, W., Lou, N., Libionka, W., Han, X., & Nedergaard, M. (2005) · Nature Neuroscience · doi:10.1038/nn1623 · Cited by 1,137 · see citing works
Calibrated functional MRI: Mapping the dynamics of oxidative metabolism
Davis, T. L., Kwong, K. K., Weisskoff, R. M., & Rosen, B. R. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.4.1834 · Cited by 1,054 · see citing works
The Effects of Changes in Pa CO 2 Cerebral Blood Volume, Blood Flow, and Vascular Mean Transit Time
Grubb, R. L., Raichle, M. E., Eichling, J. O., & Ter‐Pogossian, M. M. (1974) · Stroke · doi:10.1161/01.str.5.5.630 · Cited by 1,044 · see citing works
Lactate rise detected by 1H NMR in human visual cortex during physiologic stimulation.
Prichard, J. W., Rothman, D. L., Novotny, E. J., Petroff, O. A. C., Kuwabara, T., Avison, M. J., Howseman, A., Hanstock, C. C., & Shulman, R. G. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.13.5829 · Cited by 612 · see citing works
Brain oxygen utilization measured with O-15 radiotracers and positron emission tomography.
Mintun, M. A., Raichle, M. E., Martin, W. R. W., & Herscovitch, P. (1984) · PubMed · Cited by 608 · see citing works
Linear coupling between cerebral blood flow and oxygen consumption in activated human cortex
Hoge, R. D., Atkinson, J., Gill, B., Crelier, G. R., Marrett, S., & Pike, G. B. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.16.9403 · Cited by 564 · see citing works
Fox, P. T., & Raichle, M. E. (1984) · Journal of Neurophysiology · doi:10.1152/jn.1984.51.5.1109 · Cited by 500 · see citing works
Self-citationFunctional magnetic resonance imaging based on changes in vascular space occupancy
Lu, H., Golay, X., Pekar, J. J., & van Zijl, P. C. M. (2003) · Magnetic Resonance in Medicine · doi:10.1002/mrm.10519 · Cited by 464 · see citing works
Neuronal-glial glucose oxidation and glutamatergic-GABAergic function.
Hyder, F., Patel, A. B., Gjedde, A., Rothman, D. L., Behar, K. L., & Shulman, R. G. (2006) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600263 · Cited by 408 · see citing works
The efficiency and plasticity of mitochondrial energy transduction.
Brand, M. D. (2005) · Biochemical Society Transactions · doi:10.1042/bst0330897 · Cited by 406 · see citing works
Lebon, V., Petersen, K. F., Cline, G. W., Shen, J., Mason, G. F., Dufour, S., Behar, K. L., Shulman, G. I., & Rothman, D. L. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-05-01523.2002 · Cited by 371 · see citing works
Mintun, M. A., Lundstrom, B. N., Snyder, A. Z., Vlassenko, A. G., Shulman, G. L., & Raichle, M. E. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.111164398 · Cited by 362 · see citing works
Role of potassium in regulating blood flow and blood pressure
Haddy, F. J., Vanhoutte, P. M., & Félétou, M. (2006) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00491.2005 · Cited by 352 · see citing works
Frahm, J., Krüger, G., Merboldt, K., & Kleinschmidt, A. K. (1996) · Magnetic Resonance in Medicine · doi:10.1002/mrm.1910350202 · Cited by 327 · see citing works
Cerebral energetics and the glycogen shunt: Neurochemical basis of functional imaging
Shulman, R. G., Hyder, F., & Rothman, D. L. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.101129298 · Cited by 299 · see citing works
Mangia, S., Tkáč, I., Rolf Gruetter, A., de Moortele, P. V., Maraviglia, B., & Uǧurbil, K. (2006) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600401 · Cited by 285 · see citing works
Water diffusion, T2, and compartmentation in frog sciatic nerve
Peled, S., Cory, D. G., Raymond, S. A., Kirschner, D. A., & Jolesz, F. A. (1999) · Magnetic Resonance in Medicine · doi:10.1002/(sici)1522-2594(199911)42:5 · Cited by 189 · see citing works
Sustained Poststimulus Elevation in Cerebral Oxygen Utilization after Vascular Recovery
Lu, H., Golay, X., Pekar, J. J., et al. (2004) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/01.wcb.0000124322.60992.5c · Cited by 163 · see citing works
Mangia, S., Giove, F., Tkáč, I., Logothetis, N. K., Henry, P.-G., Olman, C. A., Maraviglia, B., Di Salle, F., & Uğurbil, K. (2009) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2008.134 · Cited by 161 · see citing works
Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain
Mintun, M. A., Vlassenko, A. G., Rundle, M. M., & Raichle, M. E. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307457100 · Cited by 157 · see citing works
Vafaee, M. S., & GJEDDE, A. H. (2000) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200004000-00012 · Cited by 153 · see citing works
Hevner, R. F., Liu, S., & Wong‐Riley, M. T. T. (1995) · Neuroscience · doi:10.1016/0306-4522(94)00514-6 · Cited by 147 · see citing works
GJEDDE, A. H., & Marrett, S. (2001) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200112000-00002 · Cited by 112 · see citing works
Ito, H., Takahashi, K., Hatazawa, J., Kim, S., & Kanno, I. (2001) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200105000-00015 · Cited by 101 · see citing works
Vafaee, M. S., Meyer, E., Marrett, S., Paus, T., Evans, A. C., & GJEDDE, A. H. (1999) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-199903000-00005 · Cited by 101 · see citing works
Kida, I., Rothman, D. L., & Hyder, F. (2006) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600409 · Cited by 98 · see citing works
NADH augments blood flow in physiologically activated retina and visual cortex
Ido, Y., Chang, K. C., & Williamson, J. R. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307458100 · Cited by 88 · see citing works
Global spatial normalization of human brain using convex hulls.
Lancaster, J. L., Fox, P. T., Downs, H., Nickerson, D., Hander, T. A., Mallah, M. E., Kochunov, P. V., & Zamarripa, F. (1999) · PubMed · Cited by 85 · see citing works
Self-citationEvaluation of MRI models in the measurement of CMRO2 and its relationship with CBF
Lin, A., Fox, P. T., Yang, Y., Lu, H., Tan, L., & Gao, J. (2008) · Magnetic Resonance in Medicine · doi:10.1002/mrm.21655 · Cited by 85 · see citing works
Self-citationRegulation of blood flow in activated human brain by cytosolic NADH/NAD + ratio
Vlassenko, A. G., Rundle, M. M., Raichle, M. E., & Mintun, M. A. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510632103 · Cited by 84 · see citing works
Metabolic heterogeneity of muscle fibres
Pette, D. (1985) · Journal of Experimental Biology · doi:10.1242/jeb.115.1.179 · Cited by 84 · see citing works
Time-Related Increase of Oxygen Utilization in Continuously Activated Human Visual Cortex
Mintun, M. A., Vlassenko, A. G., Shulman, G. L., & Snyder, A. Z. (2002) · NeuroImage · doi:10.1006/nimg.2002.1114 · Cited by 75 · see citing works
Lin, A., Fox, P. T., YANG, Y., Lu, H., TAN, L., & GAO, J. (2008) · NeuroImage · doi:10.1016/j.neuroimage.2008.08.029 · Cited by 57 · see citing works
Self-citationVlassenko, A. G., Rundle, M. M., & Mintun, M. A. (2006) · NeuroImage · doi:10.1016/j.neuroimage.2006.06.065 · Cited by 47 · see citing works
Holloway, R. G. (1997) · Neurology · doi:10.1212/wnl.49.4.1192 · Cited by 45 · see citing works
Zhu, X., Du, F., Zhang, N., Zhang, Y., Lei, H. C., Zhang, X., Qiao, H., Uǧurbil, K., & Chen, W. (2008) · Methods in molecular biology · doi:10.1007/978-1-59745-543-5_15 · Cited by 39 · see citing works
Soricelli, A., Postiglione, A., Cuocolo, A., et al. (1995) · Stroke · doi:10.1161/01.str.26.9.1572 · Cited by 39 · see citing works
4.5 Coupling of Brain Function to Metabolism: Evaluation of Energy Requirements
GJEDDE, A. H. (2007) · Springer eBooks · doi:10.1007/978-0-387-30411-3_14 · Cited by 25 · see citing works
On the Relation Between Energy Transformations in the Brain and Mental Activities
den Berg, C. J. V. (1986) · Springer eBooks · doi:10.1007/978-94-009-4448-0_9 · Cited by 15 · see citing works
Gjedde, T. (2011) · Cited by 15 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- [29]Gjedde A. In: Handbook of Neurochemistry and Molecular Neurobiology Brain Energetics. Integration of Molecular and cellular Processes. Lajtha A, Gibson GE, editors. Heidelberg: Springer; 2007. pp. 343–400. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Handbook%20of%20Neurochemistry%20and%20Molecular%20Neurobiology%20Brain%20Energetics.%20Integration%20of%20Molecular%20and%20cellular%20Processes&author=A%20Gjedde&publication_year=2007&)]
- [33]Van den Berg C. In: Energetics and Human Information Processing. Hockey GRJ, Gaillard AWK, Coles MGH, editors. Boston: Nijhoff; 1986. pp. 131–135. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Energetics%20and%20Human%20Information%20Processing&author=C%20Van%20den%20Berg&publication_year=1986&)]
Cited by
Sorted by citations
Glial and neuronal control of brain blood flow
Attwell, D., Buchan, A. M., Charpak, S., Lauritzen, M., MacVicar, B. A., & Newman, E. A. (2010) · Nature · doi:10.1038/nature09613 · Cited by 2,511 · see citing works
Brain energy metabolism: focus on Astrocyte-neuron metabolic cooperation
Bélanger, M., Allaman, I., & Magistretti, P. J. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.08.016 · Cited by 2,313 · see citing works
Synaptic Energy Use and Supply
Harris, J. J., Jolivet, R., & Attwell, D. (2012) · Neuron · doi:10.1016/j.neuron.2012.08.019 · Cited by 1,747 · see citing works
A Cellular Perspective on Brain Energy Metabolism and Functional Imaging
Magistretti, P. J., & Allaman, I. (2015) · Neuron · doi:10.1016/j.neuron.2015.03.035 · Cited by 1,285 · see citing works
In vivo evidence for a lactate gradient from astrocytes to neurons
Mächler, P., Wyss, M. T., Elsayed, M., Stobart, J., Gutierrez, R., von Faber-Castell, A., Kaelin, V., Zuend, M., San Martín, A., Romero-Gómez, I., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.10.010 · Cited by 571 · see citing works
The energetics of CNS white matter
Harris, J. J., & Attwell, D. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.3430-11.2012 · Cited by 505 · see citing works
Hall, C. N., Klein-Flugge, M. C., Howarth, C., & Attwell, D. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.0026-12.2012 · Cited by 451 · see citing works
Role of Astrocytes in Neurovascular Coupling
Petzold, G. C., & Murthy, V. N. (2011) · Neuron · doi:10.1016/j.neuron.2011.08.009 · Cited by 409 · see citing works
Herculano-Houzel, S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017514 · Cited by 343 · see citing works
Kann, O., Papageorgiou, I. E., & Draguhn, A. (2014) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2014.104 · Cited by 295 · see citing works
The energetic brain—A review from students to students
Bordone, M. P., Salman, M. M., Titus, H. E., Amini, E., Andersen, J. V., Chakraborti, B., Diuba, A. V., Dubouskaya, T. G., Ehrke, E., Espindola de Freitas, A., et al. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14829 · Cited by 205 · see citing works
Harrison, N. A., Cooper, E., Dowell, N. G., Keramida, G., Voon, V., Critchley, H. D., & Cercignani, M. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.09.023 · Cited by 129 · see citing works
Perception is associated with the brain’s metabolic response to sensory stimulation
DiNuzzo, M., Mangia, S., Moraschi, M., Mascali, D., Hagberg, G. E., & Giove, F. (2022) · eLife · doi:10.7554/elife.71016 · Cited by 25 · see citing works
“lactate 113 production independent of oxygen availability) (Bednarik et al. 2015; Bednarik et al. 2018; Boillat 114 et al. 2020; Fernandes et al. 2020; Lin et al. 2010; Lin et al. 2012; Mangia et al. 2007a; Schaller 115 et al. 2013; Schaller et al. 2014).”
BackgroundTheriault (n.d.) · doi:10.31234/osf.io/pkzr8 · Cited by 51 · see citing works
- Authors
- Lin, A.-L., Fox, P. T., Hardies, J., Duong, T. Q., & Gao, J.-H.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- University of Chicago (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-04-19
- Volume
- 107
- Issue
- 18
- Pages
- 8446-8451
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2889577
- OpenAlex
- W2092930162
- Cited by
- 213
- References
- 48
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 10 · 2023: 11 · 2022: 17 · 2021: 11 · 2020: 10 · 2019: 8 · 2018: 11 · 2017: 18 · 2016: 16 · 2015: 15 · 2014: 25 · 2013: 10 · 2012: 14
- FWCI
- 12.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Minnesota
- National Institutes of Health
- University of Texas Health Science Center at San Antonio
- National Institute of Neurological Disorders and Stroke (R01NS045879)
- National Center for Research Resources (M01RR01346, M01RR001346)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Optical Imaging and Spectroscopy Techniques
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Keywords
- cerebral blood flow, cerebral oxygen consumption, ATP production, lactic acid production, visual cortex, hyperemia, oxidative metabolism, energy demand, neurovascular coupling, brain energy metabolism
- MeSH terms
- Adenosine Triphosphate, Adult, Aerobiosis, Anaerobiosis, Cerebrovascular Circulation, Female, Humans, Magnetic Resonance Imaging, Male, Magnetic Resonance Spectroscopy, Oxidation-Reduction, Oxygen Consumption, Visual Cortex, Nonlinear Dynamics, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
