Biophysical basis of brain activity: implications for neuroimaging
Authors: Shulman Robert G. , Hyder Fahmeed , Rothman Douglas L. 
Published: February 2003

1. Summary 288

2. Introduction 288

3. Relationship between neuroenergetics and neurotransmitter flux 294

4. A model of coupling between neuroenergetics and neurotransmission 296

5. Relationship between neuroenergetics and neural spiking frequency 297

6. Comparison with previous electrophysiological and fMRI measurements 298

7. Contributions of non-oxidative energetics to a primarily oxidative brain 299

8. Possible explanation for non-oxidative energetics contributions 300

9. A model of total neuronal activity to support cerebral function 302

10. Implications for interpretation of fMRI studies 305

11. The restless brain 306

12. Acknowledgements 310

13. Appendix A. CMRO2by13C-MRS 310

14. Appendix B.Vcycand test of model 313

15. Appendix C. CMRO2by calibrated BOLD 316

16. Appendix D. Comparison of spiking activity of a neuronal ensemble with CMRO2318

17. References 320

In vivo13C magnetic resonance spectroscopy (MRS) studies of the brain have quantitatively
assessed rates of glutamate–glutamine cycle (Vcyc) and glucose oxidation (CMRGlc(ox)) by
detecting 13C label turnover from glucose to glutamate and glutamine. Contrary to
expectations from in vitro and ex vivo studies, the in vivo13C-MRS results demonstrate that
glutamate recycling is a major metabolic pathway, inseparable from its actions of
neurotransmission. Furthermore, both in the awake human and in the anesthetized rat brain,
Vcyc and CMRGlc(ox) are stoichiometrically related, where more than two thirds of the energy
from glucose oxidation supports events associated with glutamate neurotransmission. The
high energy consumption of the brain measured at rest and its quantitative relation to
neurotransmission reflects a sizeable activity level for the resting brain. The high activity of
the non-stimulated brain, as measured by cerebral metabolic rate of oxygen use (CMRO2),
establishes a new neurophysiological basis of cerebral function that leads to reinterpreting
functional imaging data because the large baseline signal is commonly discarded in cognitive
neuroscience paradigms. Changes in energy consumption (ΔCMRO2%) can also be obtained
from magnetic resonance imaging (MRI) experiments, using the blood oxygen level-
dependent (BOLD) image contrast, provided that all the separate parameters contributing to
the functional MRI (fMRI) signal are measured. The BOLD-derived ΔCMRO2% when
compared with alterations in neuronal spiking rate (Δν%) during sensory stimulation in the
rat reveals a stoichiometric relationship, in good agreement with 13C-MRS results. Hence
fMRI when calibrated so as to provide ΔCMRO2% can provide high spatial resolution
evaluation of neuronal activity. Our studies of quantitative measurements of changes in
neuroenergetics and neurotransmission reveal that a stimulus does not provoke an arbitrary
amount of activity in a localized region, rather a total level of activity is required where the
increment is inversely related to the level of activity in the non-stimulated condition. These
biophysical experiments have established relationships between energy consumption and
neuronal activity that provide novel insights into the nature of brain function and the
interpretation of fMRI data.