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.