Several laboratories have consistently reported small concentration changes in lactate, glutamate, aspartate, and glucose in the human cortex during prolonged stimuli. However, whether such changes correlate with blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) signals have not been determined. The present study aimed at characterizing the relationship between metabolite concentrations and BOLD-fMRI signals during a block-designed paradigm of visual stimulation. Functional magnetic resonance spectroscopy (fMRS) and fMRI data were acquired from 12 volunteers. A short echo-time semi-LASER localization sequence optimized for 7 Tesla was used to achieve full signal-intensity MRS data. The group analysis confirmed that during stimulation lactate and glutamate increased by 0.26 ± 0.06 μmol/g (~30%) and 0.28 ± 0.03 μmol/g (~3%), respectively, while aspartate and glucose decreased by 0.20 ± 0.04 μmol/g (~5%) and 0.19 ± 0.03 μmol/g (~16%), respectively. The single-subject analysis revealed that BOLD-fMRI signals were positively correlated with glutamate and lactate concentration changes. The results show a linear relationship between metabolic and BOLD responses in the presence of strong excitatory sensory inputs, and support the notion that increased functional energy demands are sustained by oxidative metabolism. In addition, BOLD signals were inversely correlated with baseline γ-aminobutyric acid concentration. Finally, we discussed the critical importance of taking into account linewidth effects on metabolite quantification in fMRS paradigms. Journal of Cerebral Blood INTRODUCTIONFunctional magnetic resonance spectroscopy (fMRS) is a powerful tool that allows quantifying the dynamic of brain metabolite concentrations in the working brain in vivo. Different laboratories have recently used fMRS at ultra-high magnetic field (7 Tesla (7 T)) to measure the neurochemical responses occurring during stimulation of the human visual cortex. [1][2][3][4] The results of these studies were highly consistent with concentration changes in the order of 0.2 μmol/g being reported for aspartate (Asp), glutamate (Glu), glucose (Glc), and lactate (Lac) during prolonged visual stimuli. Similar changes of Glu and Lac have also been reported in the motor cortex. 5 The observed functional changes of metabolite concentrations support an overall increase in oxidative energy metabolism during neuronal activation. 6 In particular, the opposite changes in Glc and Lac concentrations are thought to reflect increased metabolic rate of Glc utilization and activation of the aerobic glycolytic pathway in brain cells. [7][8][9] The observed decrease in Asp and increase in Glu have been interpreted as a consequence of an increased rate of the malate-aspartate shuttle, which is associated with the increased flux into the tricarboxylic acid (TCA) cycle.

In this article, we examined theoretically the role of human cerebral glycogen in buffering the metabolic requirement of a 360-second brain stimulation, expanding our previous modeling study of neurometabolic coupling. We found that glycogen synthesis and degradation affects the relative amount of glucose taken up by neurons versus astrocytes. Under conditions of 175:115 mmol/L (B1.5:1) neuronal versus astrocytic activation-induced Na + influx ratio, B12% of astrocytic glycogen is mobilized. This results in the rapid increase of intracellular glucose-6-phosphate level on stimulation and nearly 40% mean decrease of glucose flow through hexokinase (HK) in astrocytes via product inhibition. The suppression of astrocytic glucose phosphorylation, in turn, favors the channeling of glucose from interstitium to nearby activated neurons, without a critical effect on the concurrent intercellular lactate trafficking. Under conditions of increased neuronal versus astrocytic activation-induced Na + influx ratio to 190:65 mmol/L (B3:1), glycogen is not significantly degraded and blood glucose is primarily taken up by neurons. These results support a role for astrocytic glycogen in preserving extracellular glucose for neuronal utilization, rather than providing lactate to neurons as is commonly accepted by the current 'thinking paradigm'. This might be critical in subcellular domains during functional conditions associated with fast energetic demands.

In this paper, we combined several mathematical models of cerebral metabolism and nutrient transport to investigate the energetic significance of metabolite trafficking within the brain parenchyma during a 360-secs activation. Glycolytic and oxidative cellular metabolism were homogeneously modeled between neurons and astrocytes, and the stimulation-induced neuronal versus astrocytic Na + inflow was set to 3:1. These assumptions resemble physiologic conditions and are supported by current literature. Simulations showed that glucose diffusion to the interstitium through basal lamina dominates the provision of the sugar to both neurons and astrocytes, whereas astrocytic endfeet transfer less than 4% of the total glucose supplied to the tissue. Neuronal access to paracellularly diffused glucose prevails even after halving (doubling) the ratio of neuronal versus astrocytic glycolytic (oxidative) metabolism, as well as after reducing the neuronal versus astrocytic Na + inflow to a nonphysiologic value of 1:1. Noticeably, displaced glucose equivalents as intercellularly shuttled lactate account for B6% to 7% of total brain glucose uptake, an amount comparable with the concomitant drainage of the monocarboxylate by the bloodstream. Overall, our results suggest that the control of carbon recruitment for neurons and astrocytes is exerted at the level of glucose uptake rather than that of lactate shuttle. IntroductionCerebral metabolism is traditionally assumed to be nearly fully aerobic at the organ level, with glucose as the sole energy substrate of the resting as well as the activated brain (Siesjo, 1978; Sokoloff et al, 1977). Although it has multiple metabolic fates, the glucose molecule is primarily catabolized in the brain to yield adenosine triphosphate (ATP), which is the obligatory substrate of most endergonic biochemical reactions. In particular, the hydrolysis of ATP by the Na + /K + -ATPase for the maintenance and restoration of ionic gradients is thought to establish the coupling between brain electrical activity and metabolism (Roland, 1993). The transient local increase in neural activity after physiologic stimulation raises specifically nonoxidative glucose metabolism, as revealed by the excess tissue uptake of glucose with respect to the oxygen required for its complete oxidation. Moreover, within the activated area, the intraparenchymal lactate production exceeds its use and disposal, as increases in lactate concentration during increased neuronal activity have been reported in several studies using magnetic resonance spectroscopy in the human cortex (reviewed by Mangia et al, 2009a). The critical observation that glutamate can induce glucose uptake and lactate release in cultured astrocytes (Pellerin and Magistretti, 1994), although not observed in many astrocyte preparations (Dienel and Cruz, 2004), provided adequate ground for the astrocyte-neuron lactate shuttle (ANLS) hypothesis, shifting neuronal energetics to rely significantly on www.jcbfm.com lactate derived by glycolysis in astrocytes (Magis...

Brain activity during wakefulness is associated with high metabolic rates that are believed to support information processing and memory encoding. In spite of loss of consciousness, sleep still carries a substantial energy cost. Experimental evidence supports a cerebral metabolic shift taking place during sleep that suppresses aerobic glycolysis, a hallmark of environment-oriented waking behavior and synaptic plasticity. Recent studies reveal that glial astrocytes respond to the reduction of wake-promoting neuromodulators by regulating volume, composition and glymphatic drainage of interstitial fluid. These events are accompanied by changes in neuronal discharge patterns, astrocyte-neuron interactions, synaptic transactions and underlying metabolic features. Internally-generated neuronal activity and network homeostasis are proposed to account for the high sleep-related energy demand.

For many years, a tenet of cerebral metabolism held that glucose was the obligate energy substrate of the mammalian brain and that neuronal oxidative metabolism represented the majority of this glucose utilization. In 1994, Pellerin and Magistretti formulated the astrocyte-neuron lactate shuttle (ANLS) hypothesis, in which astrocytes, not neurons, metabolized glucose, with subsequent transport of the glycolytically derived lactate to fuel the energy needs of the neuron during neurotransmission. By considering the concentrations and kinetic characteristics of the nutrient transporter proteins, Simpson et al later supported the opposite view, in which lactate flows from neurons to astrocytes, thus leading to the neuron-astrocyte lactate shuttle (NALS). Most recently, a commentary was published in this journal attempting to discredit the NALS. This challenge has stimulated the present response in which we detail the inaccuracies of the commentary and further model several different possibilities. Although our simulations continue to support the predominance of neuronal glucose utilization during activation and neuronal to astrocytic lactate flow, the most important result is that, regardless of the direction of the flow, the overall contribution of lactate to cerebral glucose metabolism is found to be so small as to make this ongoing debate 'much ado about nothing'.