Cerebral energetics and spiking frequency: The neurophysiological basis of fMRI

Abstract

Functional MRI (fMRI) is widely assumed to measure neuronal activity, but no satisfactory mechanism for this linkage has been identified. Here we derived the changes in the energetic component from the blood oxygenation level-dependent (BOLD) fMRI signal and related it to changes in the neuronal spiking frequency in the activated voxels. Extracellular recordings were used to measure changes in cerebral spiking frequency (⌬ ͞ ) of a neuronal ensemble during forepaw stimulation in the ␣-chloralose anesthetized rat. Under the same conditions localized changes in brain energy metabolism (⌬CMR O2͞CMRO2) were obtained from BOLD fMRI data in conjunction with measured changes in cerebral blood flow (⌬CBF͞CBF), cerebral blood volume (⌬CBV͞CBV), and transverse relaxation rates of tissue water (T 2 * and T2) by MRI methods at 7T. On stimulation from two different depths of anesthesia ⌬CMRO2͞CMRO2 Ϸ ⌬ ͞ . Previous 13 C magnetic resonance spectroscopy studies, under similar conditions, had shown that ⌬CMR O2͞CMRO2 was proportional to changes in glutamatergic neurotransmitter flux (⌬Vcyc͞Vcyc). These combined results show that ⌬CMR O2͞CMRO2 Ϸ ⌬Vcyc͞Vcyc Ϸ ⌬ ͞ , thereby relating the energetic basis of brain activity to neuronal spiking frequency and neurotransmitter flux. Because ⌬CMRO2͞CMRO2 had the same high spatial and temporal resolutions of the fMRI signal, these results show how BOLD imaging, when converted to ⌬CMR O2͞CMRO2, responds to localized changes in neuronal spike frequency.R elations between cerebral energy consumption and neuronal activity have been intensely studied since such a coupling was suggested by Roy and Sherrington (1). Sokoloff and coworkers (2) showed that in peripheral neurons increases in energy consumption associated with electrical activity are localized to the neuropil and are approximately proportional to spiking frequency. This proportionality suggested that quantitation of regional brain energy metabolism may provide a direct measure of cortical activity. Nearly all cerebral energy consumption is derived from glucose oxidation (3). 13 C magnetic resonance spectroscopy (MRS) studies have measured the oxidative rate of [1-13 C]glucose use by the flow of the 13 C label into neuronal glutamate pools (4). The subsequent flow of the 13 C label into astrocytic glutamine pools showed that the rates of neuronal oxidative metabolism (CMR O2 ) and glutamate neurotransmitter release͞cycling (V cyc ) are stoichiometrically related (5). The model of glutamate neurotransmitter cycling (6) supported by the 13 C MRS data provides the hypothesis that V cyc , and consequently CMR O2 , should be proportional to spiking frequency of glutamatergic neurons.In this paper we have measured the relationship between energy metabolism and the neuronal spiking frequency in the ␣-chloralose anesthetized rat during forepaw stimulation (7,8). First, ⌬CMR O2 ͞CMR O2 values were derived from multimodal MRI measurements based on the blood oxygenation leveldependent (BOLD) image-contrast as described (9-12). Second, relative sp...

Glutamatergic Function in the Resting Awake Human Brain is Supported by Uniformly High Oxidative Energy

“…4 But recent experimental studies in rodents and theoretical modeling have converged on the conclusion that majority of the resting energy consumption supports glutamatergic signaling and the energy demand changes linearly with pyramidal neuron firing rates and glutamate neurotransmitter release and reuptake. [5][6][7][8][9] Therefore in rodent models it is possible, to a first order, to show that the resting energy is primarily dedicated to total glutamatergic signaling, and the changes in neuronal signaling relative to a well-defined resting activity level can be used to calibrate changes in energy consumption during functional magnetic resonance imaging (fMRI) experiments. 10,11 In the awake human brain, however, the fraction of resting energy usage devoted to glutamatergic signaling is less well understood.…”

“…The magnitude of neuronal signaling in the human brain, and by inference the commensurate energy demand, underscores the functional relevance of resting activity and has profound implications for interpreting fMRI experiments in humans. [12][13][14] Given the rapidly increasing use of resting-state fMRI in mapping networks-defined as a subset of cortical and subcortical gray-matter regions that function together 15,16 -it is important to quantitatively establish if in the resting human the metabolic demand for neuronal signaling is high, as has been established for the rodent, 5,[7][8][9] and to what extent metabolic demand varies across gray-matter regions. 13 C magnetic resonance spectroscopy (MRS) of 13 C-labeled substrates (e.g., glucose and acetate) can measure rates of 13 C label incorporation into cell-specific pools (e.g., glutamate and gamino butyric acid (GABA) are predominantly neuronal and glutamine is predominantly glial) thereby estimating metabolic fluxes 17 of neuronal glucose oxidation (CMR glc(ox),N ) and of total glutamate neurotransmitter cycling (V cyc(tot) ).…”

Genomic and proteomic analysis of the effects of cannabinoids on normal human astrocytes

“…Both creatine and phosphocreatine serve in brain energy metabolism in association with the activity of creatine kinase (CK) (Ames, 2000). Phosphocreatine may provide a buffer for rapid, transient increases in energy demand due to the onset of neuronal firing (Smith et al, 2002). The presence of brain type B CK in Bergmann glial cells and astrocytes is very likely related to the energy requirements for ion homeostasis in the brain, as well as for metabolite and neurotransmitter trafficking between glial cells and neurons.…”

Stimulus frequency dependence of blood oxygenation level-dependent functional magnetic resonance imaging signals in the somatosensory cortex of rats

“…However, the BOLD signal peaked at an intermediate stimulus frequency during forepaw stimulation even in the gradient-echo EPI experiments at 7 T with a longer stimulus pulse width (i.e., 10 ms) (Van Camp et al, 2006). This stimulus frequency dependence may be explained on the basis of evidence suggesting that at high magnetic field strengths (>7 T), the contribution of large blood vessels decreases relative to the effect of small vessels Yacoub et al 2003); another explanation may be that neuronal responses vary according to the stimulus pulse width (Ahissar et al, 2001), which affects BOLD signals (Logothetis et al, 2001;Smith et al, 2002).…”