Evaluating the gray and white matter energy budgets of human brain function

Abstract

The insatiable appetite for energy to support human brain function is mainly supplied by glucose oxidation (CMR_glc(ox)). But how much energy is consumed for signaling and nonsignaling processes in gray/white matter is highly debated. We examined this issue by combining metabolic measurements of gray/white matter and a theoretical calculation of bottom-up energy budget using biophysical properties of neuronal/glial cells in conjunction with species-exclusive electrophysiological and morphological data. We calculated a CMR_glc(ox)-derived budget and confirmed it with experimental results measured by PET, autoradiography, ¹³C-MRS, and electrophysiology. Several conserved principles were observed regarding the energy costs for brain's signaling and nonsignaling components in both human and rat. The awake resting cortical signaling processes and mass-dependent nonsignaling processes, respectively, demand ∼70% and ∼30% of CMR_glc(ox). Inhibitory neurons and glia need 15-20% of CMR_glc(ox), with the rest demanded by excitatory neurons. Nonsignaling demands dominate in white matter, in near opposite contrast to gray matter demands. Comparison between ¹³C-MRS data and calculations suggests ∼1.2 Hz glutamatergic signaling rate in the awake human cortex, which is ∼4 times lower than signaling in the rat cortex. Top-down validated bottom-up budgets could allow computation of anatomy-based CMR_glc(ox) maps and accurate cellular level interpretation of brain metabolic imaging.

Keywords: Aerobic glycolysis; astrocyte; electroencephalography; glutamate; lactate; spiking rate.

Figure 1.

Relationship between CMR_glc(ox) and neuronal activity. (a) Comparison between cortical values of calculated total CMR_glc(ox) (calcCMR_glc(ox),T) and measured total CMR_glc(ox) (measCMR_glc(ox),T), where CMR_glc(ox),T is defined as the sum neuronal (CMR_glc(ox),N) and glial (CMR_glc(ox),A) components. Values of measCMR_glc(ox),T for rat (asterisk) and human (blue triangles) brain were derived from 2-deoxyglucose (2DG) autoradiography and fluoro-2-deoxyglucose (FDG) PET, respectively, in rat (Table S1) and human (Table S2) brain. The abbreviated labels are: PR: pentobarbital; US: urethane stimulation; AR: awake rest; AS: awake stimulation; UR: urethane rest; US2: urethane stimulation; CR: α-chloralose rest; CS: α-chloralose stimulation; HR: halothane rest; HS: halothane stimulation; for human data, VGP: persistent vegetative; VGA: acute vegetative; PRO: propofol; SEV: sevoflurane; HR: halothane rest; SLP: non-REM sleep; AWK: awake. The relationship between calcCMR_glc(ox),T and measCMR_glc(ox),T is fitted by y = −0.013 + 0.99 x, with an R² value of 0.99. (b) In rat somatosensory cortex, comparison between calculated and measured neuronal activity for the rat (asterisk), where the calculated cortical mean firing rates per neuron (calcRate) for each value of calcCMR_glc(ox),T in Figure 1(a) is plotted versus measured average neuronal firing rate per neuron (measRate). Experimental conditions and values for measRate in the rat are listed in Table S1. The relationship between calcRate and measRate is fitted by y = −0.03 + 0.955 x, with an R² value of 0.62 Note that the calcRate, similar to measRate, range is from 0 to 5 Hz for all conditions shown in the rat. (c) In human visual cortex, comparison between calculated (calcRate) and measured (measActivity) neuronal activity (triangles), where the values of calcRate for each value of calcCMR_glc(ox),T in Figure 1(a) is plotted versus measActivity given by EEG-derived bispectral index (BIS, f_BIS). Experimental conditions and values for human measActivity f_BIS are listed in Table S2. The relationship between calcRate and measActivity is fitted by y = −0.297 + 0.0198 x, with an R² value of 0.96. Note that the calcRate in human, different from to calcRate in rat, range is 0–2 Hz for all conditions shown. (d) Values of calcCMR_glc(ox),T for both rat (asterisk) and human (triangles) as a function of measured neuronal activity (measNA), which is fitted by a linear function y = 0.34 + 0.66 x, with an R² value of 0.97. Values of measNA for rat and human brain are from Tables S1 to S2, respectively. The horizontal and vertical axes are normalized to the awake resting state values of measNA and calcCMR_glc(ox),T, respectively (i.e. measNA_AR and calcCMR_glc(ox),T,AR). (e) Values of calculated neuronal CMR_glc(ox) (calcCMR_glc(ox),N) in both rat (asterisk) and human (triangles) brain as a function of measNA, which is fitted by a function 0.22 + 0.58 x, with an R² value of 0.97. The horizontal and vertical axes are normalized to the awake resting state values of measNA and calcCMR_glc(ox),T, respectively (i.e. measNA_AR and calcCMR_glc(ox),T,AR). (f) Values of calculated astrocytic CMR_glc(ox) (calcCMR_glc(ox),A) in both rat (asterisk) and human (triangles) brains as a function of measNA, which is fitted by a function y = 0.09 + 0.096 x, with an R² value of 0.87. The horizontal and vertical axes are normalized to the awake resting state values of measNA and calcCMR_glc(ox),T, respectively (i.e. measNA_AR and calcCMR_glc(ox),T,AR). See Figure S2(a) and (b) for separation of the signaling and nonsignaling components of calcCMR_glc(ox),T for all of the behavioral states in both species.

Figure 2.

Comparison of CMR_glc(ox) calculated from energy budget with experimentally measured CMR_glc(ox) by ¹³C-MRS. (a) Calculated neuronal CMR_glc(ox) (calcCMR_glc(ox),N) in both rat (asterisk) and human (triangles) brain as a function of measured neuronal activity (measNA), which is fitted by a function 0.26 + 0.76 x, with an R² value of 0.92. The horizontal and vertical axes are normalized to the awake resting state values of measNA and calcCMR_glc(ox),N, respectively (i.e. measNA_AR and calcCMR_glc(ox),T,AR). Since values above the intercept reflect signaling (i.e. measNA > 0), this plot suggests that nonsignaling-dependent energy demand of neurons is ∼ 26% of CMR_glc(ox),N,AR. This intercept derived from 2DG autoradiography, FDG PET, and electrophysiology data (Tables S1 and S2) is very similar to prior observations with ¹³C-MRS in rat and human brain (Figure S1 and Table S3). (b) The signaling-dependent CMR_glc(ox) of neuron populations (i.e. (1-intercept) × CMR_glc(ox),N,AR from Figure 2(a)) for rat and human cortex calculated (black bars) and measured by ¹³C-MRS (gray bars) shows that the signaling-dependent energy demand of neurons is 75–80% of CMR_glc(ox),N,AR. The CMR_glc(ox) experimental values for ¹³C-MRS in the rat and human are shown in Figure S1 and Table S3. (c) The fraction of astrocytic CMR_glc(ox) (CMR_glc(ox),A) in relation to CMR_glc(ox),T,AR (i.e. CMR_glc(ox),A/CMR_glc(ox),T,AR) for calculated (black bars) and measured by ¹³C-MRS (gray bars) shows that the glial energy demand is ∼20% of CMR_glc(ox),T,AR. The glial experimental values for ¹³C-MRS in the rat and human are shown in Table S4. (d) The fraction of inhibitory (GABAergic) neuronal CMR_glc(ox) (CMR_glc(ox),IN) in relation to CMR_glc(ox),N (i.e. CMR_glc(ox),IN/CMR_glc(ox),N) calculated (black bars) and measured by ¹³C-MRS (gray bars) shows that the inhibitory (GABAergic) neuronal energy demand is ∼20% of CMR_glc(ox),N. The GABAergic experimental values for ¹³C-MRS in the rat and human are shown in Table S5.

Figure 3.

Distributions of ATP usage for different cellular mechanisms in excitatory glutamatergic neurons (N_Glu), inhibitory GABAergic interneurons (N_GABA), and glial cells (Glia) for the cerebral cortex of rat and human. The different cellular components represent housekeeping (HK), resting potential (RP), action potentials (APs), glutamate or GABA recycling (glu or GABA), presynaptic calcium (Ca), and synaptic transmission (ST). Distributions of energy budget for N_Glu, N_GABA, and Glia in rat cortex for (a) awake resting state and (b) halothane anesthesia compared to similar cellular components in human cortex for (c) awake resting state and (d) halothane anesthesia. Overall, in the cerebral cortex of rat and human, the HK and RP needs are greatest, while Ca need is quite small for Glia, and ST needs are nearly half of the total for N_Glu and N_GABA. From halothane anesthesia to awake resting states, the HK needs in N_Glu, N_GABA, and Glia are increased, whereas the APs, Ca, and glu needs in N_Glu and N_GABA are decreased relatively. See Figures S2 for further details of N_Glu, N_GABA, and Glia under awake resting and halothane anesthesia states for each species.

Figure 4.

Distributions of ATP usage of different cellular mechanisms in gray matter (GM) and white matter (WM) of the human brain. The cellular components in GM represent housekeeping (HK), resting potential (RP), action potentials (AP), glutamate (and GABA) recycling (glu), presynaptic calcium (Ca), and synaptic transmission (ST). The cellular mechanisms in WM represent housekeeping (HK), resting potential (RP), neuron signaling (NS), action potentials in nerves (AP_nerve), and astrocyte calcium (glial Ca). Distributions of energy budget for (a) GM and (b) WM are shown in pie chart format where 100% represent the awake resting values of CMR_glc(ox) in each tissue type. Nonsignaling costs (i.e. RP and HK) account for 30.5% and 82.3% of GM and WM demands respectively, suggesting that the total signaling costs in GM and WM are the remaining 69.5% and 17.7% portions, respectively. While the signaling costs in GM are assigned to energy needs of synaptic activity (i.e. ST, AP, Ca, glu), the signaling costs in WM are assigned to energy needs of 2.7 billion unmyelinated axons and 41.7 billion glial cells (i.e. NS, APnerve, Glial Ca). (see SI Text, Section B for details). (c) Bar plots of CMR_glc(ox) for human brain PET data (dark gray^,) and calculated budget results (gray). For calculation, signaling (“sig” in the bar plot) and nonsignaling (“Nonsig” in the bar plot) components in GM and WM are shown in absolute value, and the nonsignaling component in GM is double the energy demand in WM. See Figure S3 for further details of GM and WM behavior at different levels of neuronal activity.