Metabolic underpinnings of activated and deactivated cortical areas in human brain

Abstract

Neuroimaging with functional MRI (fMRI) identifies activated and deactivated brain regions in task-based paradigms. These patterns of (de)activation are altered in diseases, motivating research to understand their underlying biochemical/biophysical mechanisms. Essentially, it remains unknown how aerobic metabolism of glucose to lactate (aerobic glycolysis) and excitatory-inhibitory balance of glutamatergic and GABAergic neuronal activities vary in these areas. In healthy volunteers, we investigated metabolic distinctions of activating visual cortex (VC, a task-positive area) using a visual task and deactivating posterior cingulate cortex (PCC, a task-negative area) using a cognitive task. We used fMRI-guided J-edited functional MRS (fMRS) to measure lactate, glutamate plus glutamine (Glx) and γ-aminobutyric acid (GABA), as indicators of aerobic glycolysis and excitatory-inhibitory balance, respectively. Both lactate and Glx increased upon activating VC, but did not change upon deactivating PCC. Basal GABA was negatively correlated with BOLD responses in both brain areas, but during functional tasks GABA decreased in VC upon activation and GABA increased in PCC upon deactivation, suggesting BOLD responses in relation to baseline are impacted oppositely by task-induced inhibition. In summary, opposite relations between BOLD response and GABAergic inhibition, and increases in aerobic glycolysis and glutamatergic activity distinguish the BOLD response in (de)activated areas.

Keywords: energy metabolism; glutamate-glutamine cycle; lactate; β-hydroxybutyrate (BHB); γ-aminobutyrate (GABA).

Figure 1.

fMRI-measured activations and deactivations in task-positive and task-negative areas (Table 1), respectively. (a) Flashing visual checkerboard was associated with activations in the primary visual cortex (VC, activation, task-positive area). (b) Identification of auditory emotion portrayals was associated with deactivations in task-negative brain areas, in particular, in the posterior cingulate cortex (PCC, deactivation, task-negative area). Group average fMRI-fMRS single VC (red) and PCC (blue) voxels are shown as overlays. For illustration purposes, maps were thresholded at p <.001 unc. (c, d) Localized BOLD signal change assessed using whole-brain fMRI at 3 T and single-voxel diffusion-weighted water fMRI-fMRS at 4 T consistently increased (c) and decreased (d) during activation and deactivation tasks, respectively. Whole-brain fMRI BOLD percent signal change was estimated as a difference between ROI-specific condition and baseline contrast estimates based on beta value maps. Water spectra fMRI-fMRS BOLD percent signal change between condition and baseline blocks was estimated based on T₂* values. The BOLD responses measured by fMRI and fMRI-fMRS were positively correlated. Shaded plots and error bars denote the mean and the standard deviation. Note that individual BOLD changes were averaged across J-difference edited lactate and GABA fMRI-fMRS runs.

Figure 2.

Correlations between task-induced BOLD responses and baseline GABA, Glx and lactate levels. (a, b) Normalized GABA levels correlated negatively with BOLD responses both during VC activation and PCC deactivation. (c–f) Glx or lactate levels did not correlate with BOLD responses. Solid and dashed lines in (d) denote slopes without and with two outlying Glx estimates, respectively. GABA, Glx and lactate levels were estimated assuming NAA concentration of 10 mM. Glx levels are expressed in (a.u.) because the J-editing parameters were optimized for GABA.

Figure 3.

Reciprocal task-induced GABA level changes and their correlations are seen during VC activation and PCC deactivation. (a) Decrease of GABA level during VC activation (red bar: -5.7 ± 3.3% from baseline level 2.22 ± 0.33 mM) and increase of GABA level during PCC deactivation (bluer bar: 4.5 ± 6.2% from baseline level 2.27 ± 0.30 mM). (b) Negative correlation between task-induced GABA levels and BOLD responses in VC. (c) Positive correlation between task-induced GABA levels and BOLD responses in PCC. Normalized GABA levels were estimated by reference to NAA and assuming NAA concentration of 10 mM.

Figure 4.

Task-induced Glx level changes and their correlations with VC activations and PCC deactivations. (a) Significant increase of Glx level during VC activation (3.0 ± 2.1% from baseline level 1.50 ± 0.21a.u.) and non-significant Glx level change during PCC deactivation (-0.5 ± 2.9% from baseline level 1.84 ± 0.48a.u.). (b) Significant positive correlation between task-induced Glx level and BOLD responses in VC. (c) Task-induced Glx level and BOLD responses did not correlate significantly. Glx levels were referenced to NAA assuming NAA concentration of 10 mM.

Figure 5.

Task-induced lactate level changes and their correlations with VC activations and PCC deactivations. (a) Significant lactate increase during VC activation (7.8 ± 5.4% from baseline level 0.99 ± 0.13 mM) but not during PCC deactivation (1.4 ± 4.7% from baseline level 0.97 ± 0.11 mM). BHB did not change, neither during VC activation (-3.2 ± 18.5% from baselin1e level 0.37 ± 0.09 mM), nor during PCC deactivation (2.1 ± 11.5% from baseline level 0.34 ± 0.11 mM). (b) Positive correlation between task-induced lactate change and BOLD responses in the VC. (c) Task-induced lactate change did not correlate with BOLD responses in PCC. Referenced lactate levels are estimated assuming NAA concentration of 10 mM.