The influence of moderate hypercapnia on neural activity in the anesthetized nonhuman primate

Abstract

Hypercapnia is often used as vasodilatory challenge in clinical applications and basic research. In functional magnetic resonance imaging (fMRI), elevated CO(2) is applied to derive stimulus-induced changes in the cerebral rate of oxygen consumption (CMRO(2)) by measuring cerebral blood flow and blood-oxygenation-level-dependent (BOLD) signal. Such methods, however, assume that hypercapnia has no direct effect on CMRO(2). In this study, we used combined intracortical recordings and fMRI in the visual cortex of anesthetized macaque monkeys to show that spontaneous neuronal activity is in fact significantly reduced by moderate hypercapnia. As expected, measurement of cerebral blood volume using an exogenous contrast agent and of BOLD signal showed that both are increased during hypercapnia. In contrast to this, spontaneous fluctuations of local field potentials in the beta and gamma frequency range as well as multiunit activity are reduced by approximately 15% during inhalation of 6% CO(2) (pCO(2) = 56 mmHg). A strong tendency toward a reduction of neuronal activity was also found at CO(2) inhalation of 3% (pCO(2) = 45 mmHg). This suggests that CMRO(2) might be reduced during hypercapnia and caution must be exercised when hypercapnia is applied to calibrate the BOLD signal.

Figure 1.

Anatomical slice showing 2 electrodes positioned in gray matter of macaque V1. The image was obtained after infusion of MION and as a consequence vessels and especially the intracortical veins appear dark. The distance between the electrodes is ∼5 mm. The outline of the electrode appears artificially enlarged because of the susceptibility artifact. Thus, the real dimensions of the electrode are indicated by a sketch at the right penetration site.

Figure 2.

Spontaneous activity without stimulus presentation during 3% and 6% CO₂ administration. (A) Gamma band decreased to 97.5 ± 4% and 84.7 ± 4%, beta band to 97.5 ± 5% and 89.9 ± 8% and MUA to 96.3 ± 6% and 85.3 ± 5% for the 2 levels of CO₂ inhalation (n = 9). The change in spontaneous activity in these 3 bands is highly significant for 6% CO₂ (P < 0.0005). For 3% CO₂, a trend toward neuronal activity reduction is visible (P ∼ 0.1). (B) Theta and alpha bands do not change under mild and moderate hypercapnia (P between 0.2 and 0.6). *Depicts significant changes.

Figure 3.

The averaged time course of gamma and MUA electrophysiological responses after the onset of 6% CO₂ inhalation. In 2 out of 5 sessions, the amplitude of change was much stronger for MUA than for gamma range, which was still visible in the group average. The beta band was noisier and thus not included in the figure.

Figure 4.

Time course of BOLD (gray) and MION (black) signals in primary visual cortex after the onset of 6% CO₂ inhalation. The dotted lines give the saturation levels with the standard deviation of the saturation level shown as shaded boxes.

Figure 5.

Model calculation shows how the coupling constant n between fractional changes of CBF and CMRO₂ would be affected if spontaneous activity and hence CMRO₂ is altered by hypercapnia, illustrated here with data taken from the literature (Davis et al. 1998; Stefanovic et al. 2006). The gray line at 0% CMRO₂ indicates the value assumed by the calibrated BOLD approach.