Arterial CO ₂ Fluctuations Modulate Neuronal Rhythmicity: Implications for MEG and fMRI Studies of Resting-State Networks

Abstract

A fast emerging technique for studying human resting state networks (RSNs) is based on spontaneous temporal fluctuations in neuronal oscillatory power, as measured by magnetoencephalography. However, it has been demonstrated recently that this power is sensitive to modulations in arterial CO2 concentration. Arterial CO2 can be modulated by natural fluctuations in breathing pattern, as might typically occur during the acquisition of an RSN experiment. Here, we demonstrate for the first time the fine-scale dependence of neuronal oscillatory power on arterial CO2 concentration, showing that reductions in alpha, beta, and gamma power are observed with even very mild levels of hypercapnia (increased arterial CO2). We use a graded hypercapnia paradigm and participant feedback to rule out a sensory cause, suggesting a predominantly physiological origin. Furthermore, we demonstrate that natural fluctuations in arterial CO2, without administration of inspired CO2, are of a sufficient level to influence neuronal oscillatory power significantly in the delta-, alpha-, beta-, and gamma-frequency bands. A more thorough understanding of the relationship between physiological factors and cortical rhythmicity is required. In light of these findings, existing results, paradigms, and analysis techniques for the study of resting-state brain data should be revisited.SIGNIFICANCE STATEMENT In this study, we show for the first time that neuronal oscillatory power is intimately linked to arterial CO2 concentration down to the fine-scale modulations that occur during spontaneous breathing. We extend these results to demonstrate a correlation between neuronal oscillatory power and spontaneous arterial CO2 fluctuations in awake humans at rest. This work identifies a need for studies investigating resting-state networks in the human brain to measure and account for the impact of spontaneous changes in arterial CO2 on the neuronal signals of interest. Changes in breathing pattern that are time locked to task performance could also lead to confounding effects on neuronal oscillatory power when considering the electrophysiological response to functional stimulation.

Time of day is associated with paradoxical reductions in global signal fluctuation and functional connectivity

“…The challenge of distinguishing neural fluctuations from potential respiratory artefacts is made difficult by the fact the respiratory and neural dynamics are unlikely to be independent even without the presence of artefacts. For example, a recent study found that natural fluctuations in end-tidal pCO 2 due to respiration appeared to track oscillatory power in multiple frequency bands as measured by MEG (Driver et al, 2016).…”

Controlling for the effect of arterial-CO2fluctuations in resting-state fMRI: Comparing end-tidal CO2clamping and retroactive CO2correction

“…Sustained increases in arterial CO 2 is known to suppress neuronal activity (Driver et al, 2016;Hall et al, 2011;Uh et al, 2009) , as measured using electroencephalography (Xu et al, 2011) and magnetoencephalography (Driver et al, 2016;Hall et al, 2011) . This observation spans the delta, alpha, beta and gamma bands.…”

“…This observation spans the delta, alpha, beta and gamma bands. Notably, in the resting state, CO 2 fluctuations accounts for 2% of MEG activity variance (r = 0.15) (Driver et al, 2016) . The main mechanism is proposed to be pH, which is inversely correlated with extracellular adenosine concentration.…”

Vascular physiology drives functional brain networks

“…Thus, the "more vascular" networks identified in this study may still fundamentally represent neuronal systems, but are somehow modulated by CO2 levels, whereas the associated "neuronal networks" are not specifically affected. There is emerging evidence that vascular physiology can influence neural activity [34][35][36] , and our lab has demonstrated that end-tidal CO2 changes, during gas inhalation and during resting fluctuations in breathing, can modulate neuronal rhythms as measured using magnetoencephalography (MEG) 37 . It has been further hypothesized that the vasculature may be directly involved in the brain's information processing (the so-called hemo-neural hypothesis 38 ), modulating the excitability of neural circuits via chemical, physical, and thermal mechanisms.…”

“…The BOLD contrast mechanism reflects local levels of deoxygenated hemoglobin, but this is constantly modulated by both direct vasoactive pathways and indirect neurovascular coupling mechanisms. Alternative imaging modalities such as EEG and MEG may provide better direct insight into the neural processes underpinning functional brain networks, however it is not yet fully understood how vascular physiology may manifest in these data 37 or how network activity fluctuations in these different modalities relate back to fMRI signals 45 . In this study, the dual nature of BOLD fMRI contrast, in conjunction with dual stimulus types, facilitates our ability to probe the dual nature of functional brain networks, but perhaps future research should employ multi-modal imaging to best explore these phenomena in greater detail.…”