Controlling for the effect of arterial-CO2 fluctuations in resting-state fMRI: Comparing end-tidal CO2 clamping and retroactive CO2 correction

The BOLD signal, as the basis of functional MRI, arises from both neuronal and vascular factors, with their respective contributions to resting state-fMRI still unknown. Among the factors contributing to "physiological noise", dynamic arterial CO fluctuations constitutes the strongest and the most widespread modulator of the grey-matter rs-fMRI signal. Some important questions are: (1) if we were able to clamp arterial CO such that fluctuations are removed, what would happen to rs-fMRI measures? (2) falling short of that, is it possible to retroactively correct for CO effects with equivalent outcome? In this study 13 healthy subjects underwent two rs-fMRI acquisitions. During the "clamped" run, end-tidal CO (PETCO) is clamped to the average PETCO level of each participant, while during the "free-breathing" run, the PETCO level is passively monitored but not controlled. PETCO correction was applied to the free-breathing data by convolving PETCO with its BOLD response function, and then regressing out the result. We computed the BOLD resting-state fluctuation amplitude (RSFA), as well as seed-independent mean functional connectivity (FC) as the weighted global brain connectivity (wGBC). Furthermore, connectivity between conditions were compared using coupled intrinsic-connectivity distribution (ICD) method. We ensured that PETCO clamping did not significantly alter heart-beat and respiratory variation. We found that neither PETCO clamping nor correction produced significant change in RSFA and wGBC. In terms of the ICD, PETCO clamping and correction both reduced FC strength in the majority of grey matter regions, although the effect of PETCO correction is considerably smaller than the effect of PETCO clamping. Interestingly, we found the effect of the commonly employed white-mater/cerebrospinal-fluid regression to be similar to that of PETCO clamping than global-signal regression. Nonetheless, both methods reduce functional connectivity significantly more than does PETCO clamping. Furthermore, while PETCO clamping reduced inter-subject variability in FC, PETCO correction increased the variability. Overall PETCO correction is not the equivalent of PETCO clamping, although it shifts FC values towards the same direction as clamping does.