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

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 2 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 2 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 2 effects with equivalent outcome? In this study 13 healthy subjects underwent two rs-fMRI acquisition: During the “clamped” run, end-tidal CO 2 (PETCO 2 ) is clamped to the average PETCO 2 level of each participant, while during the “free-breathing” run, the PETCO 2 level is passively monitored but not controlled. PETCO 2 correction was applied to the free-breathing data by convolving PETCO 2 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 2 clamping did not significantly alter heart-beat and respiratory variation. We found that neither PETCO 2 clamping nor correction produced significant change in RSFA and wGBC. In terms of the ICD, PETCO 2 clamping and correction both reduced FC strength in the majority of grey matter regions, although the effect of PETCO 2 correction is considerably smaller than the effect of PETCO 2 clamping. Furthermore, while PETCO 2 clamping reduced inter-subject variability in FC, PETCO 2 correction increased the variability. Overall PETCO 2 correction is not the equivalent of PETCO 2 clamping, although it shifts FC values towards the same direction as clamping does.