The Effect of CO₂ on Resting-State Functional Connectivity: Isocapnia vs. Poikilocapnia

The normal variability in breath size and frequency results in breath-to-breath variability of end-tidal PCO₂ (P_ETCO₂), the measured variable, and arterial partial pressure of carbon dioxide (PaCO₂), the independent variable affecting cerebral blood flow (CBF). This study examines the effect of variability in PaCO₂ on the pattern of resting-state functional MRI (rs-fMRI) connectivity. A region of interest (ROI)-to-ROI and Seed-to-Voxel first-level bivariate correlation, hemodynamic response function (hrf)-weighted analysis for measuring rs-fMRI connectivity was performed during two resting-state conditions: (a) normal breathing associated with breath-to-breath variation in PaCO₂ (poikilocapnia), and (b) normal breathing with breath-to-breath variability of P_ETCO₂ dampened using sequential rebreathing (isocapnia). End-tidal PCO₂ (P_ETCO₂) was used as a measurable surrogate for fluctuations of PaCO₂. During poikilocapnia, enhanced functional connections were found between the cerebellum and inferior frontal and supramarginal gyrus (SG), visual cortex and occipital fusiform gyrus; and between the primary visual network (PVN) and the hippocampal formation. During isocapnia, these associations were not seen, rather enhanced functional connections were identified in the corticostriatal pathway between the putamen and intracalacarine cortex, supracalcarine cortex (SCC), and precuneus cortex. We conclude that vascular responses to variations in P_ETCO₂, account for at least some of the observed resting state synchronization of blood oxygenation level-dependent (BOLD) signals.