Intrinsic ion dynamics underlies the temporal nature of resting-state functional connectivity

The neural mechanisms underlying the emergence of functional connectivity in resting-state fMRI remain poorly understood. Recent studies suggest that resting-state activity consists of brief periods of strong co-fluctuations among brain regions, which reflect overall functional connectivity. Others report a continuum in co-fluctuations over time, with varying degree of correlation to functional connectivity. These findings raise the critical question: what neural processes underlie the temporal structure of resting-state activity? To address this, we used a biophysically realistic whole-brain computational model in which resting-state activity emerged from temporal variations in the ion concentrations of potassium (K+) and sodium (Na+), intracellular chloride (Cl-), and the activity of the Na+/K+ ATPase. The model reproduced transient periods of high co-fluctuations, and the functional connectivity at different co-fluctuation levels correlated to varying degrees with the connectivity measured over the entire simulation, in line with experimental observations. The periods of high co-fluctuations were aligned with large changes in extracellular ion concentrations. Furthermore, critical parameters governing ion dynamics strongly affected both the timing of these transient events and the spatial structure of the resulting functional connectivity. The balance of excitatory and inhibitory activity further modulated their frequency and amplitude. Together, these results suggest that intrinsic fluctuations in ion dynamics could serve as a plausible neural mechanism for the temporal organization of co-fluctuations and resting-state functional connectivity.