Origin of slow spontaneous resting-state neuronal fluctuations in brain networks

Resting- or baseline-state low-frequency (0.01-0.2 Hz) brain activity is observed in fMRI, EEG, and local field potential recordings. These fluctuations were found to be correlated across brain regions and are thought to reflect neuronal activity fluctuations between functionally connected areas of the brain. However, the origin of these infra-slow resting-state fluctuations remains unknown. Here, using a detailed computational model of the brain network, we show that spontaneous infra-slow (<0.05 Hz) activity could originate due to the ion concentration dynamics. The computational model implemented dynamics for intra- and extracellular K⁺ and Na⁺ and intracellular Cl^- ions, Na⁺/K⁺ exchange pump, and KCC2 cotransporter. In the network model simulating resting awake-like brain state, we observed infra-slow fluctuations in the extracellular K⁺ concentration, Na⁺/K⁺ pump activation, firing rate of neurons, and local field potentials. Holding K⁺ concentration constant prevented generation of the infra-slow fluctuations. The amplitude and peak frequency of this activity were modulated by the Na⁺/K⁺ pump, AMPA/GABA synaptic currents, and glial properties. Further, in a large-scale network with long-range connections based on CoCoMac connectivity data, the infra-slow fluctuations became synchronized among remote clusters similar to the resting-state activity observed in vivo. Overall, our study proposes that ion concentration dynamics mediated by neuronal and glial activity may contribute to the generation of very slow spontaneous fluctuations of brain activity that are reported as the resting-state fluctuations in fMRI and EEG recordings.