Role of GABA and NMDA receptors in shaping cortical timescales and large-scale network dynamics

Abstract

Cortical brain regions integrate information across different timescales, ranging from fast sensory processing to longer integration windows, allowing cognitive functions like working memory. At the large-scale, brain regions organize into transient network states that rapidly switch over time and similarly contribute to cognition. Both cortical timescales and large-scale network dynamics are proposed to be determined by the balance between recurrent synaptic excitation and GABAergic inhibition. Here, we pharmacologically manipulated synaptic transmission at GABAA and NMDA receptors in 60 healthy male participants and acquired resting-state magnetoencephalography. Neuronal timescales followed a hierarchical gradient with shorter timescales in early sensory regions. Increasing GABAergic activity prolonged neuronal timescales across cortical regions. This effect was most prominent in the frontal default mode and in the dorsal attention network. Notably, dynamic network analyses revealed that the occurrence probability of the frontal default mode network increased, whereas the occurrence of the dorsal attention network was reduced. NMDA receptor modulation resulted in no significant changes. Together, these findings provide causal evidence that GABAergic inhibition is a key regulator of cortical temporal organization, linking microscale synaptic mechanisms to neuronal timescales and network dynamics that support diverse cognitive function.