Cortical excitability inversely modulates fMRI connectivity via low-frequency neuronal coupling

The neural mechanisms supporting fMRI connectivity are poorly understood. Leveraging an aggregated analysis of novel and existing chemogenetic manipulations and electrophysiological recordings in the mouse medial prefrontal cortex (PFC), we show that local cortical excitability inversely modulates large-scale fMRI connectivity. Specifically, we find that bidirectional chemogenetic manipulations of cortical excitability produce opposite effects on fMRI connectivity, resulting in fMRI hypoconnectivity when excitability is enhanced, and fMRI hyperconnectivity when excitability is suppressed, despite corresponding increases or decreases in local neuronal firing. Notably, while each chemogenetic manipulation produces a distinct profile of interareal electrophysiological coherence, only low-frequency (< 4Hz) coherence predicts the direction and magnitude of the ensuing fMRI connectivity changes. Biophysical network modelling shows that the observed electrophysiological coherence profiles can arise from the interaction between direct inter-area communication changes mediated by local firing-rate variations, and shared larger-scale low-frequency covariation of ongoing neuronal activity. Together, our results reveal an inverse relationship between regional cortical excitability and large-scale fMRI connectivity, and indicate that fMRI connectivity is primarily supported by low frequency (<4 Hz) electrophysiological coupling. These findings open new avenues for modeling and interpreting fMRI connectivity in health, and in response to pathological or exogenous perturbations linked to cortical excitability.