Regional cortical excitability critically biases interareal fMRI connectivity

Resting-state fMRI (rsfMRI) is widely used to map brain network organization in healthy and pathological states. However, the neural underpinnings governing brainwide fMRI functional connectivity (interareal activity correlation) remain unclear. Neocortical excitatory/inhibitory (E/I) balance critically affects local and long-range information processing and can conceivably bias fMRI connectivity, as suggested by the widely reported neocortical E/I imbalance and altered fMRI connectivity in multiple brain disorders. Here, we combine chemogenetics, rsfMRI and electrophysiology to causally probe how neocortical E/I balance affects fMRI connectivity and its underlying electrophysiological coupling. Using chemogenetics, we elevated E/I balance in the mouse prefrontal cortex by either increasing the excitability of pyramidal neurons, or by inhibiting parvalbumin-positive interneurons. Electrophysiological recordings showed that both manipulations increased firing activity in the PFC, but with distinct spectral signatures. Despite these electrophysiological differences, the two manipulations produced largely comparable patterns of fMRI hypo-connectivity. To relate fMRI connectivity changes to underlying neural rhythms, we turned to multielectrode electrophysiology. We found that the two manipulations had dissociable LFP coherency profiles across frequencies. However, slow-δ (0.1-4 Hz) LFP coupling was found to be predictive of fMRI connectivity modulation across manipulations. Importantly, this relationship also held upon analysis of chemogenetic silencing of the PFC. These results show that fMRI connectivity is disproportionally sensitive to slow-frequency LFP coupling, and suggest that the relationship between neural activity and fMRI connectivity is critically shaped by local E/I balance. Our results also point at a possible mechanistic link between E/I imbalance and connectivity disruption in neuropathology.