Differential Excitatory-Inhibitory Balance within Dorsolateral Prefrontal Cortex Shapes Inter-network Interactions in Working Memory

Working memory involves complex activation of and interactions among multiple brain areas. However, little is known about how these large-scale activity and interaction patterns relate to resting state activity and originate from excitatory and inhibitory interactions. Here, we combine the analysis of fMRI activation, functional and structural connectivity with large-scale neural network modelling and molecular-enriched PET analysis to show how the excitatory and inhibitory neuronal activities within dorsolateral prefrontal cortex (DLPFC) relate to the inter-network interactions and activation patterns aroused by working memory tasks. Our results indicate that the activation and interaction of the frontoparietal and default-mode networks, which differ between resting state and working memory, depend on the level of DLPFC activity and on its functional and structural interactions with these networks. By perturbing a large-scale neural network model developed using resting-state fMRI and performing molecular-enriched analysis on both fMRI and PET images, we find evidence that a differential activation of excitatory and inhibitory vs neuron populations within DLPFC may ignite the transition from the resting state to working memory. Our study provides a mechanistic understanding of how regional DLPFC excitatory and inhibitory neural activity combines with functional and structural inter-area connections to support the large-scale network dynamics supporting working memory.