Inferring the direction of rhythmic neural transmission via inter-regional phase-amplitude coupling (ir-PAC)

Abstract

Phase-amplitude coupling (PAC) estimates the statistical dependence between the phase of a low-frequency and the amplitude of a high-frequency component of local field potentials (LFP). Characterizing the relationship between nested oscillations in LFPs, PAC has become a powerful tool for understanding neural dynamics in both animals and humans. In this work, we introduce a new application for this measure to two LFPs to infer the direction and strength of rhythmic neural transmission between distinct networks. Based on recently accumulating evidence that transmembrane currents related to action potentials contribute a broad-band component to LFP in the high-gamma band, we hypothesized that PAC calculated between high-gamma in one LFP and low-frequency oscillations in another would relate the output (spiking) of one area to the input (soma/dendritic postsynaptic potentials) of the other. We tested this hypothesis on theta-band long range communications between hippocampus and prefrontal cortex (PFC) and theta-band short range communications between different regions within the hippocampus. The results were interpreted within the known anatomical connections predicting hippocampus[->]PFC and DG[->]CA3[->]CA1, i.e., theta transmission is unidirectional in both cases: from hippocampus to PFC and along the tri-synaptic pathway within hippocampus. We found that (1) hippocampal high-gamma amplitude was significantly coupled to theta phase in PFC, but not vice versa; (2) similarly, high-gamma amplitude in DG was significantly coupled to CA1 theta phase, but not vice versa, and (3) the DG high-gamma-CA1 theta PAC was significantly correlated with DG[->]CA1 Granger causality, a well-established analytical measure of directional neural transmission. These results support the hypothesis that inter-regional PAC (ir-PAC) can be used to relate the output of a \"driver\" network (i.e., high gamma) to the input of a \"receiver\" network (i.e., theta) and thereby establish the direction and strength of rhythmic neural transmission.