Asymmetric Frequency-Specific Feedforward and Feedback Information Flow between Hippocampus and Prefrontal Cortex during Verbal Memory Encoding and Recall.

Hippocampus and prefrontal cortex (PFC) circuits are thought to play a prominent role in human episodic memory, but the precise nature, and electrophysiological basis, of directed information flow between these regions and their role in verbal memory formation has remained elusive. Here we investigate nonlinear causal interactions between hippocampus and lateral PFC using intracranial EEG recordings (26 participants, 16 females) during verbal memory encoding and recall tasks. Direction-specific information theoretic analysis revealed higher causal information flow from the hippocampus to PFC than in the reverse direction. Crucially, this pattern was observed during both memory encoding and recall, and the strength of causal interactions was significantly greater during memory task performance than resting baseline. Further analyses revealed frequency specificity of interactions with greater causal information flow from hippocampus to the PFC in the delta-theta frequency band (0.5-8 Hz); in contrast, PFC to hippocampus causal information flow were stronger in the beta band (12-30 Hz). Across all hippocampus-PFC electrode pairs, propagation delay between the source and target signals was estimated to be 17.7 ms, which is physiologically meaningful and corresponds to directional signal interactions on a timescale consistent with monosynaptic influence. Our findings identify distinct asymmetric feedforward and feedback signaling mechanisms between the hippocampus and PFC and their dissociable roles in memory recall, demonstrate that these regions preferentially use different frequency channels, and provide novel insights into the electrophysiological basis of directed information flow during episodic memory formation in the human brain.SIGNIFICANCE STATEMENT Hippocampal-PFC circuits play a critical role in episodic memory in rodents, nonhuman primates, and humans. Investigations using noninvasive fMRI techniques have provided insights into coactivation of the hippocampus and PFC during memory formation; however, the electrophysiological basis of dynamic causal hippocampal-PFC interactions in the human brain is poorly understood. Here, we use data from a large cohort of intracranial EEG recordings to investigate the neurophysiological underpinnings of asymmetric feedforward and feedback hippocampal-PFC interactions and their nonlinear causal dynamics during both episodic memory encoding and recall. Our findings provide novel insights into the electrophysiological basis of directed bottom-up and top-down information flow during episodic memory formation in the human brain.