Successful working memory linked to theta connectivity patterns in the hippocampal-entorhinal circuit

Working memory (WM) is the ability to actively maintain information for a short time and is central to human behavior. Rodent studies have proposed that hippocampal-entorhinal communication supports WM maintenance. However, the exact neural mechanisms of this interaction in WM remains unclear in humans. To address these questions, we combined machine learning analyses with intracranial electroencephalography (iEEG) recordings from the hippocampus and the entorhinal cortex (EC) in human participants, who maintained a set of letters in their WM. We found that WM maintenance was accompanied by elevated bidirectional hippocampal-EC information exchange via the theta band (2-8 Hz) and bidirectional cross-region theta-gamma phase-amplitude coupling (PAC). Further decoding analyses showed that the unidirectional inter-regional communication, with both theta oscillations in the hippocampus modulating EC gamma activity and theta band-coordinated information flow from the hippocampus, could decode correct performance at the level of participants. Taken together, our results demonstrate that theta functional coupling in the hippocampal-EC supports the maintenance of WM information via a specific pattern of frequency and direction. This connectivity-based coding could shed light on the neural mechanisms of WM processing. SignificanceRecent studies suggest a role for the hippocampus in working memory. How does the hippocampus coordinate with other brain regions to retain working memory information? The entorhinal cortex (EC) is the main gateway for information between the hippocampus and neocortex. To delineate whether (and how) the hippocampus and the entorhinal cortex interact during working memory and whether such interaction supports successful working memory, we used machine learning analyses of human intracranial EEG recordings while patients performed working memory tasks. Our results suggest that the human hippocampal-EC circuit supports working memory and is maintained in specific connectivity patterns, with a theta band (2-8 Hz)-coordinated unidirectional influence from the hippocampus to the EC. Our findings reveal that dynamic unidirectional interactions within the hippocampal-EC circuit underlie working memory and can contribute to a mechanistic circuit understanding of working memory.