Hippocampal neural fluctuation between memory encoding and retrieval states during a working memory task in humans

Background Working memory (WM) is essential for everyday life, yet its neural mechanism remains unclear. Although the hippocampus plays a critical role in memory consolidation and retrieval, its role in WM tasks has yet to be fully elucidated. We hypothesized that multiunit activities in the hippocampus alter their representations depending on the memory load and phase of a WM task, particularly in relation to sharp-wave ripple complexes (SWRs), which are known as various cognitive biomarkers. Methods We used an open dataset of intracranial electroencephalogram (iEEG) data and multiunit activity recorded from the medial temporal lobe (MTL) of nine patients with epilepsy. The MTL includes the hippocampus, entorhinal cortex, and amygdala. During the recording, all subjects performed an eight-second Sternberg test, in which they memorized sets of four, six, or eight letters (encoding phase), waited for three seconds (maintenance phase), and recalled whether a probe letter was included (Match IN task) or not (Mismatch OUT task) (retrieval phase). We used Gaussian-process factor analysis to visualize the neural trajectories of multiunit activity in MTL regions during the task. We also detected SWRs from the iEEG data in the hippocampus. Findings We found that the trajectory distance between phases of the Sternberg task was larger in the hippocampus compared to the entorhinal cortex and amygdala. Additionally, the trajectory distance between the encoding and retrieval phases was memory load dependent. Moreover, a transient trajectory increase was detected during SWRs. Finally, the trajectory direction of the hippocampus fluctuated between the encoding and retrieval states, and the balance of the fluctuation was shifted to the retrieval state during SWR periods. Interpretation Our results demonstrate the involvement of the hippocampus during a WM task. Furthermore, it is suggested that SWR in the retrieval phase plays a role in memory retrieval for a WM task. Our results provide new insight into the two-stage model of memory formation. ### Competing Interest Statement The authors have declared no competing interest.