Opposing effects of slow and fast theta synchrony on working memory in the human hippocampal-orbitofrontal network

Gray, S. M.; Dede, A. J.; Cross, Z. R.; Saez, I.; Girgis, F.; Chang, E. F.; Auguste, K.; Shaikhouni, A.; Knight, R. T.; Johnson, E. L.

doi:10.64898/2026.05.10.724153

bioRxiv · 10.64898/2026.05.10.724153

Opposing effects of slow and fast theta synchrony on working memory in the human hippocampal-orbitofrontal network

Gray, S. M.·Dede, A. J.·Cross, Z. R.·Saez, I.·Girgis, F.·Chang, E. F.·Auguste, K.·Shaikhouni, A.·Knight, R. T.·Johnson, E. L.

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Abstract

Working memory (WM) enables us to maintain and manipulate information over time, but how the brain organizes sequential information locally and across networks remains unclear. Recent work suggests that slow and fast theta oscillations serve different roles in memory, yet their distinct contributions to sequential WM are unknown. Based on evidence that the hippocampus (HC) and orbitofrontal cortex (OFC) support sequential WM and that slower theta cycles provide optimal temporal windows for organizing items in WM, we predicted that these regions would coordinate via slow theta dynamics. We analyzed intracranial EEG from the HC, OFC, and amygdala (AMY) in 21 neurosurgical patients (7 female, 13-54 years of age; M {+/-} SD, 30 {+/-} 11.2 years) performing a delayed match-to-sample WM task. We assessed phase locking between regions, phase-amplitude coupling within regions, and neuronal phase coding for slow (~1-4.5 Hz) and fast (~4.5-8 Hz) theta oscillations. We found significant slow and fast theta synchrony between all regions, but identical anatomical pathways produced opposing behavioral effects depending on oscillatory frequency, particularly during higher cognitive demand. Slow theta synchrony was associated with faster response times (RTs), while fast theta synchrony between HC and OFC hindered both accuracy and RTs. Unexpectedly, AMY modulated RT through demand-dependent slow theta synchrony, where AMY-OFC synchrony predicted faster RTs during maintenance and HC-AMY synchrony predicted faster RTs during higher cognitive demand. Sustained coupling between slow theta oscillations and high-frequency broadband activity within each region suggests that local organization coincides with beneficial network behavioral effects. These results establish a frequency-opponent mechanism in which theta oscillation frequencies determine whether HC-OFC circuits facilitate or impair sequential WM.

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Gray, S. M., Dede, A. J., Cross, Z. R., Saez, I., Girgis, F., Chang, E. F., Auguste, K., Shaikhouni, A., Knight, R. T., Johnson, E. L.. 2026-05-11. Opposing effects of slow and fast theta synchrony on working memory in the human hippocampal-orbitofrontal network. https://doi.org/10.64898/2026.05.10.724153

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