Theta-Frequency Oscillatory Mechanisms for Human Hippocampal Function


Findings in both humans and animal models have associated the hippocampal theta oscillation with hippocampal memory function. In animal models, previous research supports that the theta oscillation contributes to memory via phase-dependent changes in hippocampal network connectivity, wherein memory encoding versus retrieval are optimized at different phases of the theta oscillation. However, it is unclear whether this phase-dependence exists in humans. In this dissertation, I describe two lines of research I carried out to investigate how theta phase impacts human hippocampal physiology and memory function. First, using network-targeted intracranial stimulation and invasive recordings of the human hippocampus, I assessed whether hippocampal connectivity with network afferents varies according to theta phase. I observed a continuous relationship between local theta phase at stimulation onset and the amplitude of the hippocampalevoked response, supporting phase-dependent changes in hippocampal connectivity with its network. Next, to investigate whether associative memory encoding and retrieval performance vary with the theta oscillation, I attempted to causally manipulate hippocampal theta phase using theta-patterned noninvasive transcranial magnetic stimulation targeted to a cortical location in the hippocampal network. Although I observed a significant effect of stimulated phase on memory encoding performance, it was unclear whether stimulation successfully impacted hippocampal theta. Collectively, these findings demonstrate that the human hippocampus undergoes phase-dependent changes in network connectivity, confirming a putative oscillatory mechanism for hippocampal function. These findings suggest that phase-dependent hippocampal connectivity changes occur locally according to long axis position, rather than globally throughout the hippocampus. Finally, I discuss potential future research directions to better characterize this phase-dependence, including assessing the impact of long axis position on local connectivity and developing new approaches to experimentally manipulate theta phase during task performance.

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