Human hippocampal responses to network stimulation vary with theta phase

Abstract

Hippocampal memory function is thought to be supported by distinct connectivity states, with strong extrahippocampal input benefitting encoding and weak extrahippocampal input benefitting retrieval. Previous research in rodents suggests that the hippocampal theta oscillation orchestrates the transition between these states, with opposite phase angles respectively predicting minimal and maximal extrahippocampal input. However, it is unclear whether this phase dependence exists in humans. We used network-targeted stimulation to investigate whether hippocampal receptivity to network input varies with theta phase in humans of both sexes. Intracranial local field potentials were recorded from individuals with epilepsy undergoing medically necessary stereotactic electroencephalographic recording. In each subject, biphasic bipolar direct electrical stimulation was delivered to lateral temporal sites with demonstrated connectivity to hippocampus. Stimulation evoked ipsilateral hippocampal potentials with distinct early and late negative components. Using evoked-component amplitude to measure functional connectivity, we assessed whether different phases of hippocampal theta reflected distinct connectivity states. Stimulation enhanced both early and late component amplitudes when delivered during the observed theta peak relative to trough. Analysis of estimated theta phase delays between stimulation locations and hippocampus suggested that hippocampal response amplitude was maximized when stimulation influenced hippocampal activity at approximately 90° before the trough of its theta rhythm. The pattern of theta phase dependence observed in hippocampus was not identified for amygdala and orbitofrontal cortex control locations. These findings demonstrate that theta phase reflects connectivity states of human hippocampal networks, confirming a putative mechanism by which oscillations modulate local hippocampal processing.