Human hippocampal responses to network intracranial stimulation vary with theta phase

Sarah M. Lurie*, James E. Kragel, Stephan U. Schuele, Joel L. Voss

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Hippocampal-dependent memory is thought to be supported by distinct connectivity states, with strong input to the hippocampus benefitting encoding and weak input benefitting retrieval. Previous research in rodents suggests that the hippocampal theta oscillation orchestrates the transition between these states, with opposite phase angles predicting minimal versus maximal input. We investigated whether this phase dependence exists in humans using network-targeted intracranial stimulation. 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. Lateral temporal stimulation evoked ipsilateral hippo-campal potentials with distinct early and late components. Using evoked component amplitude to measure functional connectivity, we assessed whether the phase of hippocampal theta predicted relatively high versus low connectivity. We observed an increase in the continuous phase–amplitude relationship selective to the early and late components of the response evoked by lateral temporal stimulation. The maximal difference in these evoked component amplitudes occurred across 180 degrees of separation in the hippocampal theta rhythm; that is, the greatest difference in component amplitude was observed when stimulation was delivered at theta peak versus trough. The pattern of theta-phase dependence observed for hippocampus was not identified for control loca-tions. These findings demonstrate that hippocampal receptivity to input varies with theta phase, suggesting that theta phase reflects connectivity states of human hippocampal networks. These findings confirm a putative mechanism by which neural oscillations modulate human hippocampal function.

Original languageEnglish (US)
Article numbere78395
StatePublished - 2022

ASJC Scopus subject areas

  • General Immunology and Microbiology
  • General Biochemistry, Genetics and Molecular Biology
  • General Neuroscience


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