Human hippocampal ripples coordinate planning sequences and compositional representations in neocortex.
He L., Wang X., Zhang J., Xiao Z., Hu X., Schwartenbeck P., Bakermans J., Behrens T., Liu Y.
The human brain excels at solving novel problems by flexibly recombining a limited set of familiar elements, often through the internal planning of sequences that assemble these elements into new configurations. Although the hippocampus and medial prefrontal cortex (mPFC) are known to support such flexible planning, the neuronal mechanisms underlying their interaction remain unclear. Here we recorded high-resolution intracranial electroencephalography simultaneously from the hippocampus and cortical regions of 28 patients with epilepsy performing two LEGO-like inference tasks. We replicated key neuroimaging findings and, crucially, reveal how mPFC representations are dynamically updated around hippocampal ripples to encode inferred solutions as compositional structures. Hippocampal ripples shift mPFC representations toward the inferred relational configuration, facilitated by replay that reorganizes building blocks into candidate sequences. Replay is strongest during ripple periods, closely coordinates with mPFC activity and is predictive of efficient inferential behavior. Together, hippocampal ripples and replay emerge as a key mechanism for dynamically updating cortical representations online to support planning and inference.