Closed-loop control of theta oscillations enhances human hippocampal network connectivity

Theta oscillations are implicated in regulating information flow within cortico-hippocampal networks to support memory and cognition. However, causal evidence tying theta oscillations to network communication in humans is lacking. Here we report experimental findings using a closed-loop, phase-locking algorithm to apply direct electrical stimulation to neocortical nodes of the hippocampal network precisely timed to ongoing hippocampal theta rhythms in human neurosurgical patients. We show that repetitive stimulation of lateral temporal cortex synchronized to hippocampal theta increases hippocampal theta while it is delivered, suggesting theta entrainment of hippocampal neural activity. After stimulation, network connectivity is persistently increased relative to baseline, as indicated by theta-phase synchrony of hippocampus to neocortex and increased amplitudes of the hippocampal evoked response to isolated neocortical stimulation. These indicators of network connectivity are not affected by control stimulation delivered with approximately the same rhythm but without phase locking to hippocampal theta. These findings support the causal role of theta oscillations in routing neural signals across the hippocampal network and suggest phase-synchronized stimulation as a promising method to modulate theta- and hippocampal-dependent behaviors.