Frequency-specific noninvasive modulation of memory retrieval and its relationship with hippocampal network connectivity

Episodic memory is thought to rely on interactions of the hippocampus with other regions of the distributed hippocampal-cortical network (HCN) via interregional activity synchrony in the theta frequency band. We sought to causally test this hypothesis using network-targeted transcranial magnetic stimulation. Healthy human participants completed four experimental sessions, each involving a different stimulation pattern delivered to the same individualized parietal cortex location of the HCN for all sessions. There were three active stimulation conditions, including continuous theta-burst stimulation, intermittent theta-burst stimulation, and beta-frequency (20-Hz) repetitive stimulation, and one sham condition. Resting-state fMRI and episodic memory testing were used to assess the impact of stimulation on hippocampal fMRI connectivity related to retrieval success. We hypothesized that theta-burst stimulation conditions would most strongly influence hippocampal-HCN fMRI connectivity and retrieval, given the hypothesized relevance of theta-band activity for HCN memory function. Continuous theta-burst stimulation improved item retrieval success relative to sham and relative to beta-frequency stimulation, whereas intermittent theta-burst stimulation led to numerical but nonsignificant item retrieval improvement. Mean hippocampal fMRI connectivity did not vary for any stimulation conditions, whereas individual differences in retrieval improvements due to continuous theta-burst stimulation were associated with corresponding increases in fMRI connectivity between the hippocampus and other HCN locations. No such memory-related connectivity effects were identified for the other stimulation conditions, indicating that only continuous theta-burst stimulation affected memory-related hippocampal-HCN connectivity. Furthermore, these effects were specific to the targeted HCN, with no significant memory-related fMRI connectivity effects for two distinct control brain networks. These findings support a causal role for fMRI connectivity of the hippocampus with the HCN in episodic memory retrieval and indicate that contributions of this network to retrieval are particularly sensitive to continuous theta-burst noninvasive stimulation.