Hippocampal rhythm modulation via frequency-tuned trigeminal nerve stimulation

Trigeminal nerve stimulation (TNS) is a non-invasive method for modulating brain activity through peripheral afferent pathways. Although pulse-based stimulation has been commonly used, the impact of sinusoidal alternating current stimulation of the trigeminal nerve (TN-ACS) on hippocampal network activity remains unclear. This study examined the effects of TN-ACS delivered at 8 Hz (theta) and 40 Hz (gamma) on neuronal activity in the rat hippocampus. We applied 3 min of TN-ACS at different frequencies in rats and recorded neural activity from the hippocampus using multi-channel electrophysiology. We analyzed spike-phase entrainment in CA1, spike rate, power spectral changes in local field potentials (LFP, focusing on off-frequency stimulation effects), and spike-field coherence between CA3 LFPs and CA1 spikes. Our results showed that TN-ACS modulated hippocampal dynamics in a frequency-specific manner. 40 Hz stimulation enhanced spike-phase locking in CA1, while 8 Hz did not. At the single neuron level, theta-band coherence between CA3 LFPs and CA1 spikes showed a wide range of effects. At the group level, theta-band coherence decreased during 8 Hz stimulation and increased during 40 Hz stimulation. Spike rates remained stable across all conditions. To our knowledge, this is the first study to demonstrate that TN-ACS can entrain hippocampal spike timing and modulate interregional coherence without affecting overall firing rates. These novel findings indicate that TN-ACS can selectively shape deep brain rhythms, highlighting 40 Hz TN-ACS as a promising intervention for targeting memory-related processes.