Non-Invasive Temporal Interference Electrical Stimulation Modulates Neurotransmitter Release and Improves Aberrant Neural Oscillations in Alzheimer's Disease

Background: Modulating brain oscillations has significant therapeutic promise. Traditional non-invasive neuromodulation techniques can alleviate clinical signs of Alzheimer's disease (AD) by restoring normal neural oscillatory activity in certain brain regions. As a novel non-invasive brain modulation technique, temporal interference (TI) has been demonstrated to precisely control hippocampus neural oscillations while minimizing its impact on cortical neural activity, but its exact mechanism of action is still unclear. Method: We simulated and experimentally measured the intracranial electric field under TI to determine the precision of TI intervention. Subsequently, TI stimulation was applied to the APP/PS1 transgenic AD mouse model, and the impact of TI stimulation on the stimulated brain region was compared from the perspectives of behavior, electrophysiology, and cell biology. Results: This work showed that in the APP/PS1 Alzheimer's disease mice model, TI stimulation significantly increased GABA levels and decreased NMDA receptor activation at the targeted region. Following neurotransmitter regulation, the rhythm of the gamma oscillations they associate also changed. This, in turn, influenced other memory-related neural oscillation frequencies and brain regions through cross-frequency coupling and brain connectivity, ultimately improving the behavioral performance of AD model mice. Conclusions: The results of our work demonstrated how TI stimulation alters brain oscillations to enhance memory in mice with Alzheimer's disease, offering a possible theoretical foundation for TI's clinical application.