Sleep stage-specific effects of 0.75 Hz phase-synchronized rTMS and tACS on delta frequency activity during sleep

Slow oscillatory activity during non-rapid-eye-movement (NREM) sleep plays a crucial role in both physical health and cognitive functions. Enhancing slow oscillatory activity during sleep has the potential to benefit these domains, yet an optimal stimulation protocol has not been established. This study aimed to investigate whether repetitive transcranial magnetic stimulation (rTMS), synchronized with the trough phase of 0.75 Hz transcranial alternating current stimulation (tACS) can modulate EEG activity in the delta frequency range during sleep and enhance cognitive functions. Healthy adults participated in a within-subject, counterbalanced study design comparing real and sham stimulation conditions. Combined rTMS and tACS was applied over the bilateral prefrontal cortex before sleep. We evaluated (1) power spectral density and functional connectivity within the delta frequency range during resting state and sleep, (2) retention of declarative memory learned before sleep, and (3) sleep parameters including spindle activity, sleep stage ratios, sleep onset latency and sleep efficiency. The combined rTMS and tACS protocol significantly increased delta oscillatory activity during the N3 sleep stage compared to sham. Functional connectivity, as measured by global efficiency, was enhanced during the N2 sleep stage. However, the stimulation did not improve declarative memory retention, spindle activity or other sleep parameters. These findings demonstrate the potential of combined rTMS and tACS as a non-invasive method to enhance delta oscillatory activity during sleep. While the stimulation did not improve memory performance, its ability to modulate delta activity during sleep suggests potential clinical applications for addressing pathological alterations in slow wave activity during sleep. State of SignificanceSlow oscillatory activity during non-rapid eye movement (NREM) sleep is relevant for declarative memory consolidation and overall sleep quality. However, noninvasive brain-stimulation methods to selectively modulate these oscillations remain elusive. In this study, we show that pre-sleep application of repetitive transcranial magnetic stimulation (rTMS) synchronized to the trough of 0.75 Hz transcranial alternating current stimulation (tACS) significantly enhances delta oscillatory activity during N3 sleep and increases global functional connectivity during N2 sleep in healthy humans without sleep disturbances without altering sleep structure. Our findings indicate that rTMS synchronized to the trough of the tACS exerts sleep-stage-specific effects on delta oscillatory activity. This stimulation protocol represents a promising approach for restoring pathological slow-wave activity during sleep in clinical populations.