Background <p>Slow waves are oscillations that reflect rhythmic alternation of neuronal activity and mediate key restorative functions of non-rapid eye movement (NREM) sleep. Left ventromedial prefrontal cortex regions are a “hot spot” for slow wave generation. The enhancement of slow wave activity (SWA, 0.5-4 Hz) has been shown to be beneficial, as in improving memory performance. To overcome limitations of current techniques, we assessed the ability of a non-invasive neuromodulatory tool, Transcranial Electrical Stimulation with Temporal Interference (TES-TI), to enhance SWA during NREM sleep overnight in healthy humans.</p> Methods <p>The current study is an interim analysis focused on the effects of TES-TI during NREM sleep in a laboratory setting. Two high frequency carriers with 1 Hz difference (TES^15kHz-TI^1Hz) produced amplitude-modulated temporal interference at 1Hz. Data were collected at the University of Wisconsin-Madison as part of the STRENGTHEN study (ClinicalTrials.gov, NCT06267521, 02/12/2024, single-blind, non-random allocation). Eligible participants were healthy adults (ages 18–50) assigned in parallel to one of four groups: (Group 1) TES^15kHz (0 Hz difference frequency) 2 nights per week and meditation; (Group 2) TES^15kHz-TI^1Hz (1 Hz difference frequency) 2 nights per week and sham meditation; (Group 3) TES^15kHz-TI^1Hz 1 night per week and meditation; (Group 4) TES^15kHz-TI^1Hz 2 nights per week and meditation. Stimulation targeting left ventromedial prefrontal cortex occurred during NREM sleep over repeated nights ( ~ 10 stimulation periods, 3-min each, first half of night, 1-2 nights/week, 4-week protocol). Twenty-one participants (Groups 2, 3, 4) received TES^15kHz-TI^1Hz and seven participants received TES^15kHz (Group 1). SWA was measured using simultaneous high-density electroencephalography with polysomnography.</p> Results <p>We show that SWA is increased with TES^15kHz-TI^1Hz (<i>N</i> = 21 total; <i>N</i> = 5 Group 2, <i>N</i> = 10 Group 3, <i>N</i> = 6 Group 4), and the effect outlasts the stimulation period; higher frequencies (sigma and beta) decrease. During stimulation, SWA is greater in TES^15kHz-TI^1Hz than pure TES^15kHz (<i>N</i> = 7 Group 1). The incremental effects of TES^15kHz-TI^1Hz on SWA between first and last intervention night are positively associated with subjective ratings of restorative sleep.</p> Conclusions <p>To our knowledge, this is the first study demonstrating that TES-TI enhances SWA and potentially its restorative function.</p>