Thalamic transcranial electrical stimulation with temporal interference enhances sleep spindle activity during a daytime nap

Abstract Introduction Sleep spindles are electroencephalographic elements characteristic of non-rapid eye movement sleep generated by thalamo-cortical interactions. Spindles have been linked to some of the cognitive benefits afforded by sleep and high spindle activity is associated with increased arousal threshold. Here, we demonstrate that targeting the thalamus with Transcranial Electrical Stimulation with Temporal Interference (TES-TI) can enhance spindle activity. Methods 46 participants (24 ± 9.5 years; 58.7% F) underwent thalamic TES-TI stimulation during daytime naps. Three stimulation protocols with 15kHz carrier frequency were tested during stage 2 of non-rapid eye movement sleep (N2): fixed difference frequency of 10 Hz (TES 15k Hz -TI 10Hz ), difference frequency matched to individual spindle peak (TES 15k Hz -TI Peak ), and no difference frequency (TES 15k Hz ). Spectral power in the spindle (sigma) band and integrated spindle activity (ISA) were compared before and during the stimulation, and across stimulation protocols. Results TES 15k Hz -TI 10Hz stimulation was associated with a significant increase in sigma band power (Δx̃ STIM-PRE = 0.46 log 10 µV 2 , p = 0.0042) and ISA (Δx̃ STIM-PRE = 4.064 µV/s, p = 0.030). Cluster-based analysis localized the increase in sigma power across the entire scalp (p = 0.008). Linear mixed effects models showed that both sigma band power and ISA during stimulation increased significantly more in TES 15k Hz -TI 10Hz compared to the other experimental condition. Conclusions This study provides evidence supporting the successful use of TES-TI targeting the thalamus to enhance sleep spindle activity. Stimulation at a fixed difference frequency of 10 Hz increased sigma band power and ISA, whereas neither stimulation matched to individual sigma band peak nor TES alone produced comparable effects. These promising results warrant further investigations into the cognitive and clinical impact of TES-TI, a non-invasive neuromodulation tool that can reach deep brain regions. Statement of significance This study provides evidence that thalamo-cortical networks, which are central to many physiological and pathological brain activities, can be modulated non-invasively in humans. More specifically, the findings show that transcranial electrical stimulation with temporal interference targeting the thalamus can selectively enhance sleep spindle activity. This work introduces a new strategy for precisely targeting sleep-generating mechanisms regulated by deep brain circuits without surgery or medication. Key next steps include determining whether this increase in spindle activity can positively impact cognition and assessing the translational potential of this approach for clinical populations.