Enhancing Sleep Spindle Activity through Thalamic TI-TES: Neuromodulatory Foundations for Targeting Thalamocortical Dysfunction in Schizophrenia - PROJECT SUMMARY Sleep spindle deficits are a promising biomarker and therapeutic target for schizophrenia spectrum disor- der (SSD), as they reflect underlying dysfunction in thalamocortical circuits. However, current non-invasive neuromodulation techniques lack the depth and precision to directly target deep brain structures like the thala- mus, where sleep spindles are generated. Temporal interference transcranial electric stimulation (TI-TES) of- fers a novel approach to selectively stimulate deep brain regions, such as the thalamus, while minimizing elec- tric fields elsewhere. Additionally, TI-TES permits simultaneous stimulation and high-density EEG (hdEEG) ac- quisition during sleep, a combination pioneered by the research team. Supported by preliminary data, the over- all objective of this project is to demonstrate that TI-TES can effectively target thalamic circuits and enhance sleep spindle activity in healthy subjects during non-rapid eye movement (NREM) sleep. Specifically, this pro- ject aims to 1) identify the optimal TI-TES parameters (frequency, location) for enhancing spindle frequency activity (SFA), and 2) determine the differential effects of thalamic TI-TES on fast and slow spindle subtypes, slow waves, and SO-spindle coupling. The central hypothesis is that slow and fast spindle subtypes can be selectively enhanced by modulating the location and frequency of thalamic TI-TES. The rationale for this pro- ject is that focal thalamic stimulation could restore normal spindle activity in SSD patients in a personalized manner, potentially improving thalamocortical connectivity and addressing broader neurobiological deficits. To achieve these aims, personalized, multipolar TI-TES combined with hdEEG will be applied to healthy subjects during the N2 sleep stages of a 90 min afternoon nap. Each participant will undergo bilateral thalamic stimulation at three target locations (broad thalamic, anterior, posterior) across separate nap sessions in a ran- domized, counterbalanced crossover design. Within each session, randomized stimulation frequencies will range from 8-16 Hz, along with a SHAM condition. Under Aim 1, increases in 8-16 Hz spectral power will serve as the primary metric for identifying the most effective stimulation parameters. Under Aim 2, detailed analyses of the recorded hdEEG data will explore the number, density, amplitude, duration, and topography of slow and fast spindles, as well as slow waves, and SO-spindle coupling. Individual spindles and slow waves will be iden- tified using automated detection algorithms. This research is highly innovative as it represents the first use of TI-TES to enhance sleep spindle activity, and, based on available literature, the first attempt to directly elicit spindles through thalamic stimulation in humans. The proposed research is significant because it is expected to provide strong scientific justification for future clinical trials of non-invasive neuromodulation therapies aimed at restoring normal spindle activity and alleviating thalamocortical dysfunction in patients with SSD, where cur- rent treatments remain inadequate.
