The project aims to use transcranial electrical stimulation with temporal interference (TES-TI) to increase the production of sleep slow waves and enhance the restorative power of sleep, thereby counteracting cognitive impairment (mental fatigue) and its underlying cause (brain fatigue). TES-TI is a novel transcranial electrical stimulation approach based on temporal interference among multiple high-frequency electric fields (above 2000 Hz) that can be steered to achieve maximal effects throughout the depth of the brain. We will target TES-TI to deep brain regions where the majority of sleep slow waves propagate to enforce the restorative function of sleep on brain circuits, as previously demonstrated by our group. We will recruit healthy individuals whose sleep is subjectively “non-restorative.” We expect that TES-TI power naps will be more effective than sham naps in producing sleep slow waves and promoting restorative sleep. This study will lay the groundwork for applying TES-TI throughout the night (power sleep). The ultimate goal is the development of a portable, scalable, power sleep device for the general public.

Mental fatigue and non-restorative sleep impair attention, learning, and overall well-being. Sleep slow waves during NREM sleep drive synaptic down-selection, memory consolidation, and cellular restoration – but many people report naps that fail to feel restorative.

We apply TES-TI – steered, high-frequency electric fields that interfere to create low-frequency envelopes – to deep brain regions (e.g., insular cortex) during 90-minute afternoon naps in adults with self-reported non-restorative sleep. By bypassing brainstem arousal systems, TES-TI selectively amplifies slow waves without waking participants.

TES-TI is based on delivering multiple electric fields to the brain at slightly different frequencies in the kHz range (Figure 1). During TES-TI, two (or more) pairs of electrodes on the head each deliver a high frequency alternating current (f1 and f2), typically ~2-5 kHz. These frequencies are high enough that by themselves they do not affect neural mechanisms. However, if slightly different (f1=2000 Hz and f2=2001 Hz), the superposition of the induced electric fields creates an envelope oscillating at the low-frequency difference (Δf=1 Hz), which can affect neuronal activity. The maximal amplitude of the envelope can be steered by optimizing the electrode placement and current intensity ratio across stimulation channels. In this way, neuromodulation can be selectively targeted toward specific brain regions, including deep ones, while minimizing collateral effects in nearby and overlying areas. The effectiveness of TES-TI in modulating neural activity and plasticity has been validated in rodent and primate models, as well as in several clinical applications in humans. Thus, TES-TI can selectively activate deep regions, such as the hippocampus, without activating the overlying cortical neurons, and can be steered to other brain regions without physically moving the electrodes. As shown with fMRI and behavioral experiments, TES-TI can focally modulate hippocampal activity and enhance the accuracy of episodic memories in healthy humans. Also, theta-burst patterned TES-TI targeting the striatum can increase activity in the striatum and its associated motor network and enhance motor learning capacity.

While most studies so far have employed 2 high-frequency channels for TES-TI, it is now possible to combine multiple channels - currently up to 8 - in order to further increase the focality of the stimulation (while reducing the current provided by each channel). Our state-of-the-art TI-solutions device is equipped with 8 channels and the associated planning software. A schematic illustration of the mTI principle and an example of the increased focality is provided below (Figure 2, courtesy of Adam Williamson).

Personalization of interventions and precise targeting of brain regions are increasingly recognized as critical ingredients for effective therapy. A key advantage of TES-TI, compared to conventional TES, is its ability to focus the TI envelope precisely and at any depth. This makes it possible to fully personalize the stimulation regime. The TI-solutions software allows us to load an individual subject’s MRI to further refine the stimulation parameters based on his or her specific anatomy. If funding through other sources permits, we will perform MRI scans on our subjects and thereby achieve greater precision by personalizing the stimulation parameters.