Electrostimulation (ES) is a versatile and efficient tool for interrogating, altering, and manipulating neural activities in health and disease. Deep brain ES delivered with implanted electrodes requires an elaborate neurosurgery and carries risks of tissue damage, bleeding, stroke, infection, and inflammation. This limits the use of deep brain ES for disease diagnostics and conditions that may not justify the risks. Non-invasive targeted deep brain ES has long been a major quest, with countless potential applications. The challenge is avoiding stimulation near surface electrodes, where the electric field is the strongest, while stimulating at a depth by a (much) weaker electric field. One way to stimulate at a distance is by temporal interference (TI) of two high-frequency sine waves delivered with a small frequency shift. The interference of two such waves creates an amplitude-modulated stimulus at the target. Assumed demodulation of this signal by neurons leads to their excitation at the modulation frequency. Here, we introduce an entirely different concept of the temporal interference, based on (a) complete cancellation of identical frequency carrier signals at the target, and (b) on the introduction of transient distortions in one or both these signals. The distortions, such as a brief frequency or phase shift, will be concealed by the strong periodic signal near the stimulating electrodes and will not lead to excitation at the surface. However, these distortions will add up at the remote target location. They will stand out from the “silent” background and will readily lead to excitation despite the attenuation of the electric field with distance. We will perform mechanistic studies which support this next generation TI (NG-TI) stimulation paradigm. We will continue with the design and experimental evaluation of different NG-TI protocols in vitro, in comparison with the “standard” TI. We will systematically analyze the impact of TI stimulation parameters, to achieve targeted tuning and modulation of individual neurons and neuronal circuitry. We hypothesize that NG-TI can be improved for more focal stimulation, with much better penetration. It will have lower electric charge stimulation threshold and enable better steerability than the standard TI. The most efficient NG-TI protocols will further be validated by in vivo animal experiments. We will qualitatively compare targeting, possible off-site effects, current consumption, and steerability of NG-TI and the standard TI. We will also define the feasibility and model the electric field parameters for NG-TI stimulation at distances useful for medical applications. The effects will be linked to dielectric and physiological properties of neurons and neural tissue, to build predictive models for non-invasive deep brain stimulation in large animal and human trials. This project will lay the ground to translate the NG-TI technology for disease diagnosis and treatment.

We will analyze cellular and membrane mechanisms of excitation of neurons by modulated periodic stimuli and introduce a novel paradigm of non-invasive deep brain stimulation. We will design, test, and tune new protocols for the next generation temporal interference stimulation. We will utilize the novel interference targeting protocols for neuromodulation selectively at a distance, for clinical applications such as non-invasive deep brain stimulation.