Noninvasive Deep Brain Stimulation via Temporally Interfering Electric Fields

Abstract

SummaryWe report a noninvasive strategy for electrically stimulating neurons at depth. By delivering to the brain multiple electric fields at frequencies too high to recruit neural firing, but which differ by a frequency within the dynamic range of neural firing, we can electrically stimulate neurons throughout a region where interference between the multiple fields results in a prominent electric field envelope modulated at the difference frequency. We validated this temporal interference (TI) concept via modeling and physics experiments, and verified that neurons in the living mouse brain could follow the electric field envelope. We demonstrate the utility of TI stimulation by stimulating neurons in the hippocampus of living mice without recruiting neurons of the overlying cortex. Finally, we show that by altering the currents delivered to a set of immobile electrodes, we can steerably evoke different motor patterns in living mice.

Can transcranial electric stimulation with multiple electrodes reach deep targets?

“…This multi-electrode approach is sometimes referred to as high-definition transcranial electric stimulation (HD-TES) [4,5], and can be combined with any desired stimulation waveform. More recent efforts propose to use multiple electrodes with specific waveforms to reach deep targets in the brain [6], or to increase intensity of stimulation [6,7] propose “interferential stimulation” with sinusoidal waveforms of similar frequency delivered through two electrode pairs. The investigators suggest that interference of these two waveforms results in maximal modulation of oscillating fields deep inside the brain.…”

Neuromodulation with transcranial focused ultrasound

“…To improve focus at depth, researchers have attempted to superimpose magnetic or electric fields by using multiple sources. 7,20 However, a tightening of focus in a central region accompanies a deterioration in regions surrounding the ancillary sources. Thus, noninvasive and targeted stimulation of specific nuclei or pathways deep in the brain has remained elusive.…”

Noninvasive Neuromodulation Goes Deep

“…With noninvasive stimulation, the intensity of electromagnetic fields drops off with distance from the surface of the head, meaning that superficial brain areas are activated first. In this issue of Cell , Grossman et al (2017) exploit a long-standing acoustical phenomenon to propose a form of noninvasive electrical brain stimulation capable of stimulating deep brain areas in a selective manner: “temporal interference” (TI) stimulation.…”

“…Grossman et al (2017) first applied TI stimulation to the skulls of anesthetized mice, reporting that stimulation with 2 and 2.01 kHz evokes firing at a rate of 10 Hz (matching the difference of the two applied frequencies) in the somatosensory cortex and hippocampus, as measured by patch clamp electro-physiology. In separate experiments, the authors used c- fos labeling to show that TI stimulation preferentially activates hippocampal over cortical neurons.…”

“…Whereas Grossman et al (2017) experimented with manual adjustment of parameters such as inter-electrode distance, the development of automated algorithms (Dmochowski et al, 2011) will efficiently identify the optimal combination of electrode locations and applied intensities that steer the envelope of the beating electric field to the targeted brain region. As a first step, Grossman and colleagues suggest the feasibility of functionally meaningful noninvasive deep brain stimulation—a breakthrough if translated to clinical interventions as well as efforts to map human brain circuits.…”