Overcoming the Barriers to Effective Transcranial Temporal Interference Stimulation in Humans

Remedies for treatment resistance in psychiatric and neurological disorders is a great unmet need. Invasive neuromodulation, such as deep brain stimulation (DBS), applied to a targeted brain region is one option that has helped regulate or modify, abnormal electrical patterns in many patients with neurological deficits; However, invasive approaches carry significant risks while having limited targeting flexibility. Transcranial temporal interference stimulation (TIS) is a non-invasive neuromodulation method with much more favorable focus in deep brain targets than traditional forms of transcranial alternating current stimulation (tACS). tTIS achieves its focal effect by delivering two sinusoidal currents, that are both high in frequency, but that are slightly different from one another (e.g. 1000 kHz and 1020 kHz) through electrodes placed on the scalp. Frequencies that are in the kilohertz range alone do not elicit neuronal response, however the interaction of the two high-frequency currents creates an electric field with a high-frequency carrier (fc, e.g. 1010 kHZ) that is modulated by a low-frequency beat (fb, e.g. 20 Hz). If fc is high enough (\>1 kHz) and fb low enough (\<100 Hz), neurons respond much more strongly to fb than fc.

Safety and tolerability of TIS has recently been demonstrated in humans with findings indicating that TIS poses no greater risk than other common non-invasive techniques for transcranial current stimulation (TCS). The spatial distribution of the beat field (Eb) is distinct from other noninvasive stimulation methods in three ways: 1) it is focal, 2) it can peak deep in the brain, 3) it can be steered through the brain without moving the electrodes. These features have been demonstrated in mouse experiments, and in human simulation studies.

In humans, motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) applied to the motor cortex provide an established assay of corticospinal excitability. TMS experiments have provided direct evidence that phase-dependent neuromodulation can be induced by transcranial alternating current stimulation (tACS), a form of transcranial current stimulation that is similar to temporal interference stimulation (TIS) but lacks focality and steerability, yet has been key to understanding its neurophysiological effects in humans. For example, recent experimental results showed that TMS pulses time locked to tACS over motor cortex induced MEP amplitude modulation that was dependent on the phase of the tACS oscillatory currents. Building on this finding, the investigators will provide TMS pulses to motor cortex during tTIS and investigate whether neuromodulation of corticospinal excitability depends on the phase of beat frequency (fb). Similar to the experiments that showed neural activation in mice, the investigators will also investigate whether the strength of the effect depends on the carrier frequency (fc). The investigators will use computationally optimized electrode placement, with high- and low-frequency controls, to test that effects are unambiguously due to fb. Finally, the investigators will assess corticospinal excitability PRE and POST stimulation to investigate neuroplasticity induced by TIS. The knowledge gained in this experiment will demonstrate the extent to which modulation effects of TIS in humans are due entrainment of neural activity at fb. This information will provide a basis for the future use of tTIS for clinical applications.

• Offline neuroplastic effects from pre to post [Time frame: Periprocedural]
• Offline neuroplastic post effects [Time frame: Periprocedural]