Noninvasive Temporal Interference Stimulation of the Subthalamic Nucleus in Parkinson's Disease Reduces Beta Activity

Abstract

Background: Temporal interference stimulation (TIS) is a novel noninvasive electrical stimulation technique to focally modulate deep brain regions; a minimum of two high-frequency signals (f₁ and f₂ > 1 kHz) interfere to create an envelope-modulated signal at a deep brain target with the frequency of modulation equal to the difference frequency: Δf = |f₂ - f₁|.

Objective: The goals of this study were to verify the capability of TIS to modulate the subthalamic nucleus (STN) with Δf and to compare the effect of TIS and conventional deep brain stimulation (DBS) on the STN beta oscillations in patients with Parkinson's disease (PD).

Methods: DBS leads remained externalized after implantation, allowing local field potentials (LFPs) recordings in eight patients with PD. TIS was performed initially by two pairs (f₁ = 9.00 kHz; f₂ = 9.13 kHz, 4 mA peak-peak per pair maximum) of scalp electrodes placed in temporoparietal regions to focus the envelope signal maximum (Δf = 130 Hz) at the motor part of the STN target.

Results: The comparison between the baseline LFPs and recordings after TIS and conventional DBS sessions showed substantial suppression of high beta power peak after both types of stimulation in all patients.

Conclusions: TIS has the potential to effectively modulate the STN and reduce the beta oscillatory activity in a completely noninvasive manner, as is traditionally possible only with intracranial DBS. Future studies should confirm the clinical effectiveness of TIS and determine whether TIS could be used to identify optimal DBS candidates and individualize DBS targets. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; beta power; deep brain stimulation; local field potentials; subthalamic nucleus; temporal interference stimulation.

FIG. 1

The principle of the temporal interference stimulation (TIS) targeting subthalamic nucleus (STN). (Left panel) Deep brain stimulation (DBS) electrodes are implanted in the STN, using a standard externalized process—the wires from the electrodes are connected to the battery in a subsequent surgery (leaving externalized wires for a 1‐day period, allowing access to each electrode individually). During the work, a recording is made from the DBS electrodes while stimulation is applied in three forms: DBS stimulation directly, TIS stimulation from transcutaneous electrodes, and sham stimulation (only high‐frequency carriers with no amplitude‐modulated signal from transcutaneous electrodes). (Center panel) An example of patient‐specific stimulation of the transcutaneous‐applied TIS, with a clear amplitude‐modulated signal maximum at the STN target. (Right panel) A zoom view of the targeted region showing the electrode placement with respect to the patient's STN. [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 2

The effect of stimulation on subthalamic nucleus (STN) beta oscillations in eight subjects. The first column shows the lead location in the analyzed STN. Contacts closest to the STN sweet spot selected for deep brain stimulation (DBS) and LFP sensing are marked in red. The second column presents the oscillatory part of the power spectrum under the baseline, temporal interference stimulation (TIS), and DBS conditions. The area of interest, where the pathological beta peak can be seen, is marked in gray. The third column expresses the reduction of the pathological beta peak power under the TIS and DBS conditions as compared with the baseline. The fourth column shows the interference envelope in the target and contralateral STN. [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 3

The effect of control conditions on subthalamic nucleus (STN) beta oscillations. Case example of subject no. 7's (A) oscillatory part of the power spectrum under the baseline, deep brain stimulation (DBS), temporal interference stimulation (TIS), and both sham conditions. Sham stimulation, the utilization of carrier frequencies alone (no Δf), does not reduce the beta power. Application of sham without a ramp (instantaneous on) seems to increase beta. A proper ramp ensures no transient artifacts. Case example of subject 8's (B) oscillatory part of the power spectrum under baseline, DBS, STN TIS 30 Hz, STN TIS 130 Hz, and occipital lobe TIS 130 Hz. Targeting another structure out of STN does not modulate beta peak in STN. A similar effect can be seen also for the 30‐Hz STN TIS condition. [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 4

Time evolution of beta power after the temporal interference stimulation (TIS) (A) and deep brain stimulation (DBS) (B) conditions. Beta power was evaluated as a mean power of the oscillatory part of the spectrum in the interval ±2 Hz around the maximum of patient‐specific beta peak normalized across patients. Solid line expresses the mean, and background color corresponds to the standard deviation across patients. [Color figure can be viewed at wileyonlinelibrary.com]