Evaluation of the Efficacy and Safety of Transcranial Temporal Interference Stimulation (TIS) Targeting the Subthalamic Nucleus (STN) in Parkinson's Disease: A Single-Center, Prospective, Double-Blind, Randomized Controlled Clinical Trial

Parkinson's disease is a progressive neurodegenerative disorder characterized by motor dysfunction.

Temporal Interference Stimulation (TIS) is a non-invasive deep brain stimulation technique. Its core principle involves placing two pairs of transcranial stimulation electrodes on the scalp surface, each delivering high-frequency currents with slight differences. Since the human cerebral cortex does not respond to high-frequency currents, when these two currents intersect in the deep brain (i.e., the target area), they generate a low-frequency interference wave-similar to tACS-with a frequency equal to the difference between the two currents. This enables selective modulation of deep brain regions while minimizing activation of the superficial cortex. Additionally, a breakthrough aspect of TIS is its ability to flexibly adjust the stimulation target location by modifying electrode positions and current ratios. This makes it highly suitable for future clinical applications in regulating deep brain nuclei and developing personalized diagnosis and treatment plans for Parkinson's disease (PD) patients. The technology offers a non-invasive method to alter neuronal activity in deep brain nuclei and has shown promise in improving PD motor symptoms in prior proof-of-concept studies, thereby providing a potential treatment for PD motor symptoms.

In animal models, TIS has been demonstrated to have the potential to modulate the activity of brain regions closely associated with PD motor symptoms, such as the subthalamic nucleus and globus pallidus. Preliminary clinical studies have shown that TIS stimulation of the unilateral STN in PD patients resulted in alleviation of motor symptoms such as tremor and bradykinesia before and after treatment . A recent exploratory study on TIS stimulation of the right GPi also confirmed that TIS is feasible and safe for alleviating mild PD motor symptoms, particularly bradykinesia and tremor. Compared to the right side, motor symptoms (especially bradykinesia) on the left side showed more significant improvement. PD patients with more severe bradykinesia and tremor before stimulation experienced greater improvement after TIS. Current research findings suggest that TIS has the potential to improve PD motor symptoms. However, in these two studies, some patients did not respond to TIS stimulation. Although preliminary data support the therapeutic potential of TIS for PD motor symptoms, there is still a lack of large-sample, randomized controlled, and systematic studies targeting different brain regions and parameter systems. Therefore, there is an urgent need to conduct standardized clinical trials to evaluate the optimal stimulation parameters, target selection, efficacy persistence, and safety of TIS, providing evidence-based support for its further promotion and application.

This study employs a single-center, prospective, randomized, double-blind, sham-controlled design to evaluate the efficacy and safety of TIS targeting the subthalamic nucleus in Parkinson's disease patients. The study protocol involves structural MRI scanning for all participants to establish individualized computational models, with neuronavigation techniques determining optimal electrode placement. Participants are randomized to either the active stimulation group (using 2000/2130 Hz dual-frequency configuration) or the sham control group (using 2000/2000 Hz configuration). All treatment sessions are conducted during patients' "ON" medication state, administered twice daily for 30 minutes over five consecutive days. Assessment is performed through blinded evaluation by raters unaware of group allocation using standardized scales at predetermined time points. The entire process follows structured data collection and safety monitoring protocols. This study aims to systematically evaluate the therapeutic effects and safety profile of TIS for motor symptoms in Parkinson's disease, providing an evidence base for the clinical application of this novel neuromodulation approach.