STN-tTIS With Different Intervention Intervals Versus Standard Medical Treatment for Parkinson's Disease

Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms that substantially impair quality of life. Although pharmacological therapy remains the standard treatment, long-term medication use is frequently associated with motor fluctuations and treatment-related complications. Transcranial temporal interference stimulation (tTIS) is a novel noninvasive neuromodulation technique capable of selectively modulating deep brain structures without surgery. Previous pilot studies have demonstrated that subthalamic nucleus-targeted tTIS (STN-tTIS) may improve motor symptoms in patients with PD. However, existing studies have primarily evaluated the immediate effects of single-session stimulation, and the optimal intervention interval for repeated STN-tTIS has not yet been established.

The objective of this multicenter clinical trial is to evaluate whether different intervention intervals, defined as once-weekly, twice-weekly, and five-times-weekly STN-tTIS administration, result in different therapeutic effects in patients with PD and to compare their efficacy and safety. The study will also investigate whether the intervention interval influences the durability of clinical improvement following completion of the intervention.

Approximately 60 participants with PD will be enrolled and randomly assigned to one of three active STN-tTIS treatment groups with different intervention intervals or to a control group receiving standard medical therapy alone. All participants will continue a stable antiparkinsonian medication regimen throughout the study. The treatment period will last 2 weeks, followed by a 2-week follow-up period. Clinical efficacy will be evaluated primarily by changes in motor symptoms, while additional assessments will evaluate non-motor symptoms, sleep, quality of life, cognitive function, and safety. This study will provide information regarding the influence of intervention intervals on the efficacy and safety of repeated STN-tTIS in patients with Parkinson disease and may help inform future treatment strategies.

Inclusion criteria

• 1.Aged 50-85 years, male or female. 2.Diagnosed with idiopathic Parkinson disease (PD) in accordance with the Chinese Guidelines for the Diagnosis and Treatment of Parkinson's Disease (4th Edition), with a confirmed diagnosis for at least 6 months and a stable condition, defined as no significant deterioration or major medication adjustment within the past month.

3.Receiving stable doses of antiparkinsonian medication (e.g., levodopa or dopamine agonists) and willing to maintain the medication regimen during the study.

4.Hoehn and Yahr stage 1-3 in the medication ON state. 5.Baseline MDS-UPDRS Part III total score ≥20 in the medication ON state. 6.No history of non-invasive neuromodulation therapy, or discontinuation of such therapy for at least 3 months before enrollment if previously received.

7.Normal cognitive function (MoCA score ≥24) and able to cooperate with tTIS intervention, clinical scale assessments, and basic smartphone- and smartwatch-assisted home-based motor self-assessments.

8.Able and willing to provide written informed consent and complete all required study procedures and follow-up assessments.

Exclusion criteria

• 1.Other neurological disorders that may affect motor or cognitive function. 2.Contraindications to magnetic resonance imaging (MRI), such as claustrophobia.

3.History of taking antipsychotics, antidepressants, or other medications affecting dopamine levels.

4.Psychiatric disorders (e.g., depression or schizophrenia), substance abuse, or alcohol dependence.

5.Implanted medical devices (e.g., pacemaker or defibrillator), metal implants in the cranium or spine, a personal or family history of epilepsy, or severe skull defects.

6.Previous deep brain stimulation (DBS) or other intracranial implantation surgery, or participation in another Parkinson disease clinical trial within the past 3 months.