The goal of this clinical trial is to compare the efficacy and safety of different Intervention Intervals of subthalamic nucleus-targeted transcranial temporal interference stimulation (STN-tTIS) in patients with Parkinson disease.
Previous studies suggest that STN-tTIS may improve motor symptoms in people with Parkinson disease. However, most previous studies evaluated only one stimulation session. It remains unclear how often STN-tTIS should be administered during a repeated treatment course and whether shorter intervention intervals stimulation produces greater or longer-lasting improvement without increasing adverse events.
The main questions this study aims to answer are:
1. Does STN-tTIS administered five times weekly improve motor symptoms more than standard medication treatment alone at the end of the 2-week treatment period? 2. Do once-weekly, twice-weekly, and five-times-weekly STN-tTIS produce different changes in motor symptoms? 3. Does the STN-tTIS intervention intervals influence how long its effects persist after treatment? 4. Do the different intervention intervals have different effects on non-motor symptoms, quality of life, cognitive function, and safety?
Participants will be randomly assigned to receive STN-tTIS once weekly, twice weekly, or five times weekly for 2 weeks, or to continue standard antiparkinsonian medication without additional stimulation. All participants will maintain a stable medication regimen during the study. Their motor and non-motor symptoms will be assessed during the treatment period and during a subsequent 2-week follow-up period.
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.
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.
Parallel
STN-tTIS Once Weekly
DeviceParticipants receive subthalamic nucleus-targeted transcranial temporal interference stimulation (STN-tTIS) once weekly for 2 weeks. Each stimulation session lasts 20 minutes. Two high-frequency alternating currents at 2000 Hz and 2130 Hz are delivered through two pairs of scalp electrodes, generating a 130-Hz temporal interference envelope targeting the subthalamic nucleus. Stable antiparkinsonian medication is maintained throughout the intervention period.
STN-tTIS Twice Weekly
DeviceParticipants receive subthalamic nucleus-targeted transcranial temporal interference stimulation (STN-tTIS) twice weekly for 2 weeks. Each stimulation session lasts 20 minutes. Two high-frequency alternating currents at 2000 Hz and 2130 Hz are delivered through two pairs of scalp electrodes, generating a 130-Hz temporal interference envelope targeting the subthalamic nucleus. Stable antiparkinsonian medication is maintained throughout the intervention period.
STN-tTIS Five Times Weekly
DeviceParticipants receive subthalamic nucleus-targeted transcranial temporal interference stimulation (STN-tTIS) five times weekly for 2 weeks. Each stimulation session lasts 20 minutes. Two high-frequency alternating currents at 2000 Hz and 2130 Hz are delivered through two pairs of scalp electrodes, generating a 130-Hz temporal interference envelope targeting the subthalamic nucleus. Stable antiparkinsonian medication is maintained throughout the intervention period.
Standard Antiparkinsonian Medication
DrugParticipants continue their stable antiparkinsonian medication regimen throughout the 2-week study intervention period. No additional STN-tTIS is administered.
Change From Baseline in MDS-UPDRS Part III Total Score at the End of the Intervention Period
The Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS Part III) is used to assess the severity of motor symptoms in Parkinson disease. The total score ranges from 0 to 132, with higher scores indicating greater motor impairment. The primary outcome is the change in MDS-UPDRS Part III total score from baseline to Day 12, corresponding to the end of the 2-week intervention period. Assessments are performed during the ON medication state. A greater reduction from baseline indicates greater improvement in motor symptoms.
Change From Baseline in MDS-UPDRS Part I Score
The Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part I (MDS-UPDRS Part I) assesses non-motor aspects of experiences of daily living in Parkinson disease. Scores will be assessed at baseline, Day 12, and Day 27. Higher scores indicate greater impairment. Changes from baseline will be compared among the study groups.
Change From Baseline in MDS-UPDRS Part II Score
The MDS-UPDRS Part II assesses motor aspects of experiences of daily living in Parkinson disease. Scores will be assessed at baseline, Day 12, and Day 27. Higher scores indicate greater impairment. Changes from baseline will be compared among the study groups.
Change From Baseline in MDS-UPDRS Part IV Score
The MDS-UPDRS Part IV assesses motor complications associated with Parkinson disease, including motor fluctuations and dyskinesias. Scores will be assessed at baseline, Day 12, and Day 27. Higher scores indicate greater motor complications. Changes from baseline will be compared among the study groups
Change From Baseline in Non-Motor Symptoms Scale (NMSS) Score
The Non-Motor Symptoms Scale (NMSS) is used to assess the severity and frequency of non-motor symptoms associated with Parkinson disease. Higher scores indicate a greater burden of non-motor symptoms. NMSS scores will be assessed at baseline, Day 12, and Day 27, and changes from baseline will be compared among the study groups.
Change in Remotely Assessed MDS-UPDRS Part III Score
Motor symptoms will be assessed remotely using the MDS-UPDRS Part III at prespecified time points during the intervention and follow-up periods. Longitudinal changes in remotely assessed motor scores will be evaluated to characterize changes in motor symptoms over time and compared among the study groups.
Change in Smartwatch-Derived Tremor Duration
Tremor-related signals will be continuously collected using a smartwatch worn on the baseline-defined clinically more affected side. Tremor duration will be summarized at the daily level or within prespecified time windows to evaluate longitudinal changes during the intervention and follow-up periods.
Change in Home-Based Active Motor Assessment Measures
Participants will complete standardized smartphone-guided home-based motor tasks while motion signals are recorded using a smartwatch. Assessments will be performed under standardized medication states whenever feasible. Longitudinal changes in task-based digital motor measures will be explored during the intervention and follow-up periods.
Incidence of Adverse Events and Serious Adverse Events
Safety will be assessed by monitoring the incidence, type, severity, duration, outcome, and relationship to STN-tTIS of adverse events (AEs) and serious adverse events (SAEs). Potential stimulation-related adverse events include headache, dizziness, fatigue, scalp itching or erythema, sleep disturbance, mood changes, worsening of tremor, and other treatment-emergent symptoms.
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