Comparative Study of TIS Efficacy Across Different Targets

Zhongnan Hospital18 enrolled

Overview

This prospective, randomized, participant- and outcome-assessor-blinded, parallel-group exploratory trial will compare the target-dependent clinical, neuroimaging, and electrophysiological effects of temporal interference stimulation (TIS) targeting the subthalamic nucleus (STN) or globus pallidus internus (GPi) in patients with Parkinson's disease (PD). Eighteen participants with idiopathic PD will be randomly assigned in a 1:1 ratio to the STN-TIS or GPi-TIS group. Participants will receive one 20-minute TIS session daily for 7 consecutive days. Motor symptoms will be assessed using the MDS-UPDRS Part III immediately before and after each daily stimulation session. Resting-state functional magnetic resonance imaging (fMRI) and 64-channel electroencephalography (EEG) will be performed before the first stimulation session and immediately after completion of the 7-day intervention. The primary outcomes are: (1) change in MDS-UPDRS Part III score from Day 1 before stimulation to Day 7 after stimulation; and (2) changes in regional spontaneous brain activity and seed-based functional connectivity measured using resting-state fMRI. Secondary outcomes are: (1) daily immediate changes in MDS-UPDRS Part III scores and the proportion of participants achieving at least 30% improvement at Day 7; and (2) changes in resting-state 64-channel EEG relative bandpower. Safety and tolerability will be evaluated by monitoring adverse events and local skin reactions throughout the intervention. This study aims to provide preliminary evidence regarding target-dependent functional response patterns associated with STN- and GPi-targeted TIS in PD.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Eligibility

Sex: ALLMin age: 40 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Adult males or females aged ≥40 years; 2. Diagnosis of idiopathic Parkinson's disease according to the UK Brain Bank criteria, with age of onset ≥40 years; 3. Previous or current treatment with dopamine replacement therapy (e.g., levodopa) with good response; 4. Hoehn and Yahr (H\&Y) stage 1.5-2.5; 5. Able to walk independently for at least 5 minutes without assistive devices; 6. No severe freezing of gait (FOG); 7. Disease duration ≥2 years since diagnosis, clinically stable, and able to comply with study assessments and interventions; 8. Stable medication regimen for at least 4 weeks prior to the study; 9. Signed informed consent form; subject or legal guardian is able to understand and willing to participate in this study. Exclusion Criteria: 1. Presence of other neurological disorders that may affect the study (e.g., ...); 2. Mild cognitive impairment or above (MoCA ≤23); 3. Orthopedic or other medical conditions that may affect gait or balance; 4. Contraindications to MRI, such as claustrophobia; 5. History of antipsychotic, antidepressant, or other medications that may affect dopamine levels; 6. History of other severe psychiatric disorders; 7. History of epilepsy, traumatic brain injury, or implanted metallic devices in the brain or heart (e.g., stimulators, pacemakers) or other contraindications; 8. History of electroconvulsive therapy (ECT); 9. Currently participating in other gait- or balance-related intervention training; 10. Physician-diagnosed cardiovascular risk factors for exercise.

Outcomes

Primary Outcomes

Changes in motor symptoms in PD patients

Motor symptoms will be assessed using the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS Part III). All assessments will be conducted after withdrawal of antiparkinsonian medications for at least 12 hours. The change score will be calculated as the MDS-UPDRS Part III score immediately after the final stimulation session on Day 7 minus the score immediately before the first stimulation session on Day 1. A negative change value indicates improvement in motor symptoms.

Time frame: Immediately before the first stimulation session on Day 1 and immediately after the final stimulation session on Day 7.

Changes From Baseline in Regional Spontaneous Brain Activity and Seed-Based Functional Connectivity After 7 Days of TIS

Regional spontaneous brain activity and functional connectivity will be assessed using resting-state functional magnetic resonance imaging. Regional spontaneous brain activity will be evaluated primarily using the standardized amplitude of low-frequency fluctuation (zALFF). Seed-based functional connectivity will be calculated using predefined subthalamic nucleus and globus pallidus internus seed regions, and correlation coefficients will be transformed to Fisher z values. For each imaging measure, the change value will be calculated as the post-intervention value minus the baseline value. Within-group changes and between-group differences will be evaluated to characterize stimulation-related and target-dependent brain functional response patterns.

Time frame: Baseline before the first stimulation session and immediately after completion of the 7-day intervention.

Secondary Outcomes

Immediate Changes in MDS-UPDRS Part III Scores and Clinical Response Rate During the 7-Day TIS Intervention

MDS-UPDRS Part III will be assessed immediately before and immediately after each daily stimulation session during the 7-day intervention. The immediate within-session change for each treatment day will be calculated as the post-stimulation score minus the corresponding pre-stimulation score, with negative values indicating improvement. Clinical response will also be evaluated using the percentage change in MDS-UPDRS Part III score from immediately before the first stimulation session on Day 1 to immediately after the final stimulation session on Day 7. Percentage improvement will be calculated as the Day 1 pre-stimulation score minus the Day 7 post-stimulation score, divided by the Day 1 pre-stimulation score and multiplied by 100. Participants with an improvement of at least 30% will be classified as responders, and the response rate will be calculated as the proportion of responders in each stimulation group.

Time frame: Immediately before and immediately after each stimulation session on Days 1 through 7; response rate assessed from immediately before the first stimulation session on Day 1 to immediately after the final stimulation session on Day 7.

Change From Baseline in Resting-State 64-Channel EEG Relative Bandpower After 7 Days of TIS

Resting-state 64-channel electroencephalography will be recorded under eyes-closed conditions. Relative bandpower will be calculated for predefined frequency bands, including the Parkinsonian tremor-frequency range, theta, alpha, low-beta, high-beta, and total-beta bands, across predefined scalp regions. For each region-by-frequency measure, the change value will be calculated as the post-intervention relative bandpower minus the baseline relative bandpower. Exploratory principal component analysis will be used to characterize multivariate EEG response patterns associated with STN-targeted and GPi-targeted TIS.