TIS for Brain Network Modulation and Clinical Efficacy in Parkinson's Disease

Mechanism of Temporal Interference Stimulation on Brain Networks and Its Long-term Clinical Efficacy in Parkinson's Disease

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction. While deep brain stimulation (DBS) is effective, its invasive nature limits its application in early-stage patients. Temporal interference stimulation (TIS) is a novel non-invasive technique that can target deep brain structures like the globus pallidus internus (GPi) by using high-frequency electric fields.

This study aims to evaluate the clinical value and underlying mechanisms of TIS in PD patients. The research is divided into two phases: Phase A investigates the immediate regulatory effects of 130 Hz and 40 Hz TIS on brain networks using concurrent fMRI-TIS. Phase B is a randomized, double-blind, sham-controlled trial to assess the long-term efficacy and safety of a 2-week TIS intervention on both motor and non-motor symptoms. The results will help clarify how TIS modulates deep brain networks and its potential as a non-invasive therapy for PD.

This study employs a two-phase design to systematically investigate the effects of Temporal Interference Stimulation (TIS) on Parkinson's Disease (PD).

Phase A: Acute fMRI Mechanism Study (n=15) In this crossover study, participants will undergo concurrent fMRI-TIS sessions. Two frequency envelopes will be tested: 130 Hz (to mimic DBS inhibitory effects) and 40 Hz (for gamma entrainment). The fMRI protocol follows an 8-20-8 minute design: 8 minutes of baseline, 20 minutes of concurrent stimulation, and 8 minutes of post-stimulation scan . Individualized electric field modeling based on high-resolution 3D-T1 MRI will be used to target the right GPi. Acute motor changes will be assessed using the MDS-UPDRS-III scale.

Phase B: Long-term Efficacy RCT (n=60) Participants will be randomly assigned to one of three parallel groups: 130 Hz TIS, 40 Hz TIS, or Sham stimulation. The intervention consists of 30-minute daily sessions for 2 weeks (10 sessions total).

Active Groups: TIS targeting the right GPi with individualized electrode configurations.

Sham Group: 20-second ramp-up and ramp-down to mimic skin sensation without continuous stimulation.

Clinical assessments including motor function (MDS-UPDRS), cognition (MoCA), mood (HAMD/HAMA), and sleep (PDSS-2) will be conducted at baseline, after the 2-week intervention, and at a 1-month follow-up . Long-term neuroplasticity will also be evaluated using multi-modal MRI post-intervention.

Inclusion Criteria:

• Diagnosed with Parkinson's Disease according to the Movement Disorder Society (MDS) clinical diagnostic criteria.
• Hoehn & Yahr Stage I-III (mild to moderate severity).
• Aged 45 to 65 years.
• Right-handed. Stable medication regimen for at least 1 hour before Phase A fMRI sessions and agreement to maintain a stable dosage during the 2-week Phase B intervention (unless clinically necessary).
• Able to provide informed consent by the participant or a legal guardian.

Exclusion Criteria:

• MRI contraindications, such as implanted DBS electrodes, cardiac pacemakers, or other metal implants.
• Significant cognitive impairment (MoCA score < 24) or severe psychiatric symptoms.
• History of epilepsy or structural brain lesions, including severe cerebral atrophy or cerebrovascular disease.
• Severe head tremors that would interfere with MRI scanning quality.