Clinical Efficacy of Intermittent Theta Burst Transcranial Magnetic Stimulation With Different Modes on Parkinson's Disease

Overview

TMS regulates cortical excitability through electromagnetic induction, with low-frequency stimulation suppressing and high-frequency stimulation enhancing excitability. Building on theta-gamma coupling, iTBS induces broader improvements in functional brain connectivity within a shorter stimulation period, particularly by significantly reducing abnormal variability in the prefrontal and parietal regions, demonstrating superior neuromodulatory efficiency and network remodeling capacity. This study aims to compare the symptomatic effects of different iTBS protocols on Parkinson's disease, optimize stimulation parameters, and evaluate safety, while also analyzing the time-dependent trends of therapeutic efficacy through 1- and 3-month follow-ups.

Detailed description

Transcranial magnetic stimulation, as a neuromodulatory strategy, has received increasing attention in the treatment of Parkinson's disease, demonstrating the ability to improve both motor and non-motor symptoms. Its mechanism is based on electromagnetic induction, using time-varying magnetic fields to modulate cortical neuronal activity. The effects of TMS are frequency-dependent: low-frequency stimulation (≤1 Hz) typically inhibits cortical excitability, resembling long-term depression, while high-frequency stimulation (≥10 Hz) enhances cortical excitability, analogous to long-term potentiation. Building on the mechanism of theta-gamma coupling, theta burst stimulation was developed by embedding high-frequency bursts within a theta rhythm, enabling efficient induction of LTP- and LTD-like effects. Among TBS protocols, intermittent TBS has been shown to exert clear modulatory effects on the motor cortex. Compared with 10 Hz repetitive TMS, iTBS induces broader improvements in functional connectivity across brain regions within a shorter stimulation period, particularly by significantly reducing abnormal variability in the prefrontal and parietal regions, indicating greater neuromodulatory efficiency and network remodeling capacity.

In this study, the iTBS protocol is applied based on the "Stanford Accelerated Intelligent Neuromodulation Therapy" (SAINT) approach. Patients are randomly assigned to one of three groups: a high-dose treatment group, a low-dose treatment group, or a sham stimulation group. Clinical scales are used to evaluate whether different modes of intermittent theta-burst transcranial magnetic stimulation improve motor and non-motor symptoms (particularly pain) in patients with Parkinson's disease. In addition, functional magnetic resonance imaging and electroencephalography are performed before and after treatment to explore the effects of different iTBS protocols on brain network activity and functional connectivity.

Interventions

• Procedure High-dose iTBS treatment group
  The stimulation intensity is 80% of the resting motor threshold (RMT), with an intra-burst frequency of 50 Hz and an inter-burst frequency of 5 Hz. Each train lasts 2 seconds, followed by an 8-second inter-train interval, delivering 1,800 pulses per session. The session is repeated after a 30-minute interval, with a total of 5 sessions per day (amounting to 9,000 pulses daily). Stimulation is administered for 5 consecutive days, resulting in a total of 45,000 pulses.
• Procedure Low-dose iTBS treatment group
  The stimulation intensity is 80% of the resting motor threshold (RMT), with an intra-burst frequency of 50 Hz and an inter-burst frequency of 5 Hz. Each train lasts 2 seconds, followed by an 8-second inter-train interval, delivering 1,800 pulses per session. Stimulation is administered once daily (1,800 pulses per day) for 5 consecutive days, resulting in a total of 9,000 pulses.
• Procedure Sham stimulation group
  The intervention procedure is identical to that of active stimulation, with the sole difference being the use of a specific sham coil. This sham coil has the same appearance as the active coil but is specially modified to produce no magnetic field, generating only vibration and sound.

Primary outcome measures

• Assessment with the KPPS [Time frame: at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment]
• Assessment with the MKPPS [Time frame: at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment]
• Change in Pain Intensity Scores (VAS) [Time frame: at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment]

Secondary outcome measures (11)

• Changes in MDS-UPDRS I [Time frame: at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment]
• Change in MDS-UPDRS II [Time frame: at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment]
• Change in MDS-UPDRS III [Time frame: at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment]
• Changes in PD Depression Score [Time frame: at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment]
• Changes in PD Anxiety Score [Time frame: at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment]
• Changes in PD Autonomic Symptoms Score [Time frame: at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment]
• Changes in PD Sleep Problem Score [Time frame: at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment]
• Changes in PD Daytime Sleepiness Score [Time frame: at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment]
• Changes in PD Quality of Life Score [Time frame: at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment]
• Electroencephalography [Time frame: The day before treatment and the first day after treatment completion.]
• Functional magnetic resonance imaging [Time frame: The day before treatment and the first day after treatment completion.]

Eligibility criteria

Inclusion criteria

• Aged 40-80 years; ② Diagnosis of idiopathic Parkinson's disease meeting the MDS Clinical Diagnostic Criteria for Parkinson's disease (2015 edition), with a disease duration of at least 3 years and Hoehn \& Yahr stage < 4;

• Stable use of anti-parkinsonian medication for 2 weeks prior to the study and throughout the entire study period, with no dosage adjustments; ④ Concurrently meeting the diagnostic criteria for Parkinson's disease-related pain, with a frequency of at least 3 times per week and duration of at least 3 months; Numerical Rating Scale (NRS) score ≥ 3; ⑤ Passing the TMS Safety Screening Questionnaire (TSSQ);

• Passing the MRI Safety Screening Questionnaire (MSSQ); Exclusion Criteria
• Patients with other diseases that may affect peripheral nerve sensation, including but not limited to diabetes, herpes infection, stroke, or spinal cord disorders;

• Patients with comorbid severe depression or psychiatric disorders;

• Presence of severe cognitive impairment, defined as a Mini-Mental State Examination (MMSE) score ≤ 9;

• Patients with concurrent intracranial organic lesions or a history of traumatic brain injury; ⑤ Patients with severe organic diseases involving the heart, liver, kidneys, or other vital organs; ⑥ Patients unable to undergo cranial MRI examination or TMS treatment due to claustrophobia, presence of implanted devices such as pacemakers, history of epilepsy, or other contraindications.

• Providing written informed consent.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

China · 1 center

• The Second Affiliated Hospital of Soochow University — Suzhou

Publications

• Liu S, Yang S, Wang C, Li J, Wang L. Effects of two types of repetitive transcranial magnetic stimulation on brain network in Parkinson's disease. NPJ Parkinsons Dis. 2025 Jul 1;11(1):191. doi: 10.1038/s41531-025-01054-4. PMID 40593930
• Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005 Jan 20;45(2):201-6. doi: 10.1016/j.neuron.2004.12.033. PMID 15664172
• Galanis C, Hananeia N, Lenz M, Vasheghani Farahani M, Jedlicka P, Vlachos A. Repetitive magnetic stimulation induces plasticity of excitatory synapses through cooperative pre- and postsynaptic activity. Brain Stimul. 2025 Sep-Oct;18(5):1641-1650. doi: 10.1016/j.brs.2025.08.019. Epub 2025 Aug 23. PMID 40850522
• Armstrong MJ, Okun MS. Diagnosis and Treatment of Parkinson Disease: A Review. JAMA. 2020 Feb 11;323(6):548-560. doi: 10.1001/jama.2019.22360. PMID 32044947

Identifiers

NCT: NCT07176091 · LK2025027

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗