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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| High-dose iTBS treatment group | Experimental | High-dose iTBS, 5 sessions per day for 5 consecutive days. |
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| Low-dose iTBS treatment group | Experimental | Conventional-dose iTBS, once daily for 5 consecutive days. |
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| Sham stimulation group | Sham Comparator | Administer sham stimulation |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| High-dose iTBS treatment group | Procedure | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Assessment with the KPPS | King's PD Pain Scale (KPPS) includes 14 items rating the severity and frequency of pain, each item scored by severity (0-3) multiplied by frequency (0-4), resulting in a subscore of 0 to 12, with a total possible score range from 0 to 168. Higher scores indicate greater symptom severities and more serious influence. | at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment |
| Assessment with the MKPPS | Modified King's PD Pain Scale (MKPPS)，the modified version which is more suitable for Chinese people, combined with Ford's pain subtypes basing on the original. It covers five main domains, including 16 items, each item scored by severity (0-3) multiplied by frequency (0-4), resulting in a total possible score range from 0 to 192. Higher scores indicate greater symptom severities and more serious influence. | at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment |
| Change in Pain Intensity Scores (VAS) | VAS, a 0-10 numeric rating scale with 0= no pain and 10=maximal pain. Higher scores indicate greater symptom severities and more serious influence. | at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in MDS-UPDRS I | The participants will be evaluated in their "ON" medication states. The scales used to assess non-motor symptoms included parts I (ranging from 0 to 52) and II (ranging from 0 to 52) of the MDS-UPDRS, with higher scores indicating more severe symptoms | at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment |
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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);
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.
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Second Affiliated Hospital of Soochow University | Suzhou | Jiangsu | 215000 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40593930 | Background | 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. | |
| 15664172 | Background | 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. |
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Patients will be randomised into three groups-high-dose iTBS, low-dose iTBS, and sham stimulation-at a 1:1:1 ratio.
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The figure-of-eight coils used for active or sham stimulation are similar, including the emitted sound and the scalp tapping sensation.
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| Low-dose iTBS treatment group | Procedure | 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. |
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| Sham stimulation group | Procedure | 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. |
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| Change in MDS-UPDRS II | The participants will be evaluated in their "ON" medication states. The scales used to assess non-motor symptoms included parts I (ranging from 0 to 52) and II (ranging from 0 to 52) of the MDS-UPDRS, with higher scores indicating more severe symptoms. | at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment |
| Change in MDS-UPDRS III | The participants will be evaluated in their "ON" medication states. The scales used to assess motor symptoms included parts III (ranging from 0 to 132) and IV (ranging from 0 to 24) of the MDS-UPDRS, with higher scores indicating more severe symptoms. | at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment |
| Changes in PD Depression Score | The depression score (ranging from 0 to 76 with higher scores indicating more severe depression) from the 24 items Hamilton Depression Scale (HAMD). | at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment |
| Changes in PD Anxiety Score | The anxiety score (ranging from 0 to 60 with higher scores indicating more severe anxiety) from the 14 items Hamilton Anxiety Scale (HAMA). | at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment |
| Changes in PD Autonomic Symptoms Score | The Scale for Outcomes in Parkinson's disease for Autonomic Symptoms (SCOUP-AUT, maximal score 67, with higher scores indicating higher autonomic nervous system dysfunction). | at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment |
| Changes in PD Sleep Problem Score | The sleep problem index (from 0 to 68 with higher scores indicating more severe sleep problem) from the PD Sleep Scale-2 (PDSS-2). | at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment |
| Changes in PD Daytime Sleepiness Score | The daytime sleepiness will be assessed by the Epworth Sleeping Scale (ESS), maximal score 24, with higher scores indicating more severe symptoms. | at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment |
| Changes in PD Quality of Life Score | We will also assess change in quality of life from the Parkinson's Disease Questionnaire-39 (PDQ-39), ranging from 0 to 156 with higher scores indicating more serious influence. | at baseline, on day 1 after treatment, and at 1 month and 3 months after treatment |
| Electroencephalography | The EEG examination room should be suitably arranged, kept quiet, and free from unnecessary personnel moving around, especially near the patient. Patients are instructed to wash their hair before the examination, avoid fasting, understand the precautions, and remain relaxed. Patients are asked to keep their eyes closed, stay awake, breathe calmly, sit comfortably in a chair, and keep their head still without falling asleep. The EEG cap should be fitted with appropriate tightness, with scalp impedance maintained below 20 kΩ. Earplugs are worn to minimize external interference. EEG signals are recorded using a 128-channel EEG acquisition system (Neuracle, NSH0128, China) and a 64-channel EEG cap (Greentek, Wuhan, China), with a bandpass filter of 0.1-100 Hz and a sampling rate of 1 kHz. Continuous recording is performed for at least 15 minutes. EEG data are collected at time points T0 and T1 between approximately 8:00 AM and 11:00 AM to avoid deviations due to diurnal variations within | The day before treatment and the first day after treatment completion. |
| Functional magnetic resonance imaging | Functional magnetic resonance imaging (fMRI) of the brain was performed using a Philips Ingenia Elition 3.0T MRI scanner in the Department of Radiology, Suzhou Blue Cross Brain Hospital, Jiangsu Province, China. During the MRI scan, patients lay quietly in a supine position with eyes closed, without limb movement, and with both upper extremities fixed. A standard 8-channel phase-array head coil was used. Subjects were placed in a supine position and immobilized using a standard plastic face mask and soft padding to restrict motion. Conventional SE sequence T1WI was used to acquire anatomical images [repetition time (TR) = 500 ms, echo time (TE) = 16 ms, matrix = 256 × 256, slice thickness = 5 mm, interslice gap = 1 mm, number of slices = 24]. Fluid attenuated inversion recovery (FLAIR) T2WI was performed to exclude patients with intracranial lesions [TR = 8000 ms, TE = 125 ms, inversion time (TI) = 2000 ms, number of excitations (NEX) = 1.00, field of view (FOV) = 24 cm × 18 cm, matr](streamdown:incomplete-link) | The day before treatment and the first day after treatment completion. |
| 40850522 | Background | 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. |
| 32044947 | Background | 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. |
| ID | Term |
|---|---|
| D020734 | Parkinsonian Disorders |
| ID | Term |
|---|---|
| D001480 | Basal Ganglia Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D009069 | Movement Disorders |
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| ID | Term |
|---|---|
| D065908 | Transcranial Direct Current Stimulation |
| D050781 | Transcranial Magnetic Stimulation |
| ID | Term |
|---|---|
| D004599 | Electric Stimulation Therapy |
| D013812 | Therapeutics |
| D003295 | Convulsive Therapy |
| D013000 | Psychiatric Somatic Therapies |
| D004191 | Behavioral Disciplines and Activities |
| D004597 | Electroshock |
| D011580 | Psychological Techniques |
| D055909 | Magnetic Field Therapy |
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