Repetitive Transcranial Magnetic Stimulation for Musculos... | NCT05537597

NCT05537597

Status Module

Sponsor/Collaborators Module

Oversight Module

Description Module

Detailed Description

Pain can appear as a pre-motor symptom, and its intensity could be severe enough to be the dominant non-motor symptom in the course of PD patients.

It estimated the prevalence of painful phenomena in PD to be 30 to 85% (mean 66%), which is significantly greater than the age-matched general population. Painful experiences in PD are highly heterogeneous and complex, which is difficult to describe for patients but also diagnose for neurologists. In addition, this common and disabling symptom receives inadequate analgesic treatment.

The distinction between these pain subtypes is required so that different therapeutic strategies can be established for each type of pain. The King's Parkinson's Pain scale (KPPS) was validated to identify and rate the various types of pain in PD. Fourteen items cover seven main domains, including musculoskeletal pain, chronic body pain (central or visceral), fluctuation-related pain, dyskinetic-dystonic pain, nocturnal pain, oro-facial pain, discolouration/oedema/swelling, and radicular pain. Of these subtypes, musculoskeletal pain is common.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that may be useful for the treatment of various psychiatric and neurological disorders. The mechanisms underlying rTMS effects remain to be elucidated.

rTMS is postulated to induce neuronal excitability changes in a set of cortical and subcortical areas involved in pain processing and modulation. Interestingly, M1 stimulation had a positive effect on brain structures that are related to the affective-emotional components of pain, such as the insular cortex and cingulate cortex.

The best efficacy for chronic pain has been achieved when primary motor cortex (M1) is stimulated at high frequency (5 to 20 Hz, 80% of the resting motor threshold (RMT)), as in previous rTMS studies in analgesia.

In TMS, time-varying magnetic fields generates electrical currents in the cortex. TMS pulses can either directly or trans-synaptically depolarize neurons, and these neural activities can be recorded through the skull by EEG electrodes placed on the scalp. The combination of TMS with simultaneous EEG can be used to assess excitability, inhibition, plasticity and connectivity across almost all areas of the cortical mantle.

The characterization of potential TMS-EEG predictors and markers could be the theoretical basis for verifying the response to neuromodulation protocols.

In this randomised, double-blind, placebo-controlled study, the efficacy and safety of 7 sessions of 20 Hz-rTMS delivered to M1 will be assessed in PD patients with chronic musculoskeletal pain.

A single-pulse TMS-EEG and resting-state EEG directly provide information on the cortical mechanisms before and after rTMS of M1.

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Label	Type	Description	Intervention Names
M1-rTMS group	Experimental	active M1-rTMS	Procedure: active M1-rTMS
sham-rTMS group	Sham Comparator	sham rTMS	Procedure: sham rTMS

Interventions

Name	Type	Description	Arm Group Labels	Other Names
active M1-rTMS	Procedure	Magnetic stimulation will be carried out using a MagPro X100 machine with a MCF-B70 figure-of-eight coil (Magventure, Farum). All rTMS sessions will be assisted by a neuronavigation system (TMS Navigator，Localite GmbH), maintaining the M1 target and the orientation of coil stable during stimulation sessions. The M1 target was defined as the "hand knob" region, which corresponds to the motor cortical representation of the hand, regardless of the location of pain. Stimulation paradigm consists of 20 trains of pulses with an intra-train frequency of 20 Hz, resulting in 2000 pulses for a total duration of 20 minutes. The stimulation intensity will be 80% of RMT, defined as the lowest stimulation intensity necessary to induce a visible muscle twitch of the hand contralateral to the stimulated hemisphere. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Change From Baseline Over 2 Months (Group by Time Interaction) in Modified KING'S PD Pain Scale Domain 1	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.	before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months)
Change From Baseline Over 2 Months (Group by Time Interaction) in KING'S PD Pain Scale Domain 1	KING'S PD Pain Scale (KPPS) Domain 1 focused on musculoskeletal pain, covering one item, which was scored by multiplying severity (from 0 [no pain] to 3 [very severe pain]) by frequency (from 0 [never] to 4 [all the time]), yielding sub-scores between 0 and 12. Higher scores indicate greater symptom severity.	before the first rTMS session (day 1), after rTMS therapy (day8、1month、2months)
Change in 0-10 Numeric Rating Scale	Pain intensity was assessed over the past 24 hours using a 0-10 number, where 0 indicating no pain and 10 indicating maximal pain.	before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months)

Secondary Outcomes

Measure	Description	Time Frame
Changes in Resting-state EEG Oscillations	For each EEG epoch, we computed the fast Fourier transform (FFT) algorithm to convert to frequency domain. The power values in following five frequency bands were obtained: delta (1-4Hz), theta (4-8Hz), alpha(8-13Hz), beta(13-30Hz), gamma(30-80Hz).	before the first rTMS session (day 1), after rTMS therapy (day8)

Eligibility Module

Contacts/Locations Module

Facility	Status	City	State	ZIP	Country	Contacts
Department of Neurology, Second Affiliated Hospital of Soochow University		Suzhou	Jiangsu	215004	China

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
26309254	Background	Valkovic P, Minar M, Singliarova H, Harsany J, Hanakova M, Martinkova J, Benetin J. Pain in Parkinson's Disease: A Cross-Sectional Study of Its Prevalence, Types, and Relationship to Depression and Quality of Life. PLoS One. 2015 Aug 26;10(8):e0136541. doi: 10.1371/journal.pone.0136541. eCollection 2015.
29903584	Background

IPD Sharing Statement Module

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	M1-rTMS Group	active M1-rTMS: Magnetic stimulation will be carried out using a MagPro X100 machine with a MCF-B70 figure-of-eight coil (Magventure, Farum). All rTMS sessions will be assisted by a neuronavigation system (TMS Navigator，Localite GmbH), maintaining the M1 target and the orientation of coil stable during stimulation sessions. The M1 target was defined as the "hand knob" region, which corresponds to the motor cortical representation of the hand, regardless of the location of pain. Stimulation paradigm consists of 20 trains of pulses with an intra-train frequency of 20 Hz, resulting in 2000 pulses for a total duration of 20 minutes. The stimulation intensity will be 80% of RMT, defined as the lowest stimulation intensity necessary to induce a visible muscle twitch of the hand contralateral to the stimulated hemisphere. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Uploaded Document Information

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Sep 1, 2022

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

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No data is available for this block.

Masking Info

FG00040 subjects40 patients were allocated to receive active M1-rTMS.
FG00122 subjects22 patients were allocated to receive sham-rTMS.

Type of Units Analyzed

Arm/Group Information

ID	Title	Description
BG000	M1-rTMS Group	active M1-rTMS active M1-rTMS: Magnetic stimulation will be carried out using a MagPro X100 machine with a MCF-B70 figure-of-eight coil (Magventure, Farum). All rTMS sessions will be assisted by a neuronavigation system (TMS Navigator，Localite GmbH), maintaining the M1 target and the orientation of coil stable during stimulation sessions. The M1 target was defined as the "hand knob" region, which corresponds to the motor cortical representation of the hand, regardless of the location of pain. Stimulation paradigm consists of 20 trains of pulses with an intra-train frequency of 20 Hz, resulting in 2000 pulses for a total duration of 20 minutes. The stimulation intensity will be 80% of RMT, defined as the lowest stimulation intensity necessary to induce a visible muscle twitch of the hand contralateral to the stimulated hemisphere. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.
BG001	Sham-rTMS Group	sham rTMS sham rTMS: The sham protocol was similar to the rTMS protocol. Sham stimulations will be performed with a MCF-P-B65 figure-of-eight coil (Magventure) to M1, assisted by a neuronavigation system. The following stimulation parameters will be used: stimulus frequency 20 Hz; stimulus intensity 80 % of RMT; total stimulation pulses 2,000; total stimulation time 20 min. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG00040 BG00122 BG00262

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Day 8

Title	Measurements
	OG00012.41± 0.52(11.39 to 13.47) OG00113.64± 0.40(12.19 to 15.09)

1 month

Title	Measurements
	OG000

Primary

Change From Baseline Over 2 Months (Group by Time Interaction) in KING'S PD Pain Scale Domain 1

Posted

Mean

95% Confidence Interval

score on a scale

before the first rTMS session (day 1), after rTMS therapy (day8、1month、2months)

ID	Title	Description
OG000	M1-rTMS Group	active M1-rTMS: Magnetic stimulation will be carried out using a MagPro X100 machine with a MCF-B70 figure-of-eight coil (Magventure, Farum). All rTMS sessions will be assisted by a neuronavigation system (TMS Navigator，Localite GmbH), maintaining the M1 target and the orientation of coil stable during stimulation sessions. The M1 target was defined as the "hand knob" region, which corresponds to the motor cortical representation of the hand, regardless of the location of pain. Stimulation paradigm consists of 20 trains of pulses with an intra-train frequency of 20 Hz, resulting in 2000 pulses for a total duration of 20 minutes. The stimulation intensity will be 80% of RMT, defined as the lowest stimulation intensity necessary to induce a visible muscle twitch of the hand contralateral to the stimulated hemisphere. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.
OG001	Sham-rTMS Group

Primary

Change in 0-10 Numeric Rating Scale

Pain intensity was assessed over the past 24 hours using a 0-10 number, where 0 indicating no pain and 10 indicating maximal pain.

Posted

Mean

95% Confidence Interval

units on a scale

before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months)

ID	Title	Description
OG000	M1-rTMS Group	active M1-rTMS: Magnetic stimulation will be carried out using a MagPro X100 machine with a MCF-B70 figure-of-eight coil (Magventure, Farum). All rTMS sessions will be assisted by a neuronavigation system (TMS Navigator，Localite GmbH), maintaining the M1 target and the orientation of coil stable during stimulation sessions. The M1 target was defined as the "hand knob" region, which corresponds to the motor cortical representation of the hand, regardless of the location of pain. Stimulation paradigm consists of 20 trains of pulses with an intra-train frequency of 20 Hz, resulting in 2000 pulses for a total duration of 20 minutes. The stimulation intensity will be 80% of RMT, defined as the lowest stimulation intensity necessary to induce a visible muscle twitch of the hand contralateral to the stimulated hemisphere. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.
OG001	Sham-rTMS Group	sham rTMS: The sham protocol was similar to the rTMS protocol. Sham stimulations will be performed with a MCF-P-B65 figure-of-eight coil (Magventure) to M1, assisted by a neuronavigation system. The following stimulation parameters will be used: stimulus frequency 20 Hz; stimulus intensity 80 % of RMT; total stimulation pulses 2,000; total stimulation time 20 min. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.

Secondary

Changes in Resting-state EEG Oscillations

For each EEG epoch, we computed the fast Fourier transform (FFT) algorithm to convert to frequency domain. The power values in following five frequency bands were obtained: delta (1-4Hz), theta (4-8Hz), alpha(8-13Hz), beta(13-30Hz), gamma(30-80Hz).

55 patients participated in the EEG assessment before and after treatment. However, only 30 in M1-rTMS and 17 in sham-rTMS were retained for the final analysis, as 8 patients' EEG signals were faulty.

Posted

Median

Inter-Quartile Range

ratio

before the first rTMS session (day 1), after rTMS therapy (day8)

ID	Title	Description
OG000	M1-rTMS Group	active M1-rTMS: Magnetic stimulation will be carried out using a MagPro X100 machine with a MCF-B70 figure-of-eight coil (Magventure, Farum). All rTMS sessions will be assisted by a neuronavigation system (TMS Navigator，Localite GmbH), maintaining the M1 target and the orientation of coil stable during stimulation sessions. The M1 target was defined as the "hand knob" region, which corresponds to the motor cortical representation of the hand, regardless of the location of pain. Stimulation paradigm consists of 20 trains of pulses with an intra-train frequency of 20 Hz, resulting in 2000 pulses for a total duration of 20 minutes. The stimulation intensity will be 80% of RMT, defined as the lowest stimulation intensity necessary to induce a visible muscle twitch of the hand contralateral to the stimulated hemisphere. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.

Secondary

Changes in Movement Disorder Society-Unified PD Rating Scale Part I

The participants will be evaluated in their "ON" medication states. The scale was used to assess the impact of non-motor symptoms on daily life, ranging from 0 to 52, with higher scores indicating more severe symptoms.

Posted

Mean

95% Confidence Interval

score on a scale

before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months)

ID	Title	Description
OG000	M1-rTMS Group	active M1-rTMS: Magnetic stimulation will be carried out using a MagPro X100 machine with a MCF-B70 figure-of-eight coil (Magventure, Farum). All rTMS sessions will be assisted by a neuronavigation system (TMS Navigator，Localite GmbH), maintaining the M1 target and the orientation of coil stable during stimulation sessions. The M1 target was defined as the "hand knob" region, which corresponds to the motor cortical representation of the hand, regardless of the location of pain. Stimulation paradigm consists of 20 trains of pulses with an intra-train frequency of 20 Hz, resulting in 2000 pulses for a total duration of 20 minutes. The stimulation intensity will be 80% of RMT, defined as the lowest stimulation intensity necessary to induce a visible muscle twitch of the hand contralateral to the stimulated hemisphere. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.
OG001	Sham-rTMS Group	sham rTMS: The sham protocol was similar to the rTMS protocol. Sham stimulations will be performed with a MCF-P-B65 figure-of-eight coil (Magventure) to M1, assisted by a neuronavigation system. The following stimulation parameters will be used: stimulus frequency 20 Hz; stimulus intensity 80 % of RMT; total stimulation pulses 2,000; total stimulation time 20 min. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.

Secondary

Change in Movement Disorder Society-Unified PD Rating Scale Part II

The participants will be evaluated in their "ON" medication states. The scale was used to evaluate the patient's perspective on how motor symptoms impact their ability to perform daily activities, ranging from 0 to 52, with higher scores indicating more severe symptoms.

Posted

Mean

95% Confidence Interval

score on a scale

before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months)

ID	Title	Description
OG000	M1-rTMS Group	active M1-rTMS: Magnetic stimulation will be carried out using a MagPro X100 machine with a MCF-B70 figure-of-eight coil (Magventure, Farum). All rTMS sessions will be assisted by a neuronavigation system (TMS Navigator，Localite GmbH), maintaining the M1 target and the orientation of coil stable during stimulation sessions. The M1 target was defined as the "hand knob" region, which corresponds to the motor cortical representation of the hand, regardless of the location of pain. Stimulation paradigm consists of 20 trains of pulses with an intra-train frequency of 20 Hz, resulting in 2000 pulses for a total duration of 20 minutes. The stimulation intensity will be 80% of RMT, defined as the lowest stimulation intensity necessary to induce a visible muscle twitch of the hand contralateral to the stimulated hemisphere. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.
OG001	Sham-rTMS Group

Secondary

Change in Movement Disorder Society-Unified PD Rating Scale Part III

The participants will be evaluated in their "ON" medication states. The scale was used to provide a quantitative, objective measure of motor signs, ranging from 0 to 132, with higher scores indicating more severe symptoms.

Posted

Mean

95% Confidence Interval

score on a scale

before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months)

ID	Title	Description
OG000	M1-rTMS Group	active M1-rTMS: Magnetic stimulation will be carried out using a MagPro X100 machine with a MCF-B70 figure-of-eight coil (Magventure, Farum). All rTMS sessions will be assisted by a neuronavigation system (TMS Navigator，Localite GmbH), maintaining the M1 target and the orientation of coil stable during stimulation sessions. The M1 target was defined as the "hand knob" region, which corresponds to the motor cortical representation of the hand, regardless of the location of pain. Stimulation paradigm consists of 20 trains of pulses with an intra-train frequency of 20 Hz, resulting in 2000 pulses for a total duration of 20 minutes. The stimulation intensity will be 80% of RMT, defined as the lowest stimulation intensity necessary to induce a visible muscle twitch of the hand contralateral to the stimulated hemisphere. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.
OG001	Sham-rTMS Group	sham rTMS: The sham protocol was similar to the rTMS protocol. Sham stimulations will be performed with a MCF-P-B65 figure-of-eight coil (Magventure) to M1, assisted by a neuronavigation system. The following stimulation parameters will be used: stimulus frequency 20 Hz; stimulus intensity 80 % of RMT; total stimulation pulses 2,000; total stimulation time 20 min. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.

Secondary

Change in Movement Disorder Society-Unified PD Rating Scale Part IV

The participants will be evaluated in their "ON" medication states. The scale was used to document the presence and impact of motor fluctuations and dyskinesias, ranging from 0 to 24, with higher scores indicating more severe symptoms.

Posted

Mean

95% Confidence Interval

units on a scale

before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months)

ID	Title	Description
OG000	M1-rTMS Group	active M1-rTMS: Magnetic stimulation will be carried out using a MagPro X100 machine with a MCF-B70 figure-of-eight coil (Magventure, Farum). All rTMS sessions will be assisted by a neuronavigation system (TMS Navigator，Localite GmbH), maintaining the M1 target and the orientation of coil stable during stimulation sessions. The M1 target was defined as the "hand knob" region, which corresponds to the motor cortical representation of the hand, regardless of the location of pain. Stimulation paradigm consists of 20 trains of pulses with an intra-train frequency of 20 Hz, resulting in 2000 pulses for a total duration of 20 minutes. The stimulation intensity will be 80% of RMT, defined as the lowest stimulation intensity necessary to induce a visible muscle twitch of the hand contralateral to the stimulated hemisphere. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.
OG001	Sham-rTMS Group

Secondary

Changes in Hamilton Depression Scale

The depression score (ranging from 0 to 76 with higher scores indicating more severe depression) from the 24 items Hamilton Depression Scale (HAMD).

Posted

Mean

95% Confidence Interval

score on a scale

before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months)

ID	Title	Description
OG000	M1-rTMS Group	active M1-rTMS: Magnetic stimulation will be carried out using a MagPro X100 machine with a MCF-B70 figure-of-eight coil (Magventure, Farum). All rTMS sessions will be assisted by a neuronavigation system (TMS Navigator，Localite GmbH), maintaining the M1 target and the orientation of coil stable during stimulation sessions. The M1 target was defined as the "hand knob" region, which corresponds to the motor cortical representation of the hand, regardless of the location of pain. Stimulation paradigm consists of 20 trains of pulses with an intra-train frequency of 20 Hz, resulting in 2000 pulses for a total duration of 20 minutes. The stimulation intensity will be 80% of RMT, defined as the lowest stimulation intensity necessary to induce a visible muscle twitch of the hand contralateral to the stimulated hemisphere. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.
OG001	Sham-rTMS Group	sham rTMS: The sham protocol was similar to the rTMS protocol. Sham stimulations will be performed with a MCF-P-B65 figure-of-eight coil (Magventure) to M1, assisted by a neuronavigation system. The following stimulation parameters will be used: stimulus frequency 20 Hz; stimulus intensity 80 % of RMT; total stimulation pulses 2,000; total stimulation time 20 min. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.

Secondary

Changes in Hamilton Anxiety Scale

The anxiety score (ranging from 0 to 60 with higher scores indicating more severe anxiety) from the 14 items Hamilton Anxiety Scale (HAMA).

Posted

Mean

95% Confidence Interval

score on a scale

before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months)

ID	Title	Description
OG000	M1-rTMS Group	active M1-rTMS: Magnetic stimulation will be carried out using a MagPro X100 machine with a MCF-B70 figure-of-eight coil (Magventure, Farum). All rTMS sessions will be assisted by a neuronavigation system (TMS Navigator，Localite GmbH), maintaining the M1 target and the orientation of coil stable during stimulation sessions. The M1 target was defined as the "hand knob" region, which corresponds to the motor cortical representation of the hand, regardless of the location of pain. Stimulation paradigm consists of 20 trains of pulses with an intra-train frequency of 20 Hz, resulting in 2000 pulses for a total duration of 20 minutes. The stimulation intensity will be 80% of RMT, defined as the lowest stimulation intensity necessary to induce a visible muscle twitch of the hand contralateral to the stimulated hemisphere. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.
OG001	Sham-rTMS Group	sham rTMS: The sham protocol was similar to the rTMS protocol. Sham stimulations will be performed with a MCF-P-B65 figure-of-eight coil (Magventure) to M1, assisted by a neuronavigation system. The following stimulation parameters will be used: stimulus frequency 20 Hz; stimulus intensity 80 % of RMT; total stimulation pulses 2,000; total stimulation time 20 min. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.

Secondary

Changes in PD Sleep Scale-2

The sleep problem index (from 0 to 68 with higher scores indicating more severe sleep problem) from the PD Sleep Scale-2 (PDSS-2).

Posted

Mean

95% Confidence Interval

score on a scale

before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months)

ID	Title	Description
OG000	M1-rTMS Group	active M1-rTMS: Magnetic stimulation will be carried out using a MagPro X100 machine with a MCF-B70 figure-of-eight coil (Magventure, Farum). All rTMS sessions will be assisted by a neuronavigation system (TMS Navigator，Localite GmbH), maintaining the M1 target and the orientation of coil stable during stimulation sessions. The M1 target was defined as the "hand knob" region, which corresponds to the motor cortical representation of the hand, regardless of the location of pain. Stimulation paradigm consists of 20 trains of pulses with an intra-train frequency of 20 Hz, resulting in 2000 pulses for a total duration of 20 minutes. The stimulation intensity will be 80% of RMT, defined as the lowest stimulation intensity necessary to induce a visible muscle twitch of the hand contralateral to the stimulated hemisphere. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.
OG001	Sham-rTMS Group	sham rTMS: The sham protocol was similar to the rTMS protocol. Sham stimulations will be performed with a MCF-P-B65 figure-of-eight coil (Magventure) to M1, assisted by a neuronavigation system. The following stimulation parameters will be used: stimulus frequency 20 Hz; stimulus intensity 80 % of RMT; total stimulation pulses 2,000; total stimulation time 20 min. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.

Secondary

Changes in Epworth Sleeping Scale

The daytime sleepiness was assessed by the Epworth Sleeping Scale, which has a score range of 0-24, with higher scores indicating more severe symptoms.

Posted

Mean

95% Confidence Interval

score on a scale

before the first rTMS session (day 1), after rTMS therapy at day8、1month、2months

ID	Title	Description
OG000	M1-rTMS Group	active M1-rTMS: Magnetic stimulation will be carried out using a MagPro X100 machine with a MCF-B70 figure-of-eight coil (Magventure, Farum). All rTMS sessions will be assisted by a neuronavigation system (TMS Navigator，Localite GmbH), maintaining the M1 target and the orientation of coil stable during stimulation sessions. The M1 target was defined as the "hand knob" region, which corresponds to the motor cortical representation of the hand, regardless of the location of pain. Stimulation paradigm consists of 20 trains of pulses with an intra-train frequency of 20 Hz, resulting in 2000 pulses for a total duration of 20 minutes. The stimulation intensity will be 80% of RMT, defined as the lowest stimulation intensity necessary to induce a visible muscle twitch of the hand contralateral to the stimulated hemisphere. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.
OG001	Sham-rTMS Group	sham rTMS: The sham protocol was similar to the rTMS protocol. Sham stimulations will be performed with a MCF-P-B65 figure-of-eight coil (Magventure) to M1, assisted by a neuronavigation system. The following stimulation parameters will be used: stimulus frequency 20 Hz; stimulus intensity 80 % of RMT; total stimulation pulses 2,000; total stimulation time 20 min. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.

Secondary

Changes in PD for Autonomic Symptoms

The Scale for Outcomes in Parkinson's disease for Autonomic Symptoms (SCOUP-AUT), which has a score range of 0-67, with higher scores indicating higher autonomic nervous system dysfunction.

Posted

Mean

95% Confidence Interval

score on a scale

before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months)

ID	Title	Description
OG000	M1-rTMS Group	active M1-rTMS: Magnetic stimulation will be carried out using a MagPro X100 machine with a MCF-B70 figure-of-eight coil (Magventure, Farum). All rTMS sessions will be assisted by a neuronavigation system (TMS Navigator，Localite GmbH), maintaining the M1 target and the orientation of coil stable during stimulation sessions. The M1 target was defined as the "hand knob" region, which corresponds to the motor cortical representation of the hand, regardless of the location of pain. Stimulation paradigm consists of 20 trains of pulses with an intra-train frequency of 20 Hz, resulting in 2000 pulses for a total duration of 20 minutes. The stimulation intensity will be 80% of RMT, defined as the lowest stimulation intensity necessary to induce a visible muscle twitch of the hand contralateral to the stimulated hemisphere. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.
OG001	Sham-rTMS Group	sham rTMS: The sham protocol was similar to the rTMS protocol. Sham stimulations will be performed with a MCF-P-B65 figure-of-eight coil (Magventure) to M1, assisted by a neuronavigation system. The following stimulation parameters will be used: stimulus frequency 20 Hz; stimulus intensity 80 % of RMT; total stimulation pulses 2,000; total stimulation time 20 min. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.

Secondary

Changes in PD Questionnaire-39

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.

Posted

Mean

95% Confidence Interval

score on a scale

before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months)

ID	Title	Description
OG000	M1-rTMS Group	active M1-rTMS: Magnetic stimulation will be carried out using a MagPro X100 machine with a MCF-B70 figure-of-eight coil (Magventure, Farum). All rTMS sessions will be assisted by a neuronavigation system (TMS Navigator，Localite GmbH), maintaining the M1 target and the orientation of coil stable during stimulation sessions. The M1 target was defined as the "hand knob" region, which corresponds to the motor cortical representation of the hand, regardless of the location of pain. Stimulation paradigm consists of 20 trains of pulses with an intra-train frequency of 20 Hz, resulting in 2000 pulses for a total duration of 20 minutes. The stimulation intensity will be 80% of RMT, defined as the lowest stimulation intensity necessary to induce a visible muscle twitch of the hand contralateral to the stimulated hemisphere. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.
OG001	Sham-rTMS Group	sham rTMS: The sham protocol was similar to the rTMS protocol. Sham stimulations will be performed with a MCF-P-B65 figure-of-eight coil (Magventure) to M1, assisted by a neuronavigation system. The following stimulation parameters will be used: stimulus frequency 20 Hz; stimulus intensity 80 % of RMT; total stimulation pulses 2,000; total stimulation time 20 min. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	M1-rTMS Group	active M1-rTMS: Magnetic stimulation will be carried out using a MagPro X100 machine with a MCF-B70 figure-of-eight coil (Magventure, Farum). All rTMS sessions will be assisted by a neuronavigation system (TMS Navigator，Localite GmbH), maintaining the M1 target and the orientation of coil stable during stimulation sessions. The M1 target was defined as the "hand knob" region, which corresponds to the motor cortical representation of the hand, regardless of the location of pain. Stimulation paradigm consists of 20 trains of pulses with an intra-train frequency of 20 Hz, resulting in 2000 pulses for a total duration of 20 minutes. The stimulation intensity will be 80% of RMT, defined as the lowest stimulation intensity necessary to induce a visible muscle twitch of the hand contralateral to the stimulated hemisphere. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.	0	40	0	40	15	40
EG001	Sham-rTMS Group	sham rTMS: The sham protocol was similar to the rTMS protocol. Sham stimulations will be performed with a MCF-P-B65 figure-of-eight coil (Magventure) to M1, assisted by a neuronavigation system. The following stimulation parameters will be used: stimulus frequency 20 Hz; stimulus intensity 80 % of RMT; total stimulation pulses 2,000; total stimulation time 20 min. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.	0	22	0	22	9	22

Other Adverse Events

Term	Organ System	Assessment Type	Notes	Statistical Information
dizziness	Nervous system disorders	Systematic Assessment	lasting 5-10 minutes	EG0006 events6 affected40 at risk EG0014 events4 affected22 at risk
headaches	Nervous system disorders	Systematic Assessment	persisting for approximately 1h, predominantly at the stimulation site	EG0006 events6 affected40 at risk EG0013 events3 affected22 at risk
tinnitus	Ear and labyrinth disorders	Systematic Assessment	lasting 15-30 minutes	EG0002 events2 affected40 at risk EG0011 events1 affected22 at risk
transient aggravation of tremor	Nervous system disorders	Systematic Assessment		EG0001 events1 affected40 at risk EG0011 events1 affected22 at risk

ID	Term
D010300	Parkinson Disease
D059352	Musculoskeletal Pain

Ancestor Terms

ID	Term
D020734	Parkinsonian Disorders
D001480	Basal Ganglia Diseases
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D009069	Movement Disorders
D000080874	Synucleinopathies
D019636	Neurodegenerative Diseases
D009135	Muscular Diseases
D009140	Musculoskeletal Diseases
D010146	Pain
D009461	Neurologic Manifestations
D012816	Signs and Symptoms
D013568	Pathological Conditions, Signs and Symptoms

OG00114.71± 0.97(13.20 to 16.21)

sham rTMS: The sham protocol was similar to the rTMS protocol. Sham stimulations will be performed with a MCF-P-B65 figure-of-eight coil (Magventure) to M1, assisted by a neuronavigation system.

The following stimulation parameters will be used: stimulus frequency 20 Hz; stimulus intensity 80 % of RMT; total stimulation pulses 2,000; total stimulation time 20 min.

Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.

sham rTMS: The sham protocol was similar to the rTMS protocol. Sham stimulations will be performed with a MCF-P-B65 figure-of-eight coil (Magventure) to M1, assisted by a neuronavigation system.

The following stimulation parameters will be used: stimulus frequency 20 Hz; stimulus intensity 80 % of RMT; total stimulation pulses 2,000; total stimulation time 20 min.

Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.