Effects of Combined rTMS and Treadmill Training in People With Parkinson's Disease

Repetitive Transcranial Magnetic Stimulation Promotes Gait Training in People With Parkinson's Disease - a Randomised Controlled Trial

The purpose of this study is to investigate whether the beneficial effect of treadmill training on people with Parkinson's disease can be enhanced by high- and low-frequency repetitive transcranial magnetic stimulation (rTMS).

Study Overview

• Status: Completed
• Conditions: Parkinson's Disease
• Intervention / Treatment: Device: Repetitive transcranial magnetic stimulation (rTMS); Other: Treadmill training

Detailed Description

This is a randomised placebo-controlled trial. Fifty-one participants with Parkinson's disease (PD) will be recruited from the Hong Kong PD association, a self-help group and movement disorders clinic of 3 local hospitals. Written informed consent in accordance with the Declaration of Helsinki will be obtained from all participants. Eligible participants will be randomly assigned into one of the three groups: 1Hz-TT, 25Hz-TT, and sham-TT upon recruitment. Randomisation will be generated by a computer program and group assignment will be blinded to both participants and assessor. Participant will receive either 1-Hz, 25-Hz, or sham rTMS which will last for about 20 minutes followed by 30 minutes treadmill walking training for 12 sessions, 4 times per week for 3 weeks. All assessments will be conducted 1 week before intervention and 1 day after completion of intervention, after 1-month training and at 3-month post training.

The sample size calculation is based on the significant findings of the gait speed reported by Yang et al (2013). A two-way repeated measures ANOVA design with between-subject group effect (3 levels) and within-subject time effect (4 levels) determines that 15 subjects per group are required to achieve 85% power to test the interaction effect between groups and time effect with a 5% significance level and the effect size is 0.2. By assuming 10% dropout rate, 17 subjects will be required per group.

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong, 852
    • Rehabilitation Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosed with idiopathic Parkinson's disease by a neurologist
• had been stable on anti-Parkinsonian medication
• able to walk independently for 30 meters

Exclusion Criteria:

• severe co-morbidity that may interfere with their ability to participate including significant orthopaedic or rheumatological conditions or disorders of peripheral nervous systems that may interfere with mobility or balance performance
• a diagnosis of neurological disease other than PD
• a history of psychiatric disorders
• the impossibility of inducing motor evoked potentials (MEPs)
• a score of less than 24 on the Mini-Mental State Examination
• contraindication to TMS including personal or family history of seizure disorder, metal in the head, implants of medical devices such as cardiac pacemakers or medical pumps, females subjects who are pregnant, a history of neurosurgery
• subjects with irrepressible tremor and / or dyskinesia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 25Hz-TT; Participants will receive 4s train of 25-Hz rTMS pulses with 50s inter-train interval, with an intensity of 80% resting motor threshold (RMT). Participant will receive a total of 600 rTMS pulses in 6 minutes for each hemisphere and a total of 1200 pulses followed by 30 minutes of treadmill training.	Device: Repetitive transcranial magnetic stimulation (rTMS); Repetitive TMS (rTMS) is a painless and non-invasive technique for activation of cerebral cortex based on the principle of electromagnetic induction of an electric field in the brain. rTMS will be delivered to the scalp over the leg area of the bilateral motor cortex by using a Magstim Rapid magnetic stimulator. (Magstim Company, Whitland, UK) and 90 mm double cone coil.; Other: Treadmill training; Participants will proceed to 30 minute of treadmill training after rTMS. A safety harness without body weight support will be provided. 80% of participant's over ground maximum walking speed will be halved and used for warm-up. After warming up, walking speed will be increased by 0.2 km/h every 5 minutes. Progression will be given if patients could tolerate the belt speed with appropriate step length and walk with good stability for 5 minutes. Participants will maintain the maximum speed achieved for the rest of the session or adjusted as needed. Positive verbal feedback will be given to encourage large strides and upright posture during training. The participants will be instructed to walk on treadmill without holding onto the handrails if possible. Participants will perform warm up and cool down exercise to minimize training related-injury.
Experimental: 1Hz-TT; Participants will receive a total of 600 1-Hz rTMS pulses in 10 minutes for each hemisphere and a total of 1200 pulses ,with an intensity of 80% RMT, followed by 30 minutes of treadmill training.	Device: Repetitive transcranial magnetic stimulation (rTMS); Repetitive TMS (rTMS) is a painless and non-invasive technique for activation of cerebral cortex based on the principle of electromagnetic induction of an electric field in the brain. rTMS will be delivered to the scalp over the leg area of the bilateral motor cortex by using a Magstim Rapid magnetic stimulator. (Magstim Company, Whitland, UK) and 90 mm double cone coil.; Other: Treadmill training; Participants will proceed to 30 minute of treadmill training after rTMS. A safety harness without body weight support will be provided. 80% of participant's over ground maximum walking speed will be halved and used for warm-up. After warming up, walking speed will be increased by 0.2 km/h every 5 minutes. Progression will be given if patients could tolerate the belt speed with appropriate step length and walk with good stability for 5 minutes. Participants will maintain the maximum speed achieved for the rest of the session or adjusted as needed. Positive verbal feedback will be given to encourage large strides and upright posture during training. The participants will be instructed to walk on treadmill without holding onto the handrails if possible. Participants will perform warm up and cool down exercise to minimize training related-injury.
Sham Comparator: Sham-TT; Sham rTMS will be applied over the same site as for real rTMS, however, with the cable of the coil disconnected. Another figure-of-eight coil using the same stimulation parameters (intensity, time, and frequency) as per 25Hz-TT group will be placed posterior to the subject's neck with the handle pointing backward to produce the same clicking sound effect. Sham rTMS will be followed by 30 minutes of treadmill training.	Device: Repetitive transcranial magnetic stimulation (rTMS); Repetitive TMS (rTMS) is a painless and non-invasive technique for activation of cerebral cortex based on the principle of electromagnetic induction of an electric field in the brain. rTMS will be delivered to the scalp over the leg area of the bilateral motor cortex by using a Magstim Rapid magnetic stimulator. (Magstim Company, Whitland, UK) and 90 mm double cone coil.; Other: Treadmill training; Participants will proceed to 30 minute of treadmill training after rTMS. A safety harness without body weight support will be provided. 80% of participant's over ground maximum walking speed will be halved and used for warm-up. After warming up, walking speed will be increased by 0.2 km/h every 5 minutes. Progression will be given if patients could tolerate the belt speed with appropriate step length and walk with good stability for 5 minutes. Participants will maintain the maximum speed achieved for the rest of the session or adjusted as needed. Positive verbal feedback will be given to encourage large strides and upright posture during training. The participants will be instructed to walk on treadmill without holding onto the handrails if possible. Participants will perform warm up and cool down exercise to minimize training related-injury.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fastest Walking Speed	Each participant is instructed to walk for 14 meters at their fastest walking speed for three trials. The time taken for the middle 10 meter was recorded. The average of three trials is used for analysis.	Baseline, 1 day post-intervention, 1 month post-intervention, 3 month post-intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Timed-Up-and-Go Test (iTUG)	Participants are instructed to stand up from a chair and walk for 7 meters walkway and return back to the chair turn around and sit down. Time and gait parameters during TUG were captured by the valid and reliable APDM system, which is a wearable gait and balance analysis system.	Baseline, 1 day post-intervention, 1 month post-intervention and 3 months post-intervention
the Motor Section of Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS III)	MDS-UPDRS III is a valid and reliable clinical test, will be used to evaluate severity of motor symptoms of PD. There are total of 27 items including tremor, rigidity, bradykinesia, postural instability and gait performance. Each item scores from 0-4, with 0 indicates no disability and 4 maximum disabled with total score(s) ranges from 0 to 132.	Baseline, I day post-intervention, 1 month post-intervention and 3 months post-intervention
Walking Distance in a 2 -Minute Walk Test	The 2 minute walk test will be conducted along a 20 m x 2 m hallway. A line is marked at each end of the walkway to indicate where the person is to turn. Participants will be instructed to " walk as far as possible in 2 minutes". They will be given standardised encouragement at 60 and 90 seconds during walk. Distance walked will be recorded to the nearest meter.	Baseline, 1 day post-intervention, 1 month post-intervention and 3 months post-intervention
Mini Balance Evaluation Systems Test Scores	Balance performance of participants will be assessed in 4 domains namely anticipatory postural adjustments, postural responses, sensory orientation and gait stability. Each item is rated from 0-2 with a total scores of 28. The Total scores range from 0-28, with higher scores indicate better dynamic balance.	Baseline, 1 day post-intervention, 1 month post-intervention and 3 months post-intervention
Dual-task Timed-Up-and-Go Test (DT-TUG)	For DT-TUG, participants were instructured to repeat the TUG procedure while performing a serial three substraction. Time taken to complete DT-TUG and accuracy of digital counting was recorded. One practice trial was given prior to both TUG and DT-TUG testing and average performance of three trials was used for analysis.	Baseline, 1 day post-intervention, 1 month post-intervention, 3 month-post intervention

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cortical Silent Period	Ten suprathreshold TMS stimuli (i.e. 130% RMT) will be delivered while participant performing a 20% isometric maximal contraction of Tibialis Anterior of the more affected side. Cortical silent period (CSP) measures the duration of interruption of electromyography (EMG) activity in the contracting muscle produced by TMS. CSP duration will be determined as the period between the onset of MEP and the return of baseline EMG activity measured 50 ms before the TMS stimulus.	Baseline, 1 day post-intervention, 1 month post-intervention and 3 months post-intervention
Gradient of the Recruitment Curve ( Also Known as Stimulus-response Curve)	TMS stimuli will be applied at 10% steps between 100% to 160% RMT. 10 stimuli will be delivered at each intensity. Peak to peak amplitude of 10 motor-evoked potentials (MEPs) at each stimulus intensity will be averaged offline.The cut-off intensity is set at 75% of maximum stimulator output due to discomfort perceived by majority of the participants. MEPs will be normalised with the maximal muscle action potential (MMax), which is determined by supramaximal electrical stimulation of the fibular nerve. A scatter graph will be generated with the average amplitude of MEPs as a function of stimulation intensity. The linear trend will be added to generate the linear recruitment curve slope.	Baseline, 1 day post-intervention, 1 month post-intervention and 3 months post-intervention
Short-interval-intracortical Inhibition	Short-interval-intracortical inhibition (SICI) is another measure of cortical inhibition. In a paired- pulse TMS paradigm, a test pulse will be adjusted to produce MEP of at least 0.5 millivolts which will be delivered preceded by a brief conditioned pulse set at a lower intensity of 80% RMT with inter-stimulus interval of 2 milliseconds. Two stimulators connected via a Bistim module ( Magstim Co.,Whitland, UK) will be used in this test. Ten conditioned MEPs and unconditioned MEPs will be obtained in a random order and were averaged for each condition. SICI is expressed as percentage of unconditioned test MEP amplitude.	Baseline, 1 day post-intervention, 1 month post-intervention and 3 months post-intervention

Collaborators and Investigators

• Sponsor: The Hong Kong Polytechnic University
• Investigators: Principal Investigator: Margaret Mak, PhD, The Hong Kong Polytechnic University

Publications and helpful links

General Publications

• Yang YR, Tseng CY, Chiou SY, Liao KK, Cheng SJ, Lai KL, Wang RY. Combination of rTMS and treadmill training modulates corticomotor inhibition and improves walking in Parkinson disease: a randomized trial. Neurorehabil Neural Repair. 2013 Jan;27(1):79-86. doi: 10.1177/1545968312451915. Epub 2012 Jul 10.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2016
• Primary Completion (Actual): December 1, 2018
• Study Completion (Actual): May 1, 2019

Study Registration Dates

• First Submitted: January 19, 2016
• First Submitted That Met QC Criteria: March 2, 2016
• First Posted (Estimate): March 8, 2016

Study Record Updates

• Last Update Posted (Actual): November 22, 2019
• Last Update Submitted That Met QC Criteria: November 20, 2019
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: Transcranial Magnetic Stimulation; gait training; metaplasticity
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease
• Other Study ID Numbers: HSEARS20140423002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be shared with researcher who provide a methodologically sound proposal
• IPD Sharing Time Frame: Beginning 3 months and ending 3 years following article publication
• IPD Sharing Access Criteria: request through email
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF