Repetitive Transcranial Magnetic Stimulation Promotes Gait Training in People With Parkinson's Disease - a Randomised Controlled Trial
Phase: NA
Conditions: Parkinson's Disease
Sponsor: The Hong Kong Polytechnic University

Project title:  
Effects of combined repetitive transcranial magnetic stimulation and treadmill training on 
gait performance in Parkinson’s disease – a randomised controlled trial    
 
NCT no: NCT02701647 
 
Date of document: 22 Dec 2015  
 
  
 

 
 
1. 
Project Title: 
 
Effects of combined repetitive transcranial magnetic stimulation and treadmill training on gait 
performance in Parkinson’s disease – a randomised controlled trial     
 
2. 
Project Objectives:   
 
There are three objectives in this research study: 
1. To compare short- and long-term effects of 25Hz repetitive transcranial magnetic stimulation 
(rTMS) with 1Hz rTMS followed by treadmill training on their gait performance during single task 
and dual task conditions in people with Parkinson’s disease (PD) 
2. To compare short- and long-term effects of 1Hz with 25Hz rTMS followed by treadmill training 
on corticomotor excitation and  intracortical inhibition in people with  PD.  
3. To explore whether combined rTMS and treadmill training can be transferred to enhancement of 
balance performance in people with PD 
 
3. 
Scope and Background of Research: 
 
Parkinson’s disease (PD) is a complex neurodegenerative disorder.  The cardinal motor symptoms 
of PD are resting tremor, bradykinesia, rigidity and postural instability, which cause disrupted control 
of body movement in people with PD. There are many concomitant non-motor symptoms, including 
cognitive decline affecting dual tasking ability and executive functioning. The pathophysiology of PD 
is related to the loss of dopamine producing neurons in the substantial nigra leading to depletion of 
dopamine supplying the basal ganglia. The basal ganglia consist of caudate, putamen, globus 
pallidus, subthalamic nucleus, and substantia nigra.  Voluntary movement is initiated from cerebral 
cortex and regulated by complex feedback loops that involve the cortex, thalamus, basal ganglia 
and cerebellum. Dopamine has an important role in facilitating the motor outputs in this feedback 
loop. In addition, the internal globus pallidus, the output nucleus of basal ganglia, sends phasic cues 
to the supplementary motor area to regulate movement size and hence allows well-learnt movement 
to be performed without constant conscious attention (1).  A loss of dopamine inhibits output from 
the thalamus to the cerebral cortex, leading to various motor manifestations including resting tremor, 
bradykinesia and rigidity. The defective facilitation from the basal ganglia to the motor cortices also 
affects the automaticity of movement control in a well-learnt movement sequence such as walking. 
Indeed, gait difficulty was reported to be one of the most debilitating symptoms for people with PD 
and to be able to walk effectively and safely has significant impact on their quality of life (2).   The 
most typical gait disorders in PD are hypokinetic gait pattern characterized by slow walking speed 
and short stride length. It can be accompanied by increased stride time variability associating with 
reduced gait stability. Apart from this continuous form of gait difficulty, PD patients may also 
experience some episodic gait disorders such as freezing of gait and gait festination (3). Secondary 

to the effects of reduced automaticity in movement control in PD, performing an additional task while 
walking can be very challenging for PwPD. Dual tasking during walking provokes freezing of gait in 
some cases.  
 
In terms of neurophysiology study on the central nervous system in PD, transcranial magnetic 
stimulation (TMS) has been used extensively in the recent decade to assess the cortical excitability 
and that of the corticospinal motor system via non-invasive magnetic stimulation applied to the motor 
cortex. Consistent findings have been reported for cortical excitability studies in PD (4-8). Cortical 
silent period was found to be significantly shorter and short interval intracortical inhibition was also 
found to be smaller in PD (5). Besides, decreased motor threshold and increased motor evoke 
potential at rest was reported in PD (6). These changes in the cortical excitability appears to be 
related to the pathophysiology of PD since levodopa can restore both cortical silent period and short 
interval intracortical inhibition (8). 
 
Repetitive transcranial magnetic stimulation (rTMS) refers to the regular repeated stimuli of single 
pulse TMS delivered in trains. Cortical excitability can be enhanced by high frequency rTMS (with 
rate more than 1 Hz) (9) whereas low frequency rTMS (with rate of less than 1Hz) induces 
depression of cortical activity (10). These changes in cortical excitability are transient, lasting for 
about 10-30 minutes (11, 12).  rTMS has been used to modulate the cortical excitability in PD with 
therapeutic effect (8). Regarding rTMS simulation parameters, recent meta-analysis reviewed that 
high frequency rTMS was effective in enhancing motor symptoms of PD and low frequency has little 
effect on motor function (13, 14). Moreover, stimulation of cortical motor areas was also found to 
increase the duration of cortical silent period in PD patients (8, 15, and 16). In terms of dosage, 
when using high frequency rTMS in PD a single session of rTMS found to reduce PD disease 
severity measured by Unified PD rating scale (UPDRS). More lasting effects (up to 10 days to 1 
month post-treatment) was demonstrated with multiple rTMS sessions ranging from daily treatment 
for 6-10 days and 8 sessions over 2.5 weeks (17,18,19). Regarding the stimulation frequency, Khedr 
et al. (17) compared the effects of 25Hz rTMS and 10Hz rTMS in 55 PD subjects with off levodopa 
for at least 1 week. They found that there were cumulative and long lasting improvements in UPDRS 
motor scores, walking time as well as keyboard tapping time in both 25Hz and 10Hz subject groups 
(17).  However, PD subjects received 25Hz seemed to have greater improvement as well as faster 
improvement compared with 10Hz. Lomarev and colleagues (19) also demonstrated very similar 
results in their study using the same TMS parameters (25Hz, 100% RMT) associated with an 
increased in walking speed and amplitude of the motor evoked potential. These findings suggest 
that 25 Hz rTMS simulation could be effective in enhancing motor performance and cortical 
modulation in PD patients. 
 
In addition, high frequency rTMS was found to enhance motor learning (20). Long lasting motor 
learning is achieved by long-term potentiation and long-term depression, which involve synaptic 
plastic changes related to the new learnt task (21). The transient raised excitability of the motor 
cortex through high frequency rTMS is proposed to facilitate this motor learning process (20). Other 

than this, the principal of activity dependent neuroplasticity suggests that motor learning has  to be 
task specific (22). Therefore, application of rTMS before specific motor training may boost up the 
training effect.  Yang et al (23) recently demonstrated that 12 sessions over 4 weeks of 5Hz rTMS 
and treadmill training compared with treadmill alone led to better improvement of walking and 
functional mobility performance accompanied with some positive changes in intracortical inhibition. 
This modulation of intracortical inhibition has also been shown after high intensity treadmill training 
(24).  These findings are very intriguing but further randomised control trials with more sample sizes 
are warranted to minimise bias. In addition, it is uncertain if the rTMS stimulation protocol used in 
Yang et al study is optimal. The carry over effect has also not been examined.   
 
Therefore, this research projects aim to determine a rTMS stimulation protocol that would optimise 
the beneficial effect of treadmill training in PD by comparing the 2 different stimulation frequency 
protocols i.e. 1Hz and 25 Hz. In addition, rTMS has been found to restore the intracortical inhibition 
in PD (23). The restoration of the cortical inhibition through rTMS may have therapeutic effect on 
the defective cortical-basal ganglia-cortical network in PD (8).  The inhibitory signals are essential 
for optimal execution of motor program by inhibiting other inappropriate and competing circuits. As 
discussed earlier, the basal ganglia allow well-learnt movement such as walking to be performed 
with less attention resources. Hence, it would be interesting to investigate if rTMS would enhance 
the automaticity of walking and thus better dual-task walking performance.  
 
Last but not least, it will be interesting to investigate whether combined rTMS and treadmill training 
can be transferred to enhancement of balance performance in PD as treadmill training has been 
found to reduce fall rate in PD (33). 
 
4. 
Research Methodology: 
 
Study Design:  A double-blinded randomised controlled trial  
 
Participants  
This study is divided into three parts. Ten healthy participants will be recruited for study part I; 5 
healthy participants and 5 participants with PD will be recruited for study part II; the following 
inclusion criteria for study part I & II: 1) Aged 18 and above for healthy participant and aged 40 -70 
above for PD. The exclusion criteria are as follow: 1) severe comorbidity that may interfere with their 
ability to participate in the study (e.g. chronic obstructive airway disease, angina, congestive cardiac 
failure, and significant renal or liver disease, malignancy) 2) significant orthopaedic or 
rheumatological conditions or disorders of peripheral nervous system that may interfere with tested 
ankle and foot strength and mobility 3) Female subjects who are pregnant 4) a score of less than 23 
on the Mini-Mental State Examination 5) any auditory or visual impairment 6) History of neurosurgery 
7) 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 (Appendix 1). Informed 
consent in accordance with the Declaration of Helsinki will be obtained from all participants and data 

collection will only be carried out after the approval of Hong Kong Polytechnic University Ethics 
Committee.  
 
Fifty-one participants with PD will be recruited with the following inclusion criteria for study part III: 
1) Aged 40 to 70, 2) Diagnosed with idiopathic Parkinson’s disease by a neurologist 3) Hoehn & 
Yahr Scale Stage II to III with stable medications usage 4) ability to walk independently with or 
without walking aids for 10 metres. The exclusion criteria are as  follow: 1) severe comorbidity that 
may interfere with their ability to participate in the study (e.g. chronic obstructive airway disease, 
angina, congestive cardiac failure, and significant renal or liver disease, malignancy) 2) significant 
orthopaedic or rheumatological conditions or disorders of peripheral nervous system that may 
interfere with mobility or balance performance 3) Female subjects who are pregnant 4) Neurological 
disease other than PD 5) a score of less than 23 on the Mini-Mental State Examination 6) any 
auditory or visual impairment 7) History of neurosurgery 8) 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 (Appendix 1). 9) Subjects with irrepressible tremor 
and/dyskinesia. Informed consent in accordance with the Declaration of Helsinki will be obtained 
from all participants and data collection will only be carried out after the approval of Hong Kong 
Polytechnic University Ethics Committee. 
 
The sample size calculation is based the significant findings of the gait speed and cortical silent 
period reported by Yang et al. (23).  A two-way repeated measures ANOVA design with between-
subject group effect (3 levels) and within-subject time effect (4 levels) determines that fifteen 
subjects per group are required to achieve 85% power to test the interaction effect between group 
and time effect with a 5% significance level and the effect size is 0.4.  By assuming 10% dropout 
rate, 17 subjects will be required per group. 
 
 
Experimental protocol  
Part I & II. Mapping study and reliability study  
Measures of cortical excitability including resting motor threshold (RMT) and recruitment curves will 
be obtained with transracial magnetic stimulation (TMS) for 10 healthy subjects for study part I to 
identify the optimal site for TMS stimulation of the tibialis anterior (TA) muscles.  
 
Magstim_200 magnetic stimulator (Magstim Company, Whitland, UK) and 90-mm double cone coil 
will be used to deliver TMS in this study. Each participant will be seated comfortably in a recumbent 
chair with arm and head supported by pillow. Small surface electromyography EMG electrodes will 
be attached to the belly of the TA with a ground electrode placed on the ankle. The motor evoked 
potential (MEP) in the TA will be recorded with surface EMG, which will be amplified with the band 
pass filtered between 10 and 1000Hz(Viking II Electromyography). All EMG traces will be stored for 
offline analysis.  
Skin preparation using “3M One Step” skin prep abrasive sandpaper to reduce skin impedance will 

be performed prior to the placement of the surface electrodes as well as the ground electrodes. 
 
Resting Motor Threshold  
Resting motor threshold of each participant will be determined with the following procedure: A latex 
swim cap will be placed on each participant’s head and measurement of the vertex (Cz) will be 
marked on the cap. Subjects will be instructed to relax but to keep their eyes open during the whole 
procedure. 
 
The coil is held centred over Cz, with a common longitudinal part of the coil along the 
interhemispheric fissure. Single TMS pulse will be delivered over the scalp overlying contralateral 
primary motor cortex that controls the TA. The MEPs of the bilateral tibialis anterior muscles will be 
recorded in response to TMS delivered with different coil orientation and location to determine the 
best coil orientation and hot spot. The site that evokes the largest and most consistent MEP 
amplitudes will be considered as the motor hot spot. The best coil orientation that evokes the largest 
and most consistent amplitudes will be adopted for subsequent TMS procedure of this study. This 
location with reference to Cz will be marked on the swim cap fitted for each subject.  With the 
stimulus coil placed over the hot spot, stimulus intensity will be lowered gradually in a step-wise 
manner to determine the resting motor threshold (RMT). RMT is defined by minimal intensity that 
produces a MEP of a minimum of 50μV in 5 out of 10 consecutive trials.  
 
Cortical silent period 
Cortical silent period (CSP) is defined as an interruption of electromyographic (EMG) activity in the 
corresponding contracting muscle during a TMS (26). Subject will be asked to perform a 20% 
isometric maximal contraction of the TA by flexing the ankle against a belt strapped around foot. 
The EMG activity of the muscle will be reflected on a computer screen and visible to the subject. 
The subject will be asked to maintain this constant force while TMS is applied. TMS intensity at 
130% of RMT will be delivered during the isometric of TA. Ten CSP measurements will be obtained 
within a single session. The duration of CSP will be measured from the end of the MEP to the point 
when the EMG level returns to the baseline value measured 50ms before the TMS stimulus (26, 27). 
Each CSP duration will be analysed and the mean value of 10 CSP duration will be used for further 
analysis. The duration of the cortical silent period (CSP) was used to examine the intracortical 
inhibitory mechanisms, possibly via a GABA-B mediated circuit (34).   
 
Recruitment curve  
Recruitment curve (RC) is also known as stimulus-response curve, illustrate the change in MEP size 
as a function of stimulus intensity. Recruitment curves of increasing intensities of 10% steps will be 
obtained in ten trials per step starting at 10% below RMT and increasing up to 180% of the RMT. 
MEP amplitudes are measured peak-to-peak and averaged off line. TA MEPs were expressed as a 
percentage of the TA maximum motor response (M-max).  Typically TA Max is acquired by 
stimulating the common peroneal nerve with supramaximal stimuli by bipolar surface electrodes 
placed distal to the neck of the fibular.  

 
Intracortical inhibition  
A paired conditioning-test stimulus technique will be used to measure SICI in the TA muscle 
according to Kujirai’s procedure (35). A test TMS of 120% RMT pulse will be delivered preceded by 
a brief conditioned pulse set at a lower intensity of 80% of the RMT with inter-stimulus interval of 
2ms. For each condition, 10n trials were collected and averaged. 
 
Measures of cortical excitability including resting motor threshold (RMT), recruitment curves, 
intracortical inhibition (SICI) will be obtained with transracial magnetic stimulation (TMS) for intra-
rater and test-retest reliability of all these measures will be established for Study Part II.  TMS 
assessment will be repeated twice, at least 1.5 hour apart within the same session for each study 
participant to assess the intra-rater reliability.  Study participants will be asked to returned 1 week 
after for TMS assessment to assess the test-retest reliability.  
 
Part III. Interventions  
All assessment and treatment will be carried out at the electrophysiology and Gait and balance 
laboratory. Participants will be randomised into three groups i.e. two experimental groups and a 
sham group. Participants in the experimental groups will received either 1 Hz or 25Hz real rTMS 
and control group will receive sham rTMS, followed by treadmill training for 16 sessions over 8 
weeks.  
 
Repetitive transcranial magnetic stimulation. Repetitive TMS will be delivered to the scalp over the 
leg area of the motor cortex contralateral to the more affected side by using a Magstim200 magnetic 
stimulator (Magstim Company, Whitland, UK) and 90mm double cone coil in this study. Each 
participant will be seated comfortably in a recumbent chair with legs and head supported by pillow. 
The experimental group will receive either a 1Hz or 25 Hz of real rTMS with an intensity of 80% 
resting MT, a total of 1200 rTMS pulses to both hemispheres.  For 1Hz rTMS, subjects will receive 
3 trains of 200s-1Hz with 10 seconds inter train intervals to each hemisphere in 20 minutes. For 
25Hz rTMS, subjects will receive 3 blocks (2 minutes break) of 8 trains of 1s-25Hz with 10s inter 
train intervals to each hemisphere in 20 minutes. The coil is centred over vertex and laterally offset 
to the leg area at the optimal site for response from the contralateral tibialis anterior (TA) muscle.  A 
latex swim cap will be placed on each participant’s head and measurement of the vertex will be 
marked on the cap. Subjects will be instructed to relax but to keep their eyes open during the whole 
procedure. The location of the stimulation will be marked, referenced by vertex-centred coordinates 
and recorded to maintain consistency among sessions. The sham rTMS will be delivered in the 
same setup and parameters of that of 25 Hz rTMS, however, with the cables of the coil disconnected. 
Another figure-of-eight coil delivering 25 Hz of rTMS will be placed posterior to the subject’s neck. 
Subjects in the placebo group will be told that the stimulation intensity is sub threshold for muscle 
contraction.  
 
Treadmill training. All participants will walk on a motorized treadmill after rTMS for 30 minutes.  The 

participants will wear a safety harness without body weight support during walking on the treadmill 
to prevent falls. The maximum tolerated walking speed was determined before training session. Half 
of the maximum speed will be used for a 5-minute warm up; the training walking speed will be 
increased by increments of 0.6km/h every 5 minutes. When the belt speed is increased to the highest 
speed at which the subject could walk safely and without stumbling. This maximum – achieved belt 
speed will be maintained for 5 minutes and then followed by 0.6km/h decrements. The subject will 
maintain this speed for the rest of the treadmill session for 15 minutes. If subject is unable to maintain 
this speed, it will be reduced by 0.6km/h in the next phase. If subject is able to maintain this reduced 
speed for 5 minutes, the speed will increase during the next phase by 0.6km/h.   The treadmill is not 
included throughout the training. The treadmill training session will last for 30 minutes.  
Data Collection  
Data will be collected 1 week before intervention and immediately after completion, and at 2 and 6 
months after treatment completion. All subjects will be instructed to take their customary medications 
1hour before each assessment. The assessor will be blinded to group assignment. During the 
baseline condition, demographic factors such as age, gender, duration of PD, and the number and 
daily dosage of anti-parkinsonian medications will be recorded. In each assessment session, the 
dosage of anti-parkinsonian medications will be recorded. 
 
Outcome measures 
Corticomotor excitability  
The RMT, RC, CSP duration, SICI of the tibialis anterior muscle elicited by TMS will be used to 
evaluate motor cortex excitability and inhibition using the procedure described above.  
 
Motor assessment and Functional mobility test  
1.  Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) 
 
MDS- UPDRS motor scoring will be assessed for each participant a week before the TMS 
measure. Motor section of the MDS-UPDRS will be used. There are total of 27 items [tremor at 
rest (arm and leg), action tremor (arm), rigidity (arm and leg), finger taps, hand movements, rapid 
alternating hand movements, and leg agility]. Each item scores from 0-4, with 0 indicates no 
disability and 4 maximum disabled.  
 
2. Gait and functional Performance 
 
Ten-meter walk test (10-meter walk test) and timed up and go test (TUG) were measured to 
evaluate the gait performance in both single task and dual task conditions.  Gait parameter will 
be captured by the APDM systems.  The APDM system is a valid, wearable gait and balance 
analysis system (28). The gait parameters measured includes gait speed, stride length, cadence, 
variability and asymmetry. Anticipatory postural adjustment, center of mass motion and postural 
sway path can be also measured with this system.  
 
2.1 Single task test condition:  
For 10-meter walk test, subjects will be instructed to walk at their comfortable speed and fast 

walking speed from 2m before the start line of a 10m distance and complete the walk 2m after 
the end of 10m.  Each subject will perform 3 trials for both comfortable and fast walking speed 
and data will be averaged.  
 
For TUG, Subjects will be instructed to stand up from a standardized chair, walk 3m at a 
comfortable speed, turn around, walk back to the chair and sit down. Timing will be commenced 
on the word ‘start’ and stopped once the subject sits down again with the back touching the 
backrest of the chair. Each subject will perform 3 trials of TUG with one practice trial before 
testing commences. Timed up and go test (TUG) is a functional mobility test with good validity 
and reliability (29). Poor TUG performance is associated with high fall risk in PD patients (30). 
 
2.2 Dual task test condition:  
Subjects will be asked to repeat both 10-meter walk test and TUG 3 trials each while performing 
an additional task such as serial three subtractions (counting backwards by threes aloud).   
 
3. Balance performance 
MimiBESTest will be used to measure the balance performance. MiniBEST has been validated 
to identify fallers in PD (31). High inter-rater reliability and test-retest reliability were shown (32).   
 
Statistical analysis 
All statistical analyses were performed using SPSS version 20.0 software (SPSS Inc., Chicago, IL, 
USA). Kolmogorov-Smirnov tests will be used to check the normality of data. One-way analysis of 
variance (ANOVA), Mann-Whitney U tests, and Chi-aquare tests will be used to compare the 
dependent variables (demographic data, daily dosage of levodopa, and the number of correct 
calculated answers/ walking time) among the 1Hz, 25Hz and sham groups. Two-way repeated 
measures ANOVA will be used to analyze continuous data with measurement interval (baseline, 
post-treatment, 2-month and 6-month post-treatment) as within-factor and group (1Hz, 25Hz, sham) 
as between-factor. In the case of an interaction effect between group and time being found, one-
way repeated measure ANOVA and t-tests with Bonferroni adjustment will be used to determine the 
real differences. A significance level of 0.05 was employed for analysis.  
 
5. 
Project Significance and Value: 
The progressive and disabling features of PD are the major burden to patients themselves, their 
families and society as a whole. One of the most disabling motor symptoms is gait difficulty and 
postural instability. Beneficial long-term effects of rTMS and treadmill training suggest that this 
intervention could slow down motor function deterioration and maintain gait and balance 
performance for a relatively long period of time.  To be able to walk safely and effectively will promote 
independence, enhance quality of life, prevent falls and reduced institutionalisation for people with 
PD.  
 
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Appendix 1 
 
Name of Participant: ____________________________ 
Date: _________________________________________ 
Name of Investigator: ____________________________ 
 
TMS Screening Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
Yes 
No 
Have you ever: 
(1) Had TMS before? 
 
 
 
 
 
 
 
             [   ] 
[   ] 
(2) Had a seizure?  
 
 
 
 
 
 
 
[   ] 
[   ] 
(3) Had an unexplained spell of loss of consciousness? 
 
 
 
             [   ] 
[   ] 
(4) Had a stroke? 
 
 
 
 
 
 
 
 
[   ] 
[   ] 
(5) Had a serious head injury? 
 
 
 
 
 
 
             [   ] 
[   ] 
(6) Had a surgery to your head? 
 
 
 
 
 
 
[   ] 
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(7) Had any neurological illnesses?  
 
 
 
 
 
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(8) Had any illness that may have caused brain injury? 
 
 
 
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Do you have any: 
(9) Frequent or severe headaches?  
 
 
 
 
 
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(10) Metal in your head region (inside or outside)?  
 
 
 
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(11) Implants of medical devices such as cardiac pacemakers, or medical pumps? 
             
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(12) Are you taking any medications? 
 
 
 
 
 
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(13) Are you pregnant? 
 
 
 
 
 
 
 
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(14) Does anyone in your family have epilepsy? 
 
 
 
 
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(15) Do you need any further explanation of TMS or its associated risks?  
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For any ‘YES’ response, please provide detailed information underneath.