Repetitive Transcranial Magnetic Stimulation (rTMS) for the Treatment of Freezing of Gait in Parkinson's Disease
Phase: NA
Conditions: Parkinson's Disease
Sponsor: Xuanwu Hospital, Beijing

Clinical Protocol 
rTMS for the Treatment of Freezing of Gait in 
Parkinson's Disease 
2018-06-28 
SPONSOR: Xuanwu Hospital of Capital Medical University, Beijing, China 
NCT number: NCT03219892

 
1. List of abbreviations 
BOLD = blood-oxygen-level-dependent;  
FOG = freezing of gait;  
FOGQ = Freezing of Gait Questionnaire;  
H-Y = Hoehn and Yahr;  
LEDD = levodopa equivalent daily dose;  
MDS-UPDRS III =  Movement Disorder Society-Unified Parkinson’s Disease Rating 
Scale motor scores;  
MMSE = Mini-Mental State Examination;  
MMRM = mixed effect model repeated measures;  
MoCA = Montreal Cognitive Assessment;  
NC = normal controls;  
PD-FOG = Parkinson’s disease patients with freezing of gait;  
PD-noFOG: Parkinson’s disease patients without freezing of gait;  
rTMS = repetitive transcranial magnetic stimulation;  
SMA = supplementary motor area.  
 
 

2. Introduction 
Freezing of gait (FOG) is a common and debilitating symptom in patients with 
Parkinson's disease (PD), characterized by sudden and brief episodes of inability to 
produce effective forward stepping 1. FOG is a major risk factor for falls, and greatly 
contributes to reduced mobility and quality of daily life 2. Treatment of FOG has been 
perceived as a very challenging task. Although various treatment approaches exist, 
including pharmacological and surgical options, evidence is inconclusive for many 
approaches and no clear treatment protocols are available until now 3. 
Repetitive transcranial magnetic stimulation (rTMS), a noninvasive neural modulation 
technique, has been closely applied as a treatment for various neurologic and 
psychiatric disorders 4. A recent meta-analysis demonstrated that rTMS could improve 
motor symptoms for PD patients with a moderate effect size 5. To date, however, only 
few rTMS studies have focused on its efficacy on FOG in patients with parkinsonism, 
and most of them targeted the primary motor cortex or dorsolateral prefrontal cortex 6-
10. Even though some evidence indicates the involvement of the supplementary motor 
area (SMA) in the pathogenesis of FOG 11-13, no report has described the SMA rTMS 
in PD patients with FOG. 
Moreover, few studies combined functional magnetic resonance imaging (fMRI) and 
rTMS to unravel the mechanism of its beneficial effects. To address these issues, the 
investigators conducted a randomized, double-blind, sham-controlled study to explore 
the efficiency of SMA-rTMS on FOG in PD patients. 
 
3. Study objectives  
 
To explore the efficacy and neural mechanisms of rTMS over the SMA on FOG in 
PD patients. 
 
4. Trial design 
 

We will perform this current clinical trial with nested two sub-studies. Specifically this 
will include:  
1. A cross-sectional resting-state fMRI study to obtain the brain connectivity pattern 
that specific to FOG in PD patients; 
2. A randomized, double-blind, sham-controlled rTMS trial to study the clinical 
efficiency of SMA-rTMS on FOG in PD patients, as well as to investigate the underlying 
neural mechanisms by comparing the changes of the specific FOG related brain 
pattern identified in the resting-state fMRI study.  
 
5. Eligibility criteria 
The overall study will recruit three groups, including PD patients with FOG (PD-FOG), 
PD patients without FOG (PD-noFOG) and normal controls (NC). The inclusion and 
exclusion criteria are listed as below.  
For the resting-state fMRI study, we will recruit all the three groups’ subjects. For the 
rTMS study, we will invite the PD-FOG subjects from the resting-state fMRI study to 
participate into the trial.  
 
6.1 Inclusion criteria  
 
1. PD-FOG subjects 
(i) 40-80 years old; 
(ii) Patients diagnosed with idiopathic PD according to the UK Brain Bank Clinical 
Criteria;  
(iii) FOG positive: presenting with one or more of the following three criteria 11. 
1) convincing subjective reports of FOG, based on consistent behavioral 
characteristics of the phenomenon (including a typical feeling of the feet being 
“glued” to the floor);  
2) patients’ recognition of a typical phenotype by showing them a short video 
(70s) demonstrating typical freezing episodes;  

3) response to a standardized gait task that contained specific elements known 
to provoke FOG, including gait initiation, a narrow passage, dual tasking, and 
rapid 3600 axial turns in both directions 14.  
(iv) Mini-mental state examination (MMSE) questionnaire score above 24 points.  
 
2. PD-noFOG subjects:  
(i) 40-80 years old; 
(ii) Patients diagnosed with idiopathic PD according to the UK Brain Bank Clinical 
Criteria;  
(iii) FOG negative. 
(iv) Mini-mental state examination (MMSE) questionnaire score above 24 points.  
 
3. NC 
(i) 40-80 years old; 
 
6.2 Exclusion criteria 
 
(i) presence of contraindications for rs-fMRI or rTMS;  
(ii) history of deep brain stimulation surgery;  
(iii) marked rest tremor;  
(iv) comorbidities of neurological disease other than PD;  
(v) left-handedness. 
 
7. Study procedures (resting-state fMRI study) 
7.1 Ethics requirements and informed consent 
 

The whole experiments will be performed according to the Declaration of Helsinki and 
approved by the Institutional Review Board of Xuanwu Hospital of Capital Medical 
University. All subjects will give informed consent. Informed consent must be obtained 
before any trial related procedures are undertaken.  
 
7.2 Clinical assessments 
 
For all the PD patients, clinical assessments will be evaluated during their practical 
“OFF” state(withdrawal of anti-Parkinson medications for at least 12 hours), including:  
(i)Movement Disorder Society-Unified Parkinson’s Disease Rating Scale motor scores 
(MDS-UPDRS III); 
(ii)Hoehn and Yahr (H-Y) stage;  
(iii)Freezing of Gait Questionnaire (FOGQ); 
(iv)Mini-Mental State Examination (MMSE);  
(v) Montreal Cognitive Assessment (MoCA).  
 
7.3 Rs-fMRI acquisition 
 
Imaging will be carried out in a SIEMENS Trio 3T scanner. Participants will be 
instructed to keep their head still and eyes closed during scanning, but not fall asleep. 
Earplugs and a head coil with foam pads will be used to minimize machine noise and 
head motion. For PD patients, rs-fMRI scans will be acquired following a 12-hour 
period of medication withdrawal. Structural images will be acquired using a sagittal 
magnetization prepared rapid gradient echo three-dimensional T1-weighted sequence 
(repetition time [TR] = 1970 ms, echo time [TE] = 3.9 ms, inversion time [TI] = 1100 
ms, flip angle [FA] = 15°). BOLD images will be obtained using the following SE-EPI 
sequence: repetition time = 2000 ms, echo time = 30 ms, voxel size = 3.0 × 3.0 × 3.0 
mm3, slice thickness / gap = 4.0/0 mm, axial slices = 33 layers, flip angle = 90°, FOV 
= 256 mm × 256 mm, matrix size = 64 × 64, and scanning time = 8 min. 
 

7.4 Rs-fMRI data preprocessing  
 
The acquired rs-fMRI data will be preprocessed using the AFNI software package 15. 
Several pre-processing steps will be performed, including de-spiking, slice timing 
correction, and 3D isotropic reslicing.  
 
7.5 Rs-fMRI data processing  
 
We will compare the brain connectivity pattern of PD-FOG subjects with PD-noFOG 
and NC subjects respectively, thus getting the specific pattern for FOG and PD in PD-
FOG subjects.  
 
8. Study procedures (rTMS study) 
 
8.1 Ethics requirements and informed consent 
 
The whole experiments will be performed according to the Declaration of Helsinki and 
approved by the Institutional Review Board of Xuanwu Hospital of Capital Medical 
University. All subjects will give informed consent. Informed consent must be obtained 
before any trial related procedures are undertaken.  
 
8.2 Randomization and mask procedure  
 
Patients in the rTMS study will be randomly assigned (with a 2:1 ratio) by a computer-
generated block allocation into two groups, to receive either a verum (N=20) or sham 
(N=10) rTMS over SMA. The randomization sequence will be revealed only to the 
unmasked clinician responsible for the rTMS stimulation. The investigators and 
patients will be masked to the randomization group. 
 
8.3. Verum and sham treatment strategies  
 

We will perform verum or sham rTMS in ten sessions over two successive weeks, one 
session per day for five consecutive days per week. The rTMS sessions will be 
conducted one week after the acquisition of pre-rTMS fMRI acquired in the rs-fMRI 
study. To apply focal rTMS over the SMA, the stimulation site is determined as 3 cm 
anterior to the leg motor area along with the sagittal midline 16-18. The coil will be held 
so that the induced current is perpendicular to the midline. The stimulus intensity is 
set to 90% of the rest motor threshold for the first dorsal interosseous muscle when 
the primary motor hand area is stimulated. In each session, a 5-second burst of 10-
Hz rTMS will be repeated 20 times every minute (in total, 1,000 pulses, 20 minutes’ 
duration). For the sham rTMS, the same stimulation parameters will be used, but the 
coil will be placed in 90° angulation over the SMA so that no relevant current flow is 
induced in the cortical tissue 19.  
 
8.4. Study clinical assessments 
8.4.1 Baseline clinical assessments  
 
All clinical assessments for the rTMS study will be carried out in the “ON” state at the 
same time of the day, including: 
(i) MDS-UPDRS III scores; 
(ii) Gait analysis; 
(iii) FOGQ.  
 
8.4.2 Follow-up clinical assessments 
 
Follow-up evaluations for each participant (except the FOGQ) will be performed 
before rTMS and after the 5th and 10th sessions, and then 2 weeks and 4 weeks 
after the last session, defined as T1, T2, T3 and T4 respectively. The FOGQ will be 
evaluated at T2 and T4.  
(i) MDS-UPDRS III scores (T1, T2, T3 and T4); 
(ii) Gait analysis (T1, T2, T3 and T4); 
(iii) FOGQ (T2 and T4).  

 
8.4.3 post-rTMS resting state-fMRI  
Patients will undergo another resting-state fMRI scan, that is the post-rTMS fMRI 
acquisition, one or two days after the 10th session of rTMS. The acquisition paradigm, 
preprocessing and processing methods are same as used in the prior rs-fMRI study. 
 
8.5 Outcomes 
 
8.5.1 Primary clinical outcomes 
 
We will use the improvement of FOGQ score, a self-assessment scale for evaluating 
FOG severity, as the primary clinical outcome.  
 
8.5.2 Secondary clinical outcomes 
 
The MDS-UPDRS III will be included as a secondary clinical outcome to evaluate the 
rTMS effect on motor symptoms. Additionally, as FOGQ is a subjective measure, we 
also adopted an additional objective evaluation tool, a Timed Up-and-Go (TUG) test, 
as another secondary outcome. 
 
8.5.3 Secondary resting-state fMRI changes 
 
The changes of the specific brain connectivity pattern identified in the resting-state 
fMRI study will be included as another secondary outcomes.  
 
9. Recording Adverse Events  
A record of any adverse events will be recorded and the relationship to rTMS 
treatment assessed and forwarded to the study co-ordinating centre.  
 
10. Statistical analysis plan and sample size  

10.1 Sample size calculations 
 
As mentioned above, the primary clinical outcome for the rTMS study is the FOGQ 
score. Our sample size for the rTMS study will be calculated using the pooled estimate 
of within-group SDs of FOGQ obtained from a previous study 6. The sample size will 
be determined by a priori using G*Power, assuming a moderate effect size of 0.48, 
α=0.05, power=0.8, number of groups=2, number of measurements (for the primary 
outcome / FOGQ) = 3 for a two-way repeated measures analysis of variance. The total 
sample size needed is 26. Considering a dropout rate of 20%, the sample size is 33.  
 
10.2 Statistical analysis plan  
 
Demographic data will be presented as mean ± SD for continuous variables. 
Independent two samples t-test will be performed for the comparison of continuous 
variables, and the χ2 test will be used to compare categorical variables. Paired t-test 
and McNemar's test will be used to test the biomarker changes before and after rTMS. 
In order to estimate the clinical effects of rTMS on the primary and secondary clinical 
outcomes, we applied a mixed effect model repeated measures (MMRM) model to 
evaluate within group and between group differences, and also their interaction 
difference. For respondents missing one or more interviews, MMRM allows data from 
completed interviews to be retained in analyses 20. For each variable, we applied a 
separate model where the independent variables are the group (verum rTMS, sham 
rTMS) and the visit (T0, T1, T2, T3, and T4), and the group*visit condition interaction 
term. The fixed factors in these models are group and visit, while the random factor is 
the subject. The threshold for the level of significance is set at α = 0.05. All statistical 
analyses will be performed using JMP Pro 12.0 software (SAS Institute Inc., NC). 
Graphics will be created using Prism 7.0.  
 
11. Direct access to source data  
The investigators will permit trial-related monitoring, audits, REC review, and 
regulatory inspection(s), providing direct access to source data/documents. Trial 

participants are informed of this during the informed consent discussion. Participants 
will consent to provide access to their medical notes. 
 
12. Monitoring plan for the trial 
The trial will be monitored according to the monitoring plan agreed and written by the 
Sponsor. 
 
13. Finance and funding 
This work is supported by the grants from the Beijing Municipal government 
(PXM2017_026283_000002), Beijing Municipal Science & Technology Commission 
(Z161100000216140; Z171100000117013), Beijing Municipal Administration of 
Hospitals’ Mission Plan (SML20150803), Scientific and Technological Innovation 
Capacity Developing-Scientific Research Base Building-Talent Development Fund of 
Beijing Institute for Brain Disorders, National Natural Science Foundation of China 
(61473196; 81601109), and Beijing Talents Foundation (2016000021223TD07; 
2016000020124G107).  
 
14. Publication policy  
Results will be published in peer reviewed journals and presented at conferences. 
Publications policy will be decided by the steering committee. 
 
15. References 
 
1. 
Nutt JG, Bloem BR, Giladi N, Hallett M, Horak FB, Nieuwboer A. Freezing of 
gait: moving forward on a mysterious clinical phenomenon. The Lancet Neurology 
2011; 10(8): 734-44. 
2. 
Moore O, Peretz C, Giladi N. Freezing of gait affects quality of life of peoples 
with Parkinson's disease beyond its relationships with mobility and gait. Movement 
disorders : official journal of the Movement Disorder Society 2007; 22(15): 2192-5. 

3. 
Nieuwboer A, Giladi N. Characterizing freezing of gait in Parkinson's disease: 
models of an episodic phenomenon. Movement disorders : official journal of the 
Movement Disorder Society 2013; 28(11): 1509-19. 
4. 
Wassermann EM, Lisanby SH. Therapeutic application of repetitive 
transcranial magnetic stimulation: a review. Clinical neurophysiology : official journal 
of the International Federation of Clinical Neurophysiology 2001; 112(8): 1367-77. 
5. 
Chou YH, Hickey PT, Sundman M, Song AW, Chen NK. Effects of repetitive 
transcranial magnetic stimulation on motor symptoms in Parkinson disease: a 
systematic review and meta-analysis. JAMA neurology 2015; 72(4): 432-40. 
6. 
Kim MS, Hyuk Chang W, Cho JW, et al. Efficacy of cumulative high-frequency 
rTMS on freezing of gait in Parkinson's disease. Restorative neurology and 
neuroscience 2015; 33(4): 521-30. 
7. 
Dagan M, Herman T, Mirelman A, Giladi N, Hausdorff JM. The role of the 
prefrontal cortex in freezing of gait in Parkinson's disease: insights from a deep 
repetitive transcranial magnetic stimulation exploratory study. Experimental brain 
research 2017. 
8. 
Tard C, Devanne H, Defebvre L, Delval A. Single session intermittent theta-
burst stimulation on the left premotor cortex does not alleviate freezing of gait in 
Parkinson's disease. Neurosci Lett 2016. 
9. 
Chang WH, Kim MS, Park E, et al. Effect of Dual-Mode and Dual-Site 
Noninvasive Brain Stimulation on Freezing of Gait in Patients With Parkinson 
Disease. Archives of physical medicine and rehabilitation 2017; 98(7): 1283-90. 
10. 
Rektorova I, Sedlackova S, Telecka S, Hlubocky A, Rektor I. Repetitive 
transcranial stimulation for freezing of gait in Parkinson's disease. Movement 
disorders : official journal of the Movement Disorder Society 2007; 22(10): 1518-9. 
11. 
Snijders AH, Leunissen I, Bakker M, et al. Gait-related cerebral alterations in 
patients with Parkinson's disease with freezing of gait. Brain 2011; 134(Pt 1): 59-72. 
12. 
Peterson DS, Pickett KA, Duncan R, Perlmutter J, Earhart GM. Gait-related 
brain activity in people with Parkinson disease with freezing of gait. PloS one 2014; 
9(3): e90634. 

13. 
Shine JM, Matar E, Ward PB, et al. Differential neural activation patterns in 
patients with Parkinson's disease and freezing of gait in response to concurrent 
cognitive and motor load. PloS one 2013; 8(1): e52602. 
14. 
Snijders AH, Nijkrake MJ, Bakker M, Munneke M, Wind C, Bloem BR. 
Clinimetrics of freezing of gait. Movement disorders : official journal of the Movement 
Disorder Society 2008; 23 Suppl 2: S468-74. 
15. 
Cox RW. AFNI: software for analysis and visualization of functional magnetic 
resonance neuroimages. Comput Biomed Res 1996; 29(3): 162-73. 
16. 
Hamada M, Ugawa Y, Tsuji S. High-frequency rTMS over the supplementary 
motor area for treatment of Parkinson's disease. Movement disorders : official 
journal of the Movement Disorder Society 2008; 23(11): 1524-31. 
17. 
Shirota Y, Ohtsu H, Hamada M, Enomoto H, Ugawa Y. Supplementary motor 
area stimulation for Parkinson disease: a randomized controlled study.  Neurology. 
2013/03/22 ed; 2013. p. 1400-5. 
18. 
Matsunaga K, Maruyama A, Fujiwara T, Nakanishi R, Tsuji S, Rothwell JC. 
Increased corticospinal excitability after 5 Hz rTMS over the human supplementary 
motor area. The Journal of physiology 2005; 562(Pt 1): 295-306. 
19. 
Eggers C, Gunther M, Rothwell J, Timmermann L, Ruge D. Theta burst 
stimulation over the supplementary motor area in Parkinson's disease. Journal of 
neurology 2015; 262(2): 357-64. 
20. 
Kroenke K, Krebs E, Wu J, et al. Stepped Care to Optimize Pain care 
Effectiveness (SCOPE) trial study design and sample characteristics. Contemp Clin 
Trials 2013; 34(2): 270-81.