Development of Repetitive Transcranial Magnetic Stimulation (rTMS) Combined With Machine-assisted Bimanual Therapy (BT) in Upper Limb Rehabilitation
Phase: NA
Conditions: Post-stroke Upper Limb Hemiparesis, Repetitive Transcranial Magnetic Stimulation (rTMS), Bimanual Therapy, Neuromodulation
Sponsor: Chang Gung Memorial Hospital

 
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CLINICAL STUDY PROTOCOL 
 
 Development of repetitive transcranial magnetic 
stimulation (rTMS) combined with machine-assisted 
bimanual therapy (BT) in upper limb rehabilitation. 
 
VERSION NO. 4 
 DATES (2025/04/17) 
 
 
 
Pei, Yu-Cheng 
Linkou Chang Gung Memorial Hospital 
 

 
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           English Synopsis    
 
 
I. Title of Study  
Development of repetitive transcranial magnetic stimulation (rTMS) combined 
with machine-assisted bimanual therapy (BT) in upper limb rehabilitation. 
II. Indication 
1. Inclusion Criteria 
(1) Age 40-80 years; 
(2) First-onset stroke patients; 
(3) Patients diagnosed with cerebral infarction or hemorrhage through CT 
or MRI; 
(4) Signed informed consent form by the patient and their family; 
(5) Stable physiological parameters; 
(6) Stroke occurred within the last 12 months;  
(7) Patients with unilateral hand function impairment caused by the stroke; 
(8) Upper limb muscle tone (Modified Ashworth Scale, MAS) less than 3 
points; 
(9) Able to follow two-step commands. 
2. Exclusion Criteria 
(1) A history of epilepsy or family history of epilepsy; 
(2) Presence of suicidal tendencies; 
(3) Currently using medications that lower the seizure threshold; 
(4) Pregnant or planning to become pregnant; 
(5) Co-existing neurological diseases (such as multiple sclerosis, other 
neurodegenerative diseases, meningitis, brain abscess, or meningioma); 
(6) Subjects with uncontrollable migraines caused by elevated intracranial 
pressure; 
(7) Subjects taking antidepressants who cannot discontinue the medication; 
(8) Subjects with sleep disorders during rTMS treatment; 
(9) Subjects with cerebellar stroke or brainstem stroke; 
(10) Cerebral ischemic disorders resulting from traumatic brain injury; 
(11) Transient ischemic attacks (TIAs); 

 
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(12) History of bleeding tendency and other conditions affecting upper limb 
function, such as myasthenia gravis, systemic immune neuropathy, severe 
epilepsy, endocrine system disorders, wearers of external or internal 
cardiac pacemakers, individuals with metallic implants or orthopedic 
devices; 
(13) Co-existing severe heart, liver, kidney dysfunction, or other serious 
physical illnesses; 
(14) Subjects with impaired consciousness who cannot cooperate with 
examinations or treatments, such as those with mental disorders, or those 
with intellectual or cognitive impairments, severe dementia; 
(15) Presence of implanted electronic devices in the body; 
(16) Co-existing severe liver, kidney, or hematological disorders; 
(17) Special vulnerable populations; 
(18) Skin disease (e.g., pressure ulcers, trauma, cellulitis, etc.). 
III. Phase of Development: 
Not applicable. 
IV.  Study Rationale:  
The study aims to establish a therapeutic model that combines Bimanual Therapy 
(BT) with repetitive transcranial magnetic stimulation (rTMS) to investigate 
neuroplasticity modulation in stroke patients with upper limb hemiparesis. In the 
study, inhibitory rTMS will be applied to the unaffected hemisphere, and 
facilitatory rTMS will be applied to the affected hemisphere during stimulation. 
Patients will also receive BT concurrently with these rTMS stimulations. 
Functional assessments of the upper limb will be performed prior to, 
immediately after, and at 1 and 3 months follow-ups to evaluate rehabilitation 
outcomes. This study will assess rehabilitation outcomes and explore the 
associated mechanisms of brain modulation , with the goal of improving clinical 
applicability. 
 
V. Study Objectives: 
This study comprises three main objectives. First, to establish a treatment 
process and environment for utilizing rTMS to modulate neural activity in 
patients with upper limb hemiparesis caused by stroke. Second, to investigate the 
application of inhibitory stimulation, continuous theta burst stimulation (cTBS), 
to the unaffected hemisphere of the stroke-damaged brain, followed by 

 
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facilitatory stimulation, intermittent theta burst stimulation (iTBS), to the 
affected hemisphere. The intention is to employ the established treatment process 
in the first part to formulate a clinical treatment model. Third, we will further 
study functional assessments of the upper limb before treatment, immediately 
post-treatment, and at 1- and 3-month follow-ups. 
VI. Study Design 
⚫ 
Duration of Treatment 
A. The experiment for establishment of therapeutic environment. 
  Participants in the experiment for establishment of therapeutic environment 
underwent 1-3 evaluations. During this experiment, repetitive Transcranial 
Magnetic Stimulation (rTMS) was employed for brain modulation, involving two 
sets of stimuli. Each set consisted of initially administering continuous Theta 
Burst Stimulation (cTBS) to suppress the healthy side (approximately 600 
pulses), followed by intermittent Theta Burst Stimulation (iTBS) to enhance the 
lesion side (600 pulses), totaling approximately 4 minutes (around 1200 pulses). 
The intensity of iTBS and cTBS is 80-120% of Motor Threshold.  
 
Patients receiving rTMS treatment concurrently underwent machine-assisted 
bilateral upper limb training. During treatment sessions, patients were instructed 
to repeatedly perform grasping-opening tasks or engage in bilateral upper limb 
activities involving simultaneous shoulder and elbow movements while counting 
down loudly from 300. Upon completion of all training sessions, patients and 
therapists were required to complete usability and satisfaction analyses to 
evaluate equipment usability and operational satisfaction. 
 
B. The experiment for evaluation of therapeutic effects. 
Patients will be divided into three groups: a Control group, an rTMS group, and 
an rTMS+BT group. Each group will receive a 65-minute treatment session, 
administered once every two days, totaling 10 sessions and completing the entire 
course within 20 days. 
 
Control group: only received traditional rehabilitation training for 50 minutes 
and self-stretching training (15 minutes); rTMS group: received rTMS 
intervention (15 minutes) and 50 minutes of traditional rehabilitation training; 
rTMS+BT group: received rTMS intervention (15 minutes) along with BT 
meanwhile and 50 minutes of traditional rehabilitation training. 

 
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⚫ 
Number of Planned Patients 
72 participants are expected to be recruited in the trial. 
 
⚫ 
Investigational Product 
1. 
Robot-assisted palm and finger rehabilitation device 
Device name: "RM" Wearable Powered Hand Rehabilitation Device 
(Non-Sterile) 
Manufacturer: Rehabotics Medical Technology Corporation 
2. 
Bilateral proximal/distal upper limb training platform 
(1) The name of proximal upper limb training device: Non-powered upper 
limb proximal training platform 
Manufacturer: Rehabotics Medical Technology Corporation 
(2) The name of distal upper limb training device: Non-powered upper 
limb distal training equipment 
Manufacturer: developed equipment by the Rehabilitation Department 
of Chang Gung Hospital 
3. 
Repetitive transcranial magnetic stimulation (rTMS) 
Device name: Repetitive transcranial magnetic stimulation (rTMS) 
Manufacturer: Apollo Powermag 100, Mag & More, Germany. 
 
⚫ Endpoints 
The primary endpoint was evaluated through the Fugl-Meyer Assessment, while 
secondary endpoints encompassed various measures, including the Modified 
Ashworth Scale (MAS), Manual Muscle Testing (MMT) for the upper extremity, 
Action Research Arm Test (ARAT), Brunnstrom Recovery Stage, Instrumental 
Activities of Daily Living Scale (IADLs). Additionally, participants and 
therapists responded to the System Usability Scale (SUS) questionnaire, and a 
Satisfaction questionnaire was administered. 
 
⚫ Criteria for Evaluation 
1. Inclusion Criteria 
(1) Demographics and baseline characteristics of the participants were all 
available. 
(2) Participants completed all treatment sessions. 
(3) Functional assessments of the upper limb were performed at multiple 
time points: prior to, immediately after, and at 1 and 3 months 
follow-ups, without any omissions. 

 
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(4) Both participants and therapists completed the System Usability Scale 
(SUS) questionnaire and the Satisfaction questionnaire. 
2. Exclusion Criteria 
(1) Participants with unforeseen psychological issues or significant 
changes in health conditions to prevent interference with the analysis. 
(2) Participants using non-study-related medications that could potentially 
interfere with the outcomes. 
 
⚫ Statistical Methods 
Detailed demographic and medical history records are documented for each 
subject, including age, gender, time of stroke onset, location of stroke, and types 
of stroke. The clinical assessment will be conducted by a licensed occupational 
therapist with experience in treating neurological conditions. Clinical assessment 
results are being compared between groups using a student-t test. Pre and 
post-training within each group are being assessed using one-way ANOVA to 
determine improvement. One-way ANOVA is employed for inter-group 
comparisons, followed by post-hoc tests. If the data do not follow a normal 
distribution, non-parametric statistical methods are applied. Correlation analysis 
is used to explore relationships between clinical assessment results and various 
factors. Quantitative data are presented as (Mean±SEM), and a 95% confidence 
interval (p<0.05) is considered statistically significant. 
 
⚫ Duration of the Study 
The study is scheduled to span a total of three years, commencing on August 1st, 
2024, and concluding on July 31st, 2027. 
 
⚫ End of Study 
In summary, this three-year study, conducted from August 1, 2024, to July 31, 
2027, focuses on establishing an integrated approach using rTMS with BT for 
treating upper limb hemiparesis in stroke patients. The research credits the 
collaboration of participants, the medical team, and supporting institutions. We 
are optimistic that the insights gained will play a crucial role in advancing the 
field of stroke rehabilitation.