Stroke
Conditions
Brief summary
Stroke is the leading cause of function disability or impairment. Non-promising functional return from upper limb rehabilitation has been reported. With the technology advances, transcranial magnetic stimulation (TMS), which is a form of non-invasive direct brain stimulation, may act as an attenuator in regulating or modulating the cortical excitability in order to facilitate cortical re-organization and enhance behavioral performance. Various therapeutic exercise protocols have been investigated regarding their efficacy in promoting motor recovery of the affected upper limb for patients after stroke and the preliminary results were supportive. However, limited numbers of randomized control clinical trials have been published in investigating the priming or additive value of low frequency repetitive TMS (rTMS) with combination of structural motor training programs. Thus the objective of this study is: to determine the effectiveness of the combination of low frequency rTMS on contra-lesional M1 and a structured upper limb motor training program on restoring upper limb function among patients with stroke in sub-acute stage. It is hypothesized that the rTMS, when combined with a structured motor training program, confers additional therapeutic effects on upper limb motor function in subacute stroke patients, when compared with the motor training program alone. The objectives of this study is to determine the effectiveness of the combination of low frequent rTMS on contra-lesional M1 and a structured upper limb motor training program in restoring upper limb function among patients with subacute stroke.
Detailed description
The proposed study will be a randomized double-blinded controlled trial. 26 stroke patients with upper limb impairment who are receiving the outpatient physiotherapy service at the Queen Elizabeth Hospital and fulfill the eligibility criteria will be recruited and randomized into two interventional groups: (1) rTMS + exercise (rTMS-Ex) group and (2) Placebo rTMS +exercise (Placebo-Ex) group. Both rTMS-Ex and placebo-Ex group will receive 10 consecutive treatment sessions (5 sessions per week), which consists of real rTMS stimulation (rTMS-ex group) or placebo rTMS (placebo-Ex group), followed by 30-minute structured upper limb strengthening and task-specific motor training program. After 2 weeks of brain stimulation and motor training, both groups will continue with the same structured motor training program for another 10 weeks (2 sessions/ week). 1. rTMS-Ex Group 10 consecutive sessions (5 days per week for 2 weeks) of 1 Hz low frequency repetitive transcranial magnetic stimulation over contra-lesional M1 region for 1200 pulse (20 minutes) at 90% motor threshold and immediately followed by 75 minutes structured physiotherapy upper limb training. After the 10 sessions of brain stimulation, the 30-minute structured physiotherapy upper limb training program will continue for another 12 weeks (2 sessions per week) 2. Placebo-Ex Group 10 consecutive sessions (5 sessions per week for 2 weeks) of placebo stimulation over contra-lesional M1 region and immediately followed by 30 minutes of structured physiotherapy upper limb training. Then, the structured physiotherapy upper limb training will continue for another 12 weeks (2 sessions per week). Evaluation on impairment level, motor performance, physiological measurements and self -perceived disability will be performed at 4 time points: before treatment (T0), immediately after treatment (T1), one-month follow-up (T2) and three-month follow-up (T3). 2-way repeated measures ANOVA will be used to determine whether the rTMS-ex group leads to better outcomes than the placebo-ex group.
Interventions
DEVICELow frequency rTMS
1 Hz low frequency rTMS over contra-lesional M1 region for 1200 pulse at 90% resting motor threshold for 10 sessions.Patients in the rTMS-ex group will receive the experimental rTMS A Magstim Rapid Stimulator (Magstim Company, Whitland, UK) equipped with an air-cooled figure-of-eight coil (each loop 70 mm in diameter) and neuro-navigation system will be used to deliver the intervention.
BEHAVIORALstructured physiotherapy upper limb training
Structural Physiotherapy upper limb training for 30-minutes
Sponsors
The Hong Kong Polytechnic University
Queen Elizabeth Hospital, Hong Kong
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 85 Years
Healthy volunteers
No
Inclusion criteria
1. First-ever stroke 2. Age \>60 3. muscle strength \> grade 2 and \< grade 5 based on manual muscle testing of hand / fingers of the affected upper limb 4. \> 1 month and \< 6 months after the onset of stroke
Exclusion criteria
1. Substantial cognitive impairment with Mini Mental State Test \>24 2. Diagnosis of mental illness 3. Pathological conditions referred to as contra-indications for rTMS in guideline suggested by Wassermann (eg. Cardiac pacemaker, intracranial implants, implanted medication pumps, epilepsy) 4. Unstable cardio-pulmonary conditions -
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of Cortical Excitability From Baseline to at 4th Weeksand 12th Weeks Training in Motor Evoked Potential at 120% Resting MotorThreshold at Affected Hand | Baseline and at 4th weeks and at 12th weeks | Electromyographic (EMG) activity in first doral interossei measured at 120% resting motor threshold. The motor evoked potential amplitude will be measured peak to peak in millivolt(mV). Higher value mean better control |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change of Upper Limb Impairment From Baseline to at 4th Weeks & 12 th Weeks Training in Fugl-Meyer Assessment (FM) Scale | Baseline and at 4th weeks and at 12th weeks | Fugl-Meyer Assessment (FM) scale is a stroke-specific, performance-based impairment index, the scale range from 0 to 66. 25 test items included measurement of movement, coordination, and reflex action of the different parts of the paretic upper extremity. The score could range from 0 to 66. Better motor function was reflected by a higher FMA score |
| Change of Grip Strength From Baseline to at 4th Weeks and at 12th Weeks Training in Force (Kilogram ) | Baseline and at 4th weeks and at 12th weeks | Isometric hand grip strength will be measured using the hand-held dynamometer in kilogram (kg). Higher value reflect better hand grip strength |
| Change of Upper Limb Function From Baseline to at 4th Weeks Training in Action Research Arm Test (ARAT) Scale | Baseline and at 4th weeks and at 12th weeks | The 19-item Action Research Arm Test has four subscales that assess various aspects of upper limb function (i.e., pinch, grip, grasp, and gross motor). Each item was rated on a 4-point scale from 0 to 3. Scale from 0 to 57.A higher score was indicative of better upper limb function. |
| Change of Reaction Time From Baseline to at 4th Weeks and at 12th Weeks Training in Time Measurement (Seconds) | Baseline and at 4th weeks and at 12th weeks | A simple reaction time will be recorded through a computer system. Time for the patient to reaction to the signal will be measured in seconds (sec). Shorter period of time reflect better reaction time.Lower score means better result |
| Change of Health Status Measurement From Baseline to at 4th Weeks and at 12th Weeks in Stroke Impact Scale | Baseline and at 4th & 12 th weeks | The 59-item Stroke Impact Scale (SIS) is a stroke-specific, self-report, health status measure. Total range from 0 to 100. Higher score reflect better result. |
Countries
China
Participant flow
Recruitment details
A convenient sampling method was adopted. Patients who were diagnosed with their first-ever stroke and referred to the Physiotherapy Department at Queen Elizabeth Hospital for post-stroke rehabilitation between November 2015 to December 2016 were screened for eligibility by an independent physiotherapist using inclusion criterias.
Pre-assignment details
Exclusion criteria: 1. Mini Mental State Test score ≤ 24; 2. Mental illness; 3. Contra-indications to rTMS according to guidelines formulated by Wassermann (e.g., intracranial implants, epilepsy, cardiac pacemaker, implanted medication pumps); 4 Unstable cardio-pulmonary condition.
Participants by arm
| Arm | Count |
|---|---|
| (1) rTMS- PT Ex Group 1 Hz low frequency rTMS over contra-lesional M1 region for 1200 pulse (20 minutes) at 90% resting motor threshold (rMT) will conduct for 10 consecutive sessions (5 days per week for 2 weeks) and immediately followed by 30- minutes structured physiotherapy upper limb training.
After the 10 sessions of brain stimulation, the 30-minute structured physiotherapy upper limb training program will continue for another 12 weeks (2 sessions per week)
Low frequency rTMS: 1 Hz low frequency rTMS over contra-lesional M1 region for 1200 pulse at 90% resting motor threshold for 10 sessions.Patients in the rTMS-ex group will receive the experimental rTMS A Magstim Rapid Stimulator (Magstim Company, Whitland, UK) equipped with an air-cooled figure-of-eight coil (each loop 70 mm in diameter) and neuro-navigation system will be used to deliver the intervention.
structured physiotherapy upper limb training: Structural Physiotherapy upper limb training for 30-minutes | 12 |
| (2) Placebo- PT Ex Group placebo stimulation over contra-lesional M1 region will be conducted for 10 consecutive sessions (5 sessions per week for 2 weeks) of and immediately followed by 30- minutes of structured physiotherapy upper limb training.
Then, the structured physiotherapy upper limb training will continue for another 12 weeks (2 sessions per week).
Low frequency rTMS: 1 Hz low frequency rTMS over contra-lesional M1 region for 1200 pulse at 90% resting motor threshold for 10 sessions.Patients in the rTMS-ex group will receive the experimental rTMS A Magstim Rapid Stimulator (Magstim Company, Whitland, UK) equipped with an air-cooled figure-of-eight coil (each loop 70 mm in diameter) and neuro-navigation system will be used to deliver the intervention.
structured physiotherapy upper limb training: Structural Physiotherapy upper limb training for 30-minutes | 12 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
Baseline characteristics
| Characteristic | (1) rTMS- PT Ex Group | Total | (2) Placebo- PT Ex Group |
|---|---|---|---|
| Age, Continuous | 67.3 years STANDARD_DEVIATION 5.8 | 66.2 years STANDARD_DEVIATION 4.7 | 65.1 years STANDARD_DEVIATION 3.1 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Hong Kong | 12 participants | 24 participants | 12 participants |
| Sex: Female, Male Female | 5 Participants | 10 Participants | 5 Participants |
| Sex: Female, Male Male | 7 Participants | 14 Participants | 7 Participants |
| Time since stroke (weeks) | 13.6 years STANDARD_DEVIATION 5.8 | 14.3 years STANDARD_DEVIATION 6.5 | 15.1 years STANDARD_DEVIATION 7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 0 / 12 | 0 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
Change of Cortical Excitability From Baseline to at 4th Weeksand 12th Weeks Training in Motor Evoked Potential at 120% Resting MotorThreshold at Affected Hand
Electromyographic (EMG) activity in first doral interossei measured at 120% resting motor threshold. The motor evoked potential amplitude will be measured peak to peak in millivolt(mV). Higher value mean better control
Time frame: Baseline and at 4th weeks and at 12th weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rTMS Group + Exercise | Change of Cortical Excitability From Baseline to at 4th Weeksand 12th Weeks Training in Motor Evoked Potential at 120% Resting MotorThreshold at Affected Hand | Baseline | 258.3 millivolt | Standard Deviation 278 |
| rTMS Group + Exercise | Change of Cortical Excitability From Baseline to at 4th Weeksand 12th Weeks Training in Motor Evoked Potential at 120% Resting MotorThreshold at Affected Hand | At 4th week | 323.3 millivolt | Standard Deviation 279.5 |
| rTMS Group + Exercise | Change of Cortical Excitability From Baseline to at 4th Weeksand 12th Weeks Training in Motor Evoked Potential at 120% Resting MotorThreshold at Affected Hand | At 12th week | 369.1 millivolt | Standard Deviation 244.6 |
| Placebo+ Exercise | Change of Cortical Excitability From Baseline to at 4th Weeksand 12th Weeks Training in Motor Evoked Potential at 120% Resting MotorThreshold at Affected Hand | Baseline | 600 millivolt | Standard Deviation 374.6 |
| Placebo+ Exercise | Change of Cortical Excitability From Baseline to at 4th Weeksand 12th Weeks Training in Motor Evoked Potential at 120% Resting MotorThreshold at Affected Hand | At 4th week | 565 millivolt | Standard Deviation 371.7 |
| Placebo+ Exercise | Change of Cortical Excitability From Baseline to at 4th Weeksand 12th Weeks Training in Motor Evoked Potential at 120% Resting MotorThreshold at Affected Hand | At 12th week | 586 millivolt | Standard Deviation 384.9 |
Secondary
Change of Grip Strength From Baseline to at 4th Weeks and at 12th Weeks Training in Force (Kilogram )
Isometric hand grip strength will be measured using the hand-held dynamometer in kilogram (kg). Higher value reflect better hand grip strength
Time frame: Baseline and at 4th weeks and at 12th weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rTMS Group + Exercise | Change of Grip Strength From Baseline to at 4th Weeks and at 12th Weeks Training in Force (Kilogram ) | Baseline | 12.6 kilgograms | Standard Deviation 11.3 |
| rTMS Group + Exercise | Change of Grip Strength From Baseline to at 4th Weeks and at 12th Weeks Training in Force (Kilogram ) | At 4th week | 13.9 kilgograms | Standard Deviation 10.8 |
| rTMS Group + Exercise | Change of Grip Strength From Baseline to at 4th Weeks and at 12th Weeks Training in Force (Kilogram ) | At 12th week | 15.4 kilgograms | Standard Deviation 10.1 |
| Placebo+ Exercise | Change of Grip Strength From Baseline to at 4th Weeks and at 12th Weeks Training in Force (Kilogram ) | Baseline | 13.8 kilgograms | Standard Deviation 10.8 |
| Placebo+ Exercise | Change of Grip Strength From Baseline to at 4th Weeks and at 12th Weeks Training in Force (Kilogram ) | At 4th week | 13.9 kilgograms | Standard Deviation 10.5 |
| Placebo+ Exercise | Change of Grip Strength From Baseline to at 4th Weeks and at 12th Weeks Training in Force (Kilogram ) | At 12th week | 14.4 kilgograms | Standard Deviation 11.1 |
Secondary
Change of Health Status Measurement From Baseline to at 4th Weeks and at 12th Weeks in Stroke Impact Scale
The 59-item Stroke Impact Scale (SIS) is a stroke-specific, self-report, health status measure. Total range from 0 to 100. Higher score reflect better result.
Time frame: Baseline and at 4th & 12 th weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rTMS Group + Exercise | Change of Health Status Measurement From Baseline to at 4th Weeks and at 12th Weeks in Stroke Impact Scale | Baseline | 59 score on a scale | Standard Deviation 13.3 |
| rTMS Group + Exercise | Change of Health Status Measurement From Baseline to at 4th Weeks and at 12th Weeks in Stroke Impact Scale | At 4th week | 64.1 score on a scale | Standard Deviation 8.5 |
| rTMS Group + Exercise | Change of Health Status Measurement From Baseline to at 4th Weeks and at 12th Weeks in Stroke Impact Scale | At 12th week | 68.4 score on a scale | Standard Deviation 6.9 |
| Placebo+ Exercise | Change of Health Status Measurement From Baseline to at 4th Weeks and at 12th Weeks in Stroke Impact Scale | Baseline | 65.7 score on a scale | Standard Deviation 10.3 |
| Placebo+ Exercise | Change of Health Status Measurement From Baseline to at 4th Weeks and at 12th Weeks in Stroke Impact Scale | At 4th week | 69.6 score on a scale | Standard Deviation 11.2 |
| Placebo+ Exercise | Change of Health Status Measurement From Baseline to at 4th Weeks and at 12th Weeks in Stroke Impact Scale | At 12th week | 72.7 score on a scale | Standard Deviation 11.6 |
Secondary
Change of Reaction Time From Baseline to at 4th Weeks and at 12th Weeks Training in Time Measurement (Seconds)
A simple reaction time will be recorded through a computer system. Time for the patient to reaction to the signal will be measured in seconds (sec). Shorter period of time reflect better reaction time.Lower score means better result
Time frame: Baseline and at 4th weeks and at 12th weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rTMS Group + Exercise | Change of Reaction Time From Baseline to at 4th Weeks and at 12th Weeks Training in Time Measurement (Seconds) | Baseline | 985.8 seconds | Standard Deviation 439.9 |
| rTMS Group + Exercise | Change of Reaction Time From Baseline to at 4th Weeks and at 12th Weeks Training in Time Measurement (Seconds) | At 4th week | 902.2 seconds | Standard Deviation 398.6 |
| rTMS Group + Exercise | Change of Reaction Time From Baseline to at 4th Weeks and at 12th Weeks Training in Time Measurement (Seconds) | At 12th week | 837.3 seconds | Standard Deviation 309.1 |
| Placebo+ Exercise | Change of Reaction Time From Baseline to at 4th Weeks and at 12th Weeks Training in Time Measurement (Seconds) | Baseline | 654.2 seconds | Standard Deviation 285.5 |
| Placebo+ Exercise | Change of Reaction Time From Baseline to at 4th Weeks and at 12th Weeks Training in Time Measurement (Seconds) | At 4th week | 651.7 seconds | Standard Deviation 285.4 |
| Placebo+ Exercise | Change of Reaction Time From Baseline to at 4th Weeks and at 12th Weeks Training in Time Measurement (Seconds) | At 12th week | 637.9 seconds | Standard Deviation 291.2 |
Secondary
Change of Upper Limb Function From Baseline to at 4th Weeks Training in Action Research Arm Test (ARAT) Scale
The 19-item Action Research Arm Test has four subscales that assess various aspects of upper limb function (i.e., pinch, grip, grasp, and gross motor). Each item was rated on a 4-point scale from 0 to 3. Scale from 0 to 57.A higher score was indicative of better upper limb function.
Time frame: Baseline and at 4th weeks and at 12th weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rTMS Group + Exercise | Change of Upper Limb Function From Baseline to at 4th Weeks Training in Action Research Arm Test (ARAT) Scale | Baseline | 36.5 units on a scale | Standard Deviation 17.8 |
| rTMS Group + Exercise | Change of Upper Limb Function From Baseline to at 4th Weeks Training in Action Research Arm Test (ARAT) Scale | At 4th week | 45.4 units on a scale | Standard Deviation 11.4 |
| rTMS Group + Exercise | Change of Upper Limb Function From Baseline to at 4th Weeks Training in Action Research Arm Test (ARAT) Scale | At 12th week | 51.1 units on a scale | Standard Deviation 8.9 |
| Placebo+ Exercise | Change of Upper Limb Function From Baseline to at 4th Weeks Training in Action Research Arm Test (ARAT) Scale | Baseline | 41.1 units on a scale | Standard Deviation 17.8 |
| Placebo+ Exercise | Change of Upper Limb Function From Baseline to at 4th Weeks Training in Action Research Arm Test (ARAT) Scale | At 4th week | 41.1 units on a scale | Standard Deviation 1.13 |
| Placebo+ Exercise | Change of Upper Limb Function From Baseline to at 4th Weeks Training in Action Research Arm Test (ARAT) Scale | At 12th week | 43.2 units on a scale | Standard Deviation 17.9 |
Secondary
Change of Upper Limb Impairment From Baseline to at 4th Weeks & 12 th Weeks Training in Fugl-Meyer Assessment (FM) Scale
Fugl-Meyer Assessment (FM) scale is a stroke-specific, performance-based impairment index, the scale range from 0 to 66. 25 test items included measurement of movement, coordination, and reflex action of the different parts of the paretic upper extremity. The score could range from 0 to 66. Better motor function was reflected by a higher FMA score
Time frame: Baseline and at 4th weeks and at 12th weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rTMS Group + Exercise | Change of Upper Limb Impairment From Baseline to at 4th Weeks & 12 th Weeks Training in Fugl-Meyer Assessment (FM) Scale | Baseline | 46.7 score on a scale | Standard Deviation 13.9 |
| rTMS Group + Exercise | Change of Upper Limb Impairment From Baseline to at 4th Weeks & 12 th Weeks Training in Fugl-Meyer Assessment (FM) Scale | At 4th week | 52.3 score on a scale | Standard Deviation 11.9 |
| rTMS Group + Exercise | Change of Upper Limb Impairment From Baseline to at 4th Weeks & 12 th Weeks Training in Fugl-Meyer Assessment (FM) Scale | At 12th week | 57.0 score on a scale | Standard Deviation 9.6 |
| Placebo+ Exercise | Change of Upper Limb Impairment From Baseline to at 4th Weeks & 12 th Weeks Training in Fugl-Meyer Assessment (FM) Scale | Baseline | 48.8 score on a scale | Standard Deviation 14.9 |
| Placebo+ Exercise | Change of Upper Limb Impairment From Baseline to at 4th Weeks & 12 th Weeks Training in Fugl-Meyer Assessment (FM) Scale | At 4th week | 49.9 score on a scale | Standard Deviation 15.3 |
| Placebo+ Exercise | Change of Upper Limb Impairment From Baseline to at 4th Weeks & 12 th Weeks Training in Fugl-Meyer Assessment (FM) Scale | At 12th week | 53.3 score on a scale | Standard Deviation 16.4 |