Transcranial Magnetic Stimulation to Treat Parkinson's Disease

Study Overview
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Brief Summary
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This study will look at the effects of transcranial magnetic stimulation (TMS) on symptoms of Parkinson's disease. TMS is a method of brain stimulation that may be able to change the activity of the nerve cells of the brain. This study will examine the effects of a specific pattern of stimulation called intermittent theta-burst TMS (iTBS), which uses repeated magnetic pulses delivered in short bursts. People with mild to moderately severe Parkinson's disease who are between 40 and 80 years of age and whose main problems are slow movement and stiffness may be eligible for this study. Participants undergo the following tests and procedures: Random assignment to real or placebo (sham) iTBS treatment. iTBS sessions (real or sham) 4 times a week for 2 consecutive weeks. For this test, the subject sits in a comfortable chair. A wire coil is held on the subject's scalp, and a brief electrical current is passed through the coil, creating a magnetic pulse that stimulates the brain. The subject hears a click and may feel a pulling sensation on the skin under the coil. There may be a twitch in the muscles of the face, arm or leg. Test of gait (walk), hand and arm movements before and after each session. The gait test requires walking 10 meters (about 30 yards) in the same corridor with the same shoes. Extended testing. The first and last gait tests (done before starting iTBS and after the eighth session) require coming off any Parkinson's medication for at least 12 hours before the test. On these test days, subjects also undergo a clinical examination, short neuropsychological test battery, a computer-based reaction time test and depression and quality-of-life rating scales. These procedures are repeated in a follow-up visit 1 month after the last session.

Detailed Description
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Objective To demonstrate cumulative and long-lasting improvement of parkinsonian symptoms by iTBS and its safety in PD patients. Study population Patients (40-80 years of age) with PD, Hoehn and Yahr disease stage of 2 to 4 while off, being on a regimen including levodopa with a total dose of medication equal to more than 300 mg of levodopa, including their dopamine agonist agents, and having problems with walking and needing 6 seconds or more to walk a 10-meter distance. Design Randomized, double-blind, placebo (sham)-controlled study. Enrollment of 30 patients with PD in 2 groups (real versus sham stimulation). Performance (8 interventions) of iTBS with large circular coil over motor and prefrontal cortex on both sides. Assessment with standard tests of motor function over a one-month period. Outcome measure The primary endpoint is change in gait speed as assessed by the time it takes to walk 10 m. Secondary endpoints include changes in bradykinesia as assessed by measuring the time it takes to do ten combined hand and arm movements, and in total and motor UPDRS score.

Official Title
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Intermittent Theta-Burst Transcranial Magnetic Stimulation (TBS) for the Treatment of Parkinson Disease

Conditions
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Parkinson Disease

Intervention / Treatment
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* Device: Real iTBS
* Device: Sham iTBS


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Men and women aged 40 to 80 years with DOPA-responsive PD Hoehn and Yahr grade of 2 to 4 while off Must be on a regimen including levodopa. Total dose of levodopa and dopamine agonists (using dopamine equivalents) has to be equal to or more than 300 milligrams per day Problems with walking, including freezing gait time for a 10-meter distance greater than six seconds or more EXCLUSION CRITERIA: Any active psychiatric disease or evidence of dementia History of seizures and epilepsy Concurrent use of tricyclic antidepressants, neuroleptic agents, or any other licit or illicit drugs other than anti-parkinsonian agents that could lower the seizure threshold except for SSRI Pallidotomy, implanted electrodes and generator for deep brain stimulation Pregnancy Surgically or traumatically implanted foreign bodies such as a pacemaker, implanted medical pump, implanted hearing aids, metal plate in the skull, or metal implant in the skull or eyes (other than dental appliances or fillings) that may pose a physical hazard during TEP. Study would cause undue risk or stress for reasons such as tendency to fall, excessive fatigue, general frailty, or excessive apprehensiveness. Dementia as assessed by the Folstein's Mini-Mental Test Examination (MMSE less than or equal to 24/30) or mentally impaired patients having no capacity to provide their own consent (the physician establishing the diagnosis and applying UPDRS will evaluate patient's mental capacity using conventional clinical interview) Unable to walk a 10-meter distance. More than occasional falls, i.e. daily falls (corresponding to a score greater than or equal to 3 and more in UPDRS item 13), history of fall(s) with significant injuries, absence of postural response in the on condition and/or spontaneous loss of balance in the off condition (corresponding to a score of greater than or equal to 2 and greater than or equal to 3 in on/off condition, respectively, in UPDRS item 30) Pregnancy is unusual in patients with PD, grade 2-4. Urine sample for the pregnancy test will be obtained in patients of childbearing potential prior to the iTBS start, at the day of the initial interview and signing the consent form. Women of childbearing potential will be asked to take appropriate measures to prevent a pregnancy during the study.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Real iTBS<br>iTBS is a novel form of excitatory rTMS that may induce larger and longer lasting changes that standard rTMS. iTBS consists of bursts of 3 pulses at 50 Hz repeated at 200 msec intervals. The 2 sec trains were repeated 20 times every 10 sec. iTBS was applied to the primary motor and the dorsolateral prefrontal cortex bilaterally. | Device: Real iTBS<br>* Real iTBS was performed in 8 sessions over 2 successive weeks, a session/day for 4 consecutive days/week.<br>|
| Sham Comparator: Sham iTBS<br>The sham coil was placed in the same areas, and made a similar sound as the rTMS but was without a magnetic pulse. | Device: Sham iTBS<br>* Sham iTBS was performed in 8 sessions over 2 successive weeks, a session/day for 4 consecutive days/week.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gait Speed | Gait speed was assessed by measuring the time it takes to walk 10 meters. Subject's gait speed was measured while on medication and off medication for each group, i.e., real iTBS and sham iTBS. Two trials were averaged for each condition. Patients were instructed to walk fast without taking the risk of falling, wearing the same shoes and consistently using assistive devices if needed. Gait speed was measured at baseline, 1 day post intervention, and 1 month post intervention. | baseline, 1 day post iTBS | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bradykinesia | Bradykinesia refers to the slowness in executing a movement. Bradykinesia was assessed by measuring the time in seconds it takes to do the following sequence, 10 times: 1) hand closing and opening while squeezing a ball 2) elbow flexion 3) hand closing and opening, and 4) elbow extension. Subjects were allowed to practice these hand and arm movements until performance appeared not to get faster, and then were abstained from further practice to minimize learning effects. The time it takes subjects to execute the entire sequence 10 times with either the left or right arm/hand was measured. Means are reported for each group. | baseline, 1 day post iTBS | 
| Total UPDRS Score | The Total Unified Parkinson's Disease Rating Scale (UPDRS) is an overall assessment scale that quantifies the signs and symptoms of Parkinson's disease. The total UPDRS score consists of mentation, behavior, mood, activities of daily living and motor components, and ranges from 0 (not affected) to 176 (most severely affected). The total UPDRS score is obtained from patient examination, interview and patient questionnaires. | baseline, 1 day post iTBS | 
| Motor UPDRS | The Motor Unified Parkinson's Disease Rating Scale (UPDRS) includes only the motor assessment of the UPDRS (Part III) and examines speech, facial expression, tremor at rest, action tremor, rigidity, finger taps, hand movements, hand pronation and supination, leg agility, arising from chair, posture, gait, postural stability and body bradykinesia. The scores range from 0 (no motor impairment) to 108 (severe motor impairment). | baseline, 1 day post iTBS | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PD, Parkinson's Disease, Brain Stimulation, Motor Cortex, Bradykinesia, Parkinson Disease