Parkinson Disease
Conditions
Keywords
Parkinson's Disease, Brain Stimulation, Motor Cortex, Bradykinesia, Parkinson Disease, PD
Brief summary
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
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.
Interventions
DEVICEReal iTBS
Real iTBS was performed in 8 sessions over 2 successive weeks, a session/day for 4 consecutive days/week.
DEVICESham iTBS
Sham iTBS was performed in 8 sessions over 2 successive weeks, a session/day for 4 consecutive days/week.
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Mark Hallett
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Gait Speed | baseline, 1 day post iTBS | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bradykinesia | baseline, 1 day post iTBS | 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. |
| Total UPDRS Score | baseline, 1 day post iTBS | 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. |
| Motor UPDRS | baseline, 1 day post iTBS | 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). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Real iTBS iTBS is a novel form of excitatory rTMS that may induce larger and longer lasting changes than standard rTMS. iTBS consists of bursts of 3 pulses at 50 Hz repeated at 200 msec intervals. | 13 |
| Sham iTBS Sham iTBS | 13 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Total | Real iTBS | Sham iTBS |
|---|---|---|---|
| Age Continuous | 63.85 years STANDARD_DEVIATION 8.05 | 62.1 years STANDARD_DEVIATION 6.9 | 65.6 years STANDARD_DEVIATION 9 |
| Duration of disease | 8.62 years STANDARD_DEVIATION 5.87 | 10.8 years STANDARD_DEVIATION 7.1 | 6.5 years STANDARD_DEVIATION 3.4 |
| Dyskinesias Absence of dyskinesias | 15 participants | 4 participants | 11 participants |
| Dyskinesias Presence of dyskinesias | 11 participants | 9 participants | 2 participants |
| Falls Absence of falls | 25 participants | 12 participants | 13 participants |
| Falls Presence of falls | 1 participants | 1 participants | 0 participants |
| Fluctuations Absence of flucuations | 11 participants | 2 participants | 9 participants |
| Fluctuations Presence of fluctuations | 15 participants | 11 participants | 4 participants |
| Gait freezing Absence of gait freezing | 13 participants | 3 participants | 10 participants |
| Gait freezing Presence of gait freezing | 13 participants | 10 participants | 3 participants |
| Hoehn-Yahr off | 2.90 units on a scale STANDARD_DEVIATION 0.32 | 3.0 units on a scale STANDARD_DEVIATION 0.4 | 2.9 units on a scale STANDARD_DEVIATION 0.2 |
| Hoehn-Yahr on | 2.52 units on a scale STANDARD_DEVIATION 0.17 | 2.6 units on a scale STANDARD_DEVIATION 0.2 | 2.5 units on a scale STANDARD_DEVIATION 0.1 |
| Sex: Female, Male Female | 8 Participants | 6 Participants | 2 Participants |
| Sex: Female, Male Male | 18 Participants | 7 Participants | 11 Participants |
| Total LED | 956.6 milligrams STANDARD_DEVIATION 565.7 | 1180.9 milligrams STANDARD_DEVIATION 662.4 | 732.3 milligrams STANDARD_DEVIATION 344.8 |
| Tremor Absence of tremor | 7 participants | 3 participants | 4 participants |
| Tremor Presence of tremor | 19 participants | 10 participants | 9 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 13 | 1 / 13 |
| serious Total, serious adverse events | 0 / 13 | 1 / 13 |
Outcome results
Primary
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.
Time frame: baseline, 1 day post iTBS
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| On Medication Real iTBS | Gait Speed | baseline | 8.35 seconds | Standard Deviation 1.98 |
| On Medication Real iTBS | Gait Speed | 1 day post | 7.68 seconds | Standard Deviation 2.02 |
| On Medication Sham iTBS | Gait Speed | 1 day post | 7.96 seconds | Standard Deviation 2.02 |
| On Medication Sham iTBS | Gait Speed | baseline | 8.41 seconds | Standard Deviation 1.98 |
| Off Medication Real iTBS | Gait Speed | baseline | 25.84 seconds | Standard Deviation 26.1 |
| Off Medication Real iTBS | Gait Speed | 1 day post | 10.88 seconds | Standard Deviation 3.81 |
| Off Medication Sham iTBS | Gait Speed | baseline | 8.80 seconds | Standard Deviation 25 |
| Off Medication Sham iTBS | Gait Speed | 1 day post | 8.20 seconds | Standard Deviation 3.66 |
Secondary
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.
Time frame: baseline, 1 day post iTBS
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| On Medication Real iTBS | Bradykinesia | baseline | 13.69 seconds | Standard Deviation 5.33 |
| On Medication Real iTBS | Bradykinesia | 1 day post | 10.32 seconds | Standard Deviation 3.48 |
| On Medication Sham iTBS | Bradykinesia | baseline | 13.25 seconds | Standard Deviation 5.33 |
| On Medication Sham iTBS | Bradykinesia | 1 day post | 10.88 seconds | Standard Deviation 3.48 |
| Off Medication Real iTBS | Bradykinesia | baseline | 17.23 seconds | Standard Deviation 8.1 |
| Off Medication Real iTBS | Bradykinesia | 1 day post | 14.20 seconds | Standard Deviation 7.78 |
| Off Medication Sham iTBS | Bradykinesia | 1 day post | 10.80 seconds | Standard Deviation 4.03 |
| Off Medication Sham iTBS | Bradykinesia | baseline | 14.20 seconds | Standard Deviation 7.78 |
Secondary
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).
Time frame: baseline, 1 day post iTBS
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| On Medication Real iTBS | Motor UPDRS | baseline | 32.00 units on a scale | Standard Deviation 12.86 |
| On Medication Real iTBS | Motor UPDRS | 1 day post | 29.08 units on a scale | Standard Deviation 12.13 |
| On Medication Sham iTBS | Motor UPDRS | 1 day post | 32.31 units on a scale | Standard Deviation 12.13 |
| On Medication Sham iTBS | Motor UPDRS | baseline | 37.54 units on a scale | Standard Deviation 12.86 |
| Off Medication Real iTBS | Motor UPDRS | baseline | 49.00 units on a scale | Standard Deviation 12.88 |
| Off Medication Real iTBS | Motor UPDRS | 1 day post | 43.92 units on a scale | Standard Deviation 12.59 |
| Off Medication Sham iTBS | Motor UPDRS | baseline | 45.69 units on a scale | Standard Deviation 12.38 |
| Off Medication Sham iTBS | Motor UPDRS | 1 day post | 41.31 units on a scale | Standard Deviation 12.1 |
Secondary
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.
Time frame: baseline, 1 day post iTBS
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| On Medication Real iTBS | Total UPDRS Score | baseline | 55.54 units on a scale | Standard Deviation 15.81 |
| On Medication Real iTBS | Total UPDRS Score | 1 day post | 51.08 units on a scale | Standard Deviation 16.37 |
| On Medication Sham iTBS | Total UPDRS Score | 1 day post | 47.62 units on a scale | Standard Deviation 16.37 |
| On Medication Sham iTBS | Total UPDRS Score | baseline | 57.15 units on a scale | Standard Deviation 15.81 |
| Off Medication Real iTBS | Total UPDRS Score | baseline | 77.85 units on a scale | Standard Deviation 17.05 |
| Off Medication Real iTBS | Total UPDRS Score | 1 day post | 70.85 units on a scale | Standard Deviation 16.26 |
| Off Medication Sham iTBS | Total UPDRS Score | baseline | 65.92 units on a scale | Standard Deviation 17.05 |
| Off Medication Sham iTBS | Total UPDRS Score | 1 day post | 70.85 units on a scale | Standard Deviation 16.26 |