Effects of rTSMS Associated With Treadmill Training in Patients With Parkinson's Disease

Study Overview
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Brief Summary
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Gait changes appear and become the main cause of disability, loss of independence, falls, fractures and reduced quality of life for patients with Parkinson Disease. Optimal gait management is complex and challenging. Some characteristics, such as gait variability, postural instability, and postural changes, continue to worsen over time despite optimal dopaminergic treatment, suggesting that additional interventions are needed. Given the physiology of gait and postural control in humans, spinal cord stimulation is a potential target for neuromodulatory approaches to gait and postural disorders. Repetitive transspinal magnetic stimulation ( rTSMS) has attracted a lot of attention, due to the possibility of modulating motor and sensory networks in a non-invasive way, activating directly the dorsal ascending pathways and projecting to the thalamic nuclei, cerebral cortex, and brainstem nuclei, thus stimulating descending motor tracts and interrupting aberrant oscillatory activity in corticobasal nuclei circuits. The combination of non-invasive neuromodulation with other therapies can enhance the effectiveness of rehabilitation, increasing plasticity and clinical efficacy, offering a greater and more sustained effect than either therapy alone.It's recommended that patients with PD perform a specific exercise for walking, such as treadmill training (tt), that imposes an external rhythm and concentration of attention on gait, acting as an external cue or marker, promoting a more stable gait, reducing gait variability and decreasing risk of falls. It is proposed, in this study, to develop a new treatment model through the integration of two promising and complementary approaches to improve gait disorders in PD: rTSMS and tt. Thus, the investigators idealized the realization of the first randomized, double-blind, placebo-controlled, parallel, phase III clinical trial that will evaluate the efficacy of tt associated with rTSMS in patients with PD.

Detailed Description
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The primary objective is to evaluate the effects of treadmill gait training associated with repetitive transspinal magnetic stimulation on the change in rapid gait speed in Parkinson Disease patients. The investigators hypothesize that the association of repetitive transspinal magnetic stimulation with treadmill gait training should be superior to treadmill gait training alone in improving gait symptoms in patients with PD. Additionally, will be investigated the effects of treadmill gait training associated with repetitive transspinal magnetic stimulation on comfortable gait speed; in clinical and neurophysiological measures; in motor symptoms; in activities of daily living; in the ability to walk (total distance covered); in balance performance; in time to complete the turn; in the severity of the freezing of the gait; in mobility; in the level of physical activity; in the number and fear of falls and in the perception of quality of life of patients with PD. In addition, the possible side effects of the intervention will be evaluated.

Official Title
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Effects of Repetitive Trans Spinal Magnetic Stimulation Associated With Treadmill Gait Training on Gait Disorders in Patients With Parkinson's Disease

Conditions
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Parkinson Disease, Gait Disorders, Neurologic

Intervention / Treatment
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* Other: Active stimulation- intermittent theta-burst (iTBS) stimulation
* Other: Sham stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women over the age of 18; Participants with PD at Hoehn Yahr stages between 2 and 4 (moderate disease) while on-medication (i.e., at the time when their usual dopaminergic medication is clinically effective), whose primary symptom includes gait disturbance (score equal to or greater than 1 in subitem 2.12 of the MSD-UPDRS scale). Patients will be evaluated for the presence of freezing gait (freezing) through the Freezing of Gait Score (FOG-SCORE). While on on-medication, be able to walk independently for 30 meters or with a unilateral assistive device. Mini Mental State Examination (MMSE) score greater than or equal to 23. Sign the informed consent form. Exclusion Criteria: Patients with unstabilized psychiatric comorbidities; Individuals who have other neurological disorders, musculoskeletal, orthopedic, cardiovascular and respiratory disorders that may affect the ability to walk on the treadmill will be excluded. Individuals with labyrinthine problems, using medication that may interfere with balance and performance in tests and treadmill training will be excluded. Individuals who have undergone deep brain stimulation surgery or epidural spinal cord stimulation will be excluded. Patients with uncontrolled infection or other uncontrolled pre-existing medical conditions (eg uncontrolled diabetes, high blood pressure, symptomatic lung or heart disease); Concomitant treatment with other experimental drugs; Pregnant or breastfeeding women. Presence of chronic low back and lower limb pain. Patients who cannot walk without assistance (cane, crutch, walker) or help from another person. Patients with metal implants and a cardiac pacemaker. Patient with a history of neurosurgery.

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: randomized, double-blind, placebo-controlled, parallel, phase III clinical trial.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Sham repetitive transpinal magnetic stimulation<br>In the Sham group a coil will be positioned in the T2-T3 thoracic region disconnected to the stimulation device and the active coil will be positioned about 15 cm behind the patient, away from his field of vision, to provide sound stimulus. | Other: Sham stimulation<br>* During sham stimulation, a circular magnetic coil will be positioned in the T2-T3 toracic region disconnected to the stimulation device and the active coil will be positioned about 15 cm behind the patient, away from his field of vision, to provide sound stimulus. To create a sensation of muscle contraction and impression of active stimulation, the group will be submitted to the sensory effect of transcutaneous electrical neurostimulation (TENS) for 5 minutes, with surface electrodes placed in parallel at the T2-T3, with the parameters (80Hz,150ms, 60 mA).Immediately after, participants will proceed with 30 minutes of treadmill training, starting at 80% of the comfortable walking speed. Progressive speed increments of 0.2 km/h will be performed every 5 minutes as tolerated. The intensity of the exercise will be adjusted to the patient's tolerance and maintained between light to moderate intensity.<br>|
| Active Comparator: Active repetitive transpinal magnetic stimulation<br>In the Active group, the patient will receive intermittent theta burst stimulation (iTBS) in the T2-T3 region while seated using a circular magnetic coil positioned at 90º, handle facing to the right, connected to a magnetic stimulator. | Other: Active stimulation- intermittent theta-burst (iTBS) stimulation<br>* During active stimulation, patients will receive intermittent theta-burst (iTBS) stimulation in T2-T3 toracic region while seated using a circular magnetic coil positioned at 90º, handle facing to the right, connected to a magnetic stimulator.Each participant will receive a total of 1,200 rTsMS pulses at 120% of resting motor threshold, determined by abdominal muscle contractions. In 3 minutes and 58 seconds, 20 trains with 20 bursts and each burst with 3 pulses at 50 Hz repeated at 5Hz with an intertrain interval of 8 seconds will be applied.Immediately after, participants will proceed with 30 minutes of treadmill training, starting at 80% of the comfortable walking speed. Progressive speed increments of 0.2 km/h will be performed every 5 minutes as tolerated. The intensity of the exercise will be adjusted to the patient's tolerance and maintained between light to moderate intensity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 10 meter walk test- Fast walking speed | Comparison of the change in fast gait speed between active stimulation and sham stimulation during Baseline, right after the end of the 10th session and follow-up (1 month and 3 months post-intervention). Longer time to complete the test results in slower gait speed and worse performance | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 10 meter walk test- Confortable walking speed | Comparison of the change in confortable gait speed between active stimulation and sham stimulation during Baseline, right after the end of the 10th session and follow-up (1 month and 3 months post-intervention). Longer time to complete the test results in slower gait speed and worse performance | 4 months | 
| Unified Parkinson's Disease Rating Scale (MDS-UPDRS) - Part II and III | Comparison of change in Unified Parkinson's Disease Rating Scale score part II and III between active stimulation and sham stimulation in Baseline, right after the end of the 10th session and follow-up (1 month and 3 months post-intervention).MDS-PDRS part II is scored from 0 to 52 with higher scores associated with worse motor related daily activities performance. MDS-UPDRS part III is scored from 0 to 132 with higher scores associated with worse motor performance in parkinson related tests. | 4 months | 
| Freezing of Gait Score- (FOG- SCORE) | Comparison of the change in the severity of gait freezing between active stimulation and sham stimulation in Baseline, right after the end of the 10th session and follow-up (1 month and 3 months post-intervention). The Severity of gait freezing will be evaluated through the Freezing of Gait Score.The score was the sum of the 12 items and it ranges from 0 to 36 points. the higher the score, the worse the performance and severity of gait freezing. | 4 months | 
| 2 Minute Walk Test | Comparison of the change in the Walking capacity (total distance covered) and speed,evaluated through the 2 Minute Walk Test, between active stimulation and sham stimulation in Baseline, right after the end of the 10th session and follow-up (1 month and 3 months post-intervention). A shorter distance covered during 2 minutes results in a slower speed to complete the test and worse performance. | 4 months | 
| Timed up and Go (TUG) | Comparison of the change in the functional mobility between active stimulation and sham stimulation in Baseline, right after the end of the 10th session and follow-up (1 month and 3 months post-intervention), that will be evaluated through the Timed up and Go test. The time average of two measurements will be calculated. A longer average time to complete the test results in worse performance | 4 months | 
| Timed up and Go Dual Task (TUG-DT) | Comparison of the change in the Dual-task performance between active stimulation and sham stimulation Baseline, right after the end of the 10th session and follow-up (1 month and 3 months post-intervention), that will be evaluated through the Timed up and Go Dual Task test. The time average of two measurements will be calculated. A longer average time to complete the test results in worse performance | 4 months | 
| Timed 360° turn test | Comparison of the change in the time to complete the turn between active stimulation and sham stimulation in Baseline, right after the end of the 10th session and follow-up (1 month and 3 months post-intervention), that will be evaluated through the Timed 360° turn test. Will be taken 3 measurements for each side and the average of time and of the number of steps required to complete the turn will be calculated. A longer time and a greater number of steps to complete the turn suggests a greater commitment and worse performance | 4 months | 
| Mini-Balance Evaluation Systems Test (Mini-BESTest) | Comparison of change in the Balance performance between active stimulation and sham stimulation in Baseline, right after the end of the 10th session and follow-up (1 month and 3 months post-intervention), that will be measured through the Mini-Balance Evaluation Systems Test that includes 14 items scored from 0 to 2, with a maximum score of 28 and a minimum of 0, with a higher score indicating better balance performance. | 4 months | 
| Freezing of Gait Questionnaire (FOG-Q) | Comparison of change in the subjective perception of the severity and impact of freezing on gait performance between active stimulation and sham stimulation in Baseline, 15 days after the end of the 10th session (questionnaire will be applied by phone call at that time) and at follow-up (1 month and 3 months post-intervention), that will be measured through the Freezing of Gait Questionnaire, that is rated on a 5-point scale (0 to 4), with a total score ranging from 0 to 24. A higher score implies that the individual's gait performance is more affected by freezing | 4 months | 
| Falls and near falls | The occurrence of falls and near-falls will be investigated through self-report and will be compared between groups in Baseline, right after the end of the 10th session and follow-up (1 month and 3 months post-intervention). The classification of fallers and non-fallers will be obtained. | 4 months | 
| Human Activity profile (HAP) | Comparison of change in the Level of physical activity between active stimulation and sham stimulation in Baseline, 15 days after the end of the 10th session (questionnaire will be applied by phone call at that time) and at follow-up (1 month and 3 months post-intervention), that will be measured through the Human Activity profile. Tare arranged in ascending order of energy cost.Based on each response, the primary scores are calculated: the maximum activity score (EMA) and the adjusted activity score (EAA).The EAA will be used in this study. The classification of physical activity level will be established through pre-defined cutoff points, with individuals classified as inactive (less than 53), moderately active (between 53 and 74) or active (greater than 74). An increase in the score indicates an improvement in the level of physical activity | 4 months | 
| Falls Efficacy Scale- International (FES-I) | Comparison of change in the Fear of falls between active stimulation and sham stimulation in Baseline, 15 days after the end of the 10th session (questionnaire will be applied by phone call at that time) and at follow-up (1 month and 3 months post-intervention), that will be measured through the Falls Efficacy Scale- International, that presents questions about the concern with the possibility of falling when performing 16 activities. The total score is calculated by adding the values obtained in each item and can vary from 16 to 64 points, in which the lowest value corresponds to the absence of concern and the highest value to extreme concern regarding falls while carrying out the activities in the questionnaire. Thus, the higher the final score obtained, the lower the self-efficacy related to falls. | 4 months | 
| Parkinson's Disease Questionnaire -39 (PDQ-39) | The perception of quality of life will be measured in Baseline, 15 days after the end of the 10th session (questionnaire will be applied by phone call at that time) and at follow-up (1 month and 3 months post-intervention) through the Parkinson's Disease Questionnaire -39 which is scored is from 0 to 100, higher values are associated with worse quality of life. | 4 months | 
| Non-Motor Symptoms Scale (NMSS) | Comparison of change in the Non-Motor Symptoms between active stimulation and sham stimulation in Baseline, 15 days after the end of the 10th session (questionnaire will be applied by phone call at that time) and at follow-up (1 month and 3 months post-intervention) , that will be measured through the Non-Motor Symptoms Scale. The NMSS consists of 30 items and each item's score is based on severity (from 0 to 3) and frequency scores (from 1 to 4).The range for the NMSS total scores is 0-360. Higher scores indicate greater severity of non-motor symptoms | 4 months | 
| The Parkinson Disease Pain Classification System (PD-PCS) | Comparison of change in pain between active stimulation and sham stimulation in Baseline, 15 days after the end of the 10th session (questionnaire will be applied by phone call at that time) and at follow-up (1 month and 3 months post-intervention), that will be measured through Parkinson Disease Pain Classification System, which scores and classifies parkinson disease-related pain into 3 groups (nociceptive, neuropathic or nociplastic), in relation to intensity, frequency and interference in activities of daily living. Higher scores indicate greater severity of pain | 4 months | 
| Study of motor evoked potentials (MEPS) | Motor evoked potentials (MEPs) induced by transcranial magnetic stimulation (TMS) will be measured in active and sham stimulation, before the protocol starts and immediately after the 10th session.Thus, in the present study, we sought to evaluate the effects of rTSMS on the characteristics of MEPs at baseline and shortly after the end of the 10th session, evaluating whether rTSMS is a useful technique to facilitate downward impulse and promote motor function in PD. | 10 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-invasive brain stimulation, Parkinson's disease, Spinal cord stimulation, gait