Trial Outcomes & Findings for rTMS for Motor and Mood Symptoms of Parkinson's Disease (NCT NCT01080794)

Last Updated: 2017-04-13

Results Overview

To evaluate the motor symptoms in Parkinson's Disease. The UPDRS-III mean scores were reported for each group at each time point. The UPDRS-III Score Range is 0 - 56, where higher the score indicates greater severity of the motor symptoms.

Recruitment status

COMPLETED

Study phase

Target enrollment

61 participants

Primary outcome timeframe

Pre-treatment; Post-treatment 0,1,3, and 6 months.

Results posted on

2017-04-13

Participant Flow

Subjects were screened and enrolled from 6 clinical centers in the United States and 1 clinical center in Canada.

We enrolled 61 subjects into this study with a previous enrollment goal of 85. Interim analysis revealed that 61 subjects provided sufficient power for data analysis, therefore we stopped recruitment.

Participant milestones

Participant milestones
Measure	Double rTMS High frequency rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	M1 Active rTMS + DLPFC Sham rTMS High frequency stimulation of the primary motor cortex (M1) and sham stimulation of the dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	DLPFC Active rTMS + M1 Sham rTMS High frequency stimulation of the dorsolateral prefrontal cortex (DLPFC) and sham stimulation of the primary motor cortex (M1). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	Double Sham rTMS Sham rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.
Overall Study STARTED	20	14	12	15
Overall Study COMPLETED	15	12	10	13
Overall Study NOT COMPLETED	5	2	2	2

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

rTMS for Motor and Mood Symptoms of Parkinson's Disease

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Double rTMS n=20 Participants High frequency rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	M1 Active rTMS + DLPFC Sham rTMS n=14 Participants High frequency stimulation of the primary motor cortex (M1) and sham stimulation of the dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	DLPFC Active rTMS + M1 Sham rTMS n=12 Participants High frequency stimulation of the dorsolateral prefrontal cortex (DLPFC) and sham stimulation of the primary motor cortex (M1). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	Double Sham rTMS n=15 Participants Sham rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	Total n=61 Participants Total of all reporting groups
Age, Continuous	68.2 years STANDARD_DEVIATION 8.0 • n=5 Participants	62.7 years STANDARD_DEVIATION 13.0 • n=7 Participants	67.3 years STANDARD_DEVIATION 12.7 • n=5 Participants	66.2 years STANDARD_DEVIATION 12.7 • n=4 Participants	66.3 years STANDARD_DEVIATION 10.1 • n=21 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	5 Participants n=7 Participants	6 Participants n=5 Participants	4 Participants n=4 Participants	24 Participants n=21 Participants
Sex: Female, Male Male	11 Participants n=5 Participants	9 Participants n=7 Participants	6 Participants n=5 Participants	11 Participants n=4 Participants	37 Participants n=21 Participants

PRIMARY outcome

Timeframe: Pre-treatment; Post-treatment 0,1,3, and 6 months.

Outcome measures

Outcome measures
Measure	Double rTMS n=20 Participants High frequency rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	M1 Active rTMS + DLPFC Sham rTMS n=14 Participants High frequency stimulation of the primary motor cortex (M1) and sham stimulation of the dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	DLPFC Active rTMS + M1 Sham rTMS n=12 Participants High frequency stimulation of the dorsolateral prefrontal cortex (DLPFC) and sham stimulation of the primary motor cortex (M1). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	Double Sham rTMS n=15 Participants Sham rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.
Motor Subscale of the Unified Parkinson's Disease Rating Scale (UPDRS Part III) Baseline (Pre-Treatment)	32.3 units on a scale Standard Deviation 8.9	33.1 units on a scale Standard Deviation 7.8	32.8 units on a scale Standard Deviation 10.7	28.9 units on a scale Standard Deviation 6.4
Motor Subscale of the Unified Parkinson's Disease Rating Scale (UPDRS Part III) Week 1 Post-Treatment	31.2 units on a scale Standard Deviation 12.5	27.4 units on a scale Standard Deviation 8.8	30.3 units on a scale Standard Deviation 14.6	28.2 units on a scale Standard Deviation 8.8
Motor Subscale of the Unified Parkinson's Disease Rating Scale (UPDRS Part III) Month 1 Post-Treatment	30.1 units on a scale Standard Deviation 9.4	28.1 units on a scale Standard Deviation 9.1	29.3 units on a scale Standard Deviation 11.4	28.6 units on a scale Standard Deviation 7.2
Motor Subscale of the Unified Parkinson's Disease Rating Scale (UPDRS Part III) Month 3 Post-Treatment	29.6 units on a scale Standard Deviation 10.3	33.2 units on a scale Standard Deviation 12.9	31.5 units on a scale Standard Deviation 11.3	28.6 units on a scale Standard Deviation 7.8
Motor Subscale of the Unified Parkinson's Disease Rating Scale (UPDRS Part III) Month 6 Post-Treatment	30.5 units on a scale Standard Deviation 11.5	30.6 units on a scale Standard Deviation 14.4	28.8 units on a scale Standard Deviation 10.1	29.0 units on a scale Standard Deviation 5.6

PRIMARY outcome

Timeframe: Pre-treatment; Post-treatment 0,1,3, and 6 months.

To evaluate the depressive mood symptoms in PD. The HAM-D mean scores were reported for each group at each time point. The HAM-D Score Range is 0 - 56, where higher the score indicates greater severity of depressive mood symptoms.

Outcome measures

Outcome measures
Measure	Double rTMS n=20 Participants High frequency rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	M1 Active rTMS + DLPFC Sham rTMS n=14 Participants High frequency stimulation of the primary motor cortex (M1) and sham stimulation of the dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	DLPFC Active rTMS + M1 Sham rTMS n=12 Participants High frequency stimulation of the dorsolateral prefrontal cortex (DLPFC) and sham stimulation of the primary motor cortex (M1). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	Double Sham rTMS n=15 Participants Sham rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.
Hamilton Depression Scale (HAM-D) Month 3 Post-Treatment	10.7 units on a scale Standard Deviation 6.9	10.1 units on a scale Standard Deviation 5.4	10.4 units on a scale Standard Deviation 7.4	11.1 units on a scale Standard Deviation 5.0
Hamilton Depression Scale (HAM-D) Month 6 Post-Treatment	10.4 units on a scale Standard Deviation 7.5	8.6 units on a scale Standard Deviation 7.7	10.4 units on a scale Standard Deviation 4.5	10.4 units on a scale Standard Deviation 5.9
Hamilton Depression Scale (HAM-D) Baseline (Pre-Treatment)	15.2 units on a scale Standard Deviation 6.0	16.7 units on a scale Standard Deviation 3.9	13.8 units on a scale Standard Deviation 4.6	14.1 units on a scale Standard Deviation 3.7
Hamilton Depression Scale (HAM-D) Week 1 Post-Treatment	11.3 units on a scale Standard Deviation 6.2	11.2 units on a scale Standard Deviation 6.3	9.4 units on a scale Standard Deviation 5.9	9.3 units on a scale Standard Deviation 5.9
Hamilton Depression Scale (HAM-D) Month 1 Post-Treatment	10.6 units on a scale Standard Deviation 6.9	10.1 units on a scale Standard Deviation 5.4	12.4 units on a scale Standard Deviation 8.1	8.0 units on a scale Standard Deviation 3.7

SECONDARY outcome

Timeframe: Pre-treatment; Post-treatment 0,1,3, and 6 months.

To evaluate anxiety in Parkinson's Disease. The CAS mean scores were reported for each group at each time point. The CAS Score Range is 0 - 100, where higher the score indicates greater severity of the anxiety symptoms.

Outcome measures

Outcome measures
Measure	Double rTMS n=20 Participants High frequency rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	M1 Active rTMS + DLPFC Sham rTMS n=14 Participants High frequency stimulation of the primary motor cortex (M1) and sham stimulation of the dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	DLPFC Active rTMS + M1 Sham rTMS n=12 Participants High frequency stimulation of the dorsolateral prefrontal cortex (DLPFC) and sham stimulation of the primary motor cortex (M1). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	Double Sham rTMS n=15 Participants Sham rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.
Clinical Anxiety Scale (CAS) Baseline (Pre-Treatment)	36.3 units on a scale Standard Deviation 17.1	34.3 units on a scale Standard Deviation 14.1	33.4 units on a scale Standard Deviation 17.4	37.5 units on a scale Standard Deviation 16.8
Clinical Anxiety Scale (CAS) Week 1 Post Treatment	34.2 units on a scale Standard Deviation 16.7	31.0 units on a scale Standard Deviation 13.8	27.6 units on a scale Standard Deviation 17.4	32.4 units on a scale Standard Deviation 16.8
Clinical Anxiety Scale (CAS) Month 1 Post Treatment	31.7 units on a scale Standard Deviation 15.4	30.8 units on a scale Standard Deviation 12.9	30.8 units on a scale Standard Deviation 17.7	28.2 units on a scale Standard Deviation 15.3
Clinical Anxiety Scale (CAS) Month 3 Post Treatment	33.1 units on a scale Standard Deviation 17.4	27.3 units on a scale Standard Deviation 7.9	31.4 units on a scale Standard Deviation 16.7	28.5 units on a scale Standard Deviation 18.5
Clinical Anxiety Scale (CAS) Month 6 Post Treatment	33.4 units on a scale Standard Deviation 19.4	28.1 units on a scale Standard Deviation 10.9	24.8 units on a scale Standard Deviation 9.9	35.0 units on a scale Standard Deviation 15.9

SECONDARY outcome

Timeframe: Pre-treatment; Post-treatment 0,1,3, and 6 months.

To evaluate apathy in Parkinson's Disease. The AES mean scores were reported for each group at each time point. The AES Score Range is 0-42, where higher the score indicates greater severity of the apathy symptoms.

Outcome measures

Outcome measures
Measure	Double rTMS n=20 Participants High frequency rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	M1 Active rTMS + DLPFC Sham rTMS n=14 Participants High frequency stimulation of the primary motor cortex (M1) and sham stimulation of the dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	DLPFC Active rTMS + M1 Sham rTMS n=12 Participants High frequency stimulation of the dorsolateral prefrontal cortex (DLPFC) and sham stimulation of the primary motor cortex (M1). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	Double Sham rTMS n=15 Participants Sham rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.
Apathy Evaluation Scale (AES) Baseline (Pre-Treatment)	15.6 units on a scale Standard Deviation 6.1	15.9 units on a scale Standard Deviation 7.1	18.7 units on a scale Standard Deviation 8.1	16.3 units on a scale Standard Deviation 5.7
Apathy Evaluation Scale (AES) Week 1 Post Treatment	16.2 units on a scale Standard Deviation 5.1	16.9 units on a scale Standard Deviation 8.4	18.1 units on a scale Standard Deviation 8.8	15.5 units on a scale Standard Deviation 5.9
Apathy Evaluation Scale (AES) Month 1 Post Treatment	17 units on a scale Standard Deviation 6.4	14.6 units on a scale Standard Deviation 8.1	19.0 units on a scale Standard Deviation 9.7	15.0 units on a scale Standard Deviation 5.3
Apathy Evaluation Scale (AES) Month 3 Post Treatment	16.9 units on a scale Standard Deviation 7.4	15.1 units on a scale Standard Deviation 8.1	19.3 units on a scale Standard Deviation 9.3	16.1 units on a scale Standard Deviation 6.1
Apathy Evaluation Scale (AES) Month 6 Post Treatment	17.8 units on a scale Standard Deviation 9.0	12.4 units on a scale Standard Deviation 8.5	15.8 units on a scale Standard Deviation 6.2	16.2 units on a scale Standard Deviation 5.2

SECONDARY outcome

Timeframe: Pre-treatment; Post-treatment 0,1,3, and 6 months.

To assess the quality of life (QOL) in Parkinson's Disease. The PDQ-39 mean scores were reported for each group at each time point. The PDQ-39 Score Range is 0 - 156, where higher the score indicates greater impact on quality of life.

Outcome measures

Outcome measures
Measure	Double rTMS n=20 Participants High frequency rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	M1 Active rTMS + DLPFC Sham rTMS n=14 Participants High frequency stimulation of the primary motor cortex (M1) and sham stimulation of the dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	DLPFC Active rTMS + M1 Sham rTMS n=12 Participants High frequency stimulation of the dorsolateral prefrontal cortex (DLPFC) and sham stimulation of the primary motor cortex (M1). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	Double Sham rTMS n=15 Participants Sham rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.
Parkinson's Disease Questionnaire 39 (PDQ-39) Baseline (Pre-Treatment)	57.6 units on a scale Standard Deviation 25.4	61.5 units on a scale Standard Deviation 20.2	51.9 units on a scale Standard Deviation 27.5	55.5 units on a scale Standard Deviation 21.6
Parkinson's Disease Questionnaire 39 (PDQ-39) Week 1 Post Treatment	51.2 units on a scale Standard Deviation 25.4	60.7 units on a scale Standard Deviation 19.4	46.8 units on a scale Standard Deviation 27.4	43.1 units on a scale Standard Deviation 20.1
Parkinson's Disease Questionnaire 39 (PDQ-39) Month 1 Post Treatment	49.9 units on a scale Standard Deviation 23.6	56.8 units on a scale Standard Deviation 16.8	49.4 units on a scale Standard Deviation 28.1	40.9 units on a scale Standard Deviation 21.3
Parkinson's Disease Questionnaire 39 (PDQ-39) Month 3 Post Treatment	51.7 units on a scale Standard Deviation 29.6	53.1 units on a scale Standard Deviation 13.8	49.4 units on a scale Standard Deviation 30.2	43.1 units on a scale Standard Deviation 21.7
Parkinson's Disease Questionnaire 39 (PDQ-39) Month 6 Post Treatment	50.5 units on a scale Standard Deviation 25.7	48.3 units on a scale Standard Deviation 16.2	49 units on a scale Standard Deviation 20.3	47.5 units on a scale Standard Deviation 18.9

SECONDARY outcome

Timeframe: pre-treatment; 0,1,3, and 6 months post-treatment

To screen and follow cognitive function in Parkinson's Disease. The MoCA mean scores were reported for each group at each time point. The MoCA Score Range is 0 - 30, where 26-30 indicates normal cognition.

Outcome measures

Outcome measures
Measure	Double rTMS n=20 Participants High frequency rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	M1 Active rTMS + DLPFC Sham rTMS n=14 Participants High frequency stimulation of the primary motor cortex (M1) and sham stimulation of the dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	DLPFC Active rTMS + M1 Sham rTMS n=12 Participants High frequency stimulation of the dorsolateral prefrontal cortex (DLPFC) and sham stimulation of the primary motor cortex (M1). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	Double Sham rTMS n=15 Participants Sham rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.
Montreal Cognitive Assessment (MoCA) Month 6 Post Treatment	28.0 units on a scale Standard Deviation 1.0	27.9 units on a scale Standard Deviation 1.7	26.6 units on a scale Standard Deviation 2.7	28.0 units on a scale Standard Deviation 2.4
Montreal Cognitive Assessment (MoCA) Baseline (Pre-Treatment)	28.2 units on a scale Standard Deviation 2.0	26.6 units on a scale Standard Deviation 2.5	27.3 units on a scale Standard Deviation 2.7	26.2 units on a scale Standard Deviation 4.3
Montreal Cognitive Assessment (MoCA) Week 1 Post Treatment	26.8 units on a scale Standard Deviation 3.9	27.1 units on a scale Standard Deviation 3.8	26.3 units on a scale Standard Deviation 4.2	27.8 units on a scale Standard Deviation 2.4
Montreal Cognitive Assessment (MoCA) Month 1 Post Treatment	28.8 units on a scale Standard Deviation 1.6	27.2 units on a scale Standard Deviation 3.5	26.8 units on a scale Standard Deviation 2.9	28.7 units on a scale Standard Deviation 0.9
Montreal Cognitive Assessment (MoCA) Month 3 Post Treatment	26.5 units on a scale Standard Deviation 8.0	25.3 units on a scale Standard Deviation 8.6	26.7 units on a scale Standard Deviation 3.3	24.9 units on a scale Standard Deviation 8.4

SECONDARY outcome

Timeframe: Pre-treatment; Post-treatment 0,1,3, and 6 months.

To assess apathy, cognition, depression, activities of daily living (ADL), quality of life (QOL), and motor symptoms in Parkinson's Disease. The UPDRS I, II, IV total mean scores were reported for each group at each time point. The UPDRS I, II, IV scores were added together for each patient, with a total score range of 0 - 91, where higher the score indicates greater severity of the symptoms.

Outcome measures

Outcome measures
Measure	Double rTMS n=20 Participants High frequency rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	M1 Active rTMS + DLPFC Sham rTMS n=14 Participants High frequency stimulation of the primary motor cortex (M1) and sham stimulation of the dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	DLPFC Active rTMS + M1 Sham rTMS n=12 Participants High frequency stimulation of the dorsolateral prefrontal cortex (DLPFC) and sham stimulation of the primary motor cortex (M1). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	Double Sham rTMS n=15 Participants Sham rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.
Unified Parkinson's Disease Rating Scale (UPDRS) Parts I, II, and IV Baseline (Pre-Treatment)	25.4 units on a scale Standard Deviation 9.6	26.1 units on a scale Standard Deviation 8.8	21.5 units on a scale Standard Deviation 7.4	19.6 units on a scale Standard Deviation 6.6
Unified Parkinson's Disease Rating Scale (UPDRS) Parts I, II, and IV Week 1 Post Treatment	23.3 units on a scale Standard Deviation 9.8	23.2 units on a scale Standard Deviation 8.3	19.3 units on a scale Standard Deviation 7.1	15.5 units on a scale Standard Deviation 6.3
Unified Parkinson's Disease Rating Scale (UPDRS) Parts I, II, and IV Month 1 Post Treatment	21.8 units on a scale Standard Deviation 9.8	23.0 units on a scale Standard Deviation 8.8	19.9 units on a scale Standard Deviation 6.4	16.5 units on a scale Standard Deviation 6.8
Unified Parkinson's Disease Rating Scale (UPDRS) Parts I, II, and IV Month 3 Post Treatment	21.1 units on a scale Standard Deviation 12.1	23.2 units on a scale Standard Deviation 8.0	18.9 units on a scale Standard Deviation 7.9	16.9 units on a scale Standard Deviation 6.3
Unified Parkinson's Disease Rating Scale (UPDRS) Parts I, II, and IV Month 6 Post Treatment	23.8 units on a scale Standard Deviation 12.7	22.7 units on a scale Standard Deviation 7.2	20.2 units on a scale Standard Deviation 6.8	18.8 units on a scale Standard Deviation 6.6

SECONDARY outcome

Timeframe: Pre-treatment; Post-treatment 0,1,3, and 6 months.

To assess mood symptoms in Parkinson's Disease. The BDI-II mean scores were reported for each group at each time point. The BDI-II Score Range is 0 - 63, where higher the score indicates greater severity of the mood symptoms.

Outcome measures

Outcome measures
Measure	Double rTMS n=20 Participants High frequency rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	M1 Active rTMS + DLPFC Sham rTMS n=14 Participants High frequency stimulation of the primary motor cortex (M1) and sham stimulation of the dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	DLPFC Active rTMS + M1 Sham rTMS n=12 Participants High frequency stimulation of the dorsolateral prefrontal cortex (DLPFC) and sham stimulation of the primary motor cortex (M1). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	Double Sham rTMS n=15 Participants Sham rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.
Beck Depression Inventory (BDI-II) Baseline (Pre-Treatment)	23.2 units on a scale Standard Deviation 12.7	18.5 units on a scale Standard Deviation 8.3	21.7 units on a scale Standard Deviation 11.9	18.8 units on a scale Standard Deviation 8.1
Beck Depression Inventory (BDI-II) Week 1 Post Treatment	20.7 units on a scale Standard Deviation 12.0	16.5 units on a scale Standard Deviation 10.6	18.2 units on a scale Standard Deviation 13.7	13.7 units on a scale Standard Deviation 5.7
Beck Depression Inventory (BDI-II) Month 1 Post Treatment	16.4 units on a scale Standard Deviation 10.0	16.7 units on a scale Standard Deviation 10.1	20.2 units on a scale Standard Deviation 15.5	13.1 units on a scale Standard Deviation 5.5
Beck Depression Inventory (BDI-II) Month 3 Post Treatment	17.9 units on a scale Standard Deviation 11.8	19.1 units on a scale Standard Deviation 10.7	19.0 units on a scale Standard Deviation 15.3	14.7 units on a scale Standard Deviation 6.6
Beck Depression Inventory (BDI-II) Month 6 Post Treatment	20.1 units on a scale Standard Deviation 15.6	16.3 units on a scale Standard Deviation 10.8	15.7 units on a scale Standard Deviation 7.1	16.8 units on a scale Standard Deviation 7.4

SECONDARY outcome

Timeframe: Pre-treatment; Post-treatment 0,1,3, and 6 months.

To assess symptom severity and treatment response in Parkinson's Disease. The CGI mean scores were reported for each group at each time point. The CGI Score Range is 1 - 8, where higher the score indicates greater severity of illness or worsening of illness.

Outcome measures

Outcome measures
Measure	Double rTMS n=20 Participants High frequency rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	M1 Active rTMS + DLPFC Sham rTMS n=14 Participants High frequency stimulation of the primary motor cortex (M1) and sham stimulation of the dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	DLPFC Active rTMS + M1 Sham rTMS n=12 Participants High frequency stimulation of the dorsolateral prefrontal cortex (DLPFC) and sham stimulation of the primary motor cortex (M1). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	Double Sham rTMS n=15 Participants Sham rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.
Global Impression Scales Baseline (Pre-Treatment): Severity	4.9 units on a scale Standard Deviation 1.3	4.7 units on a scale Standard Deviation 1.5	4.3 units on a scale Standard Deviation 1.5	3.6 units on a scale Standard Deviation 2.1
Global Impression Scales Week 1 Post Treatment: Severity	4.8 units on a scale Standard Deviation 0.8	4.9 units on a scale Standard Deviation 0.6	4.7 units on a scale Standard Deviation 0.6	3.9 units on a scale Standard Deviation 1.2
Global Impression Scales Week 1 Post Treatment: Improvement	3.6 units on a scale Standard Deviation 0.9	3.5 units on a scale Standard Deviation 0.8	3.5 units on a scale Standard Deviation 1.0	3.0 units on a scale Standard Deviation 1.1
Global Impression Scales Month 1 Post Treatment: Severity	4.4 units on a scale Standard Deviation 1.4	4.8 units on a scale Standard Deviation 0.6	4.4 units on a scale Standard Deviation 0.7	4.1 units on a scale Standard Deviation 0.7
Global Impression Scales Month 1 Post Treatment: Improvement	3.5 units on a scale Standard Deviation 1.1	3.8 units on a scale Standard Deviation 0.8	3.7 units on a scale Standard Deviation 0.8	3.5 units on a scale Standard Deviation 1.3
Global Impression Scales Month 3 Post Treatment: Severity	4.6 units on a scale Standard Deviation 0.8	3.8 units on a scale Standard Deviation 2.4	4.4 units on a scale Standard Deviation 0.7	4.4 units on a scale Standard Deviation 0.5
Global Impression Scales Month 3 Post Treatment: Improvement	3.7 units on a scale Standard Deviation 0.6	3.4 units on a scale Standard Deviation 1.5	3.6 units on a scale Standard Deviation 1.1	3.6 units on a scale Standard Deviation 1.0
Global Impression Scales Month 6 Post Treatment: Severity	4.2 units on a scale Standard Deviation 1.6	5.0 units on a scale Standard Deviation 0.8	4.3 units on a scale Standard Deviation 0.5	4.6 units on a scale Standard Deviation 0.5
Global Impression Scales Month 6 Post Treatment: Improvement	3.5 units on a scale Standard Deviation 1.2	4.2 units on a scale Standard Deviation 0.8	3.7 units on a scale Standard Deviation 0.7	3.4 units on a scale Standard Deviation 1.2

SECONDARY outcome

Timeframe: Baseline through Month 6

To establish the safety and tolerability of rTMS in Parkinson's Disease.

Outcome measures

Outcome measures
Measure	Double rTMS n=20 Participants High frequency rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	M1 Active rTMS + DLPFC Sham rTMS n=14 Participants High frequency stimulation of the primary motor cortex (M1) and sham stimulation of the dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	DLPFC Active rTMS + M1 Sham rTMS n=12 Participants High frequency stimulation of the dorsolateral prefrontal cortex (DLPFC) and sham stimulation of the primary motor cortex (M1). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	Double Sham rTMS n=15 Participants Sham rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.
The Number All Types of Adverse Events.	18 incidents of an adverse event	14 incidents of an adverse event	1 incidents of an adverse event	1 incidents of an adverse event

Adverse Events

Double rTMS

Serious events: 1 serious events

Other events: 5 other events

Deaths: 0 deaths

M1 Active rTMS + DLPFC Sham rTMS

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

DLPFC Active rTMS + M1 Sham rTMS

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Double Sham rTMS

Serious events: 1 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Double rTMS n=20 participants at risk High frequency rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	M1 Active rTMS + DLPFC Sham rTMS n=14 participants at risk High frequency stimulation of the primary motor cortex (M1) and sham stimulation of the dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	DLPFC Active rTMS + M1 Sham rTMS n=12 participants at risk High frequency stimulation of the dorsolateral prefrontal cortex (DLPFC) and sham stimulation of the primary motor cortex (M1). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	Double Sham rTMS n=15 participants at risk Sham rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.
Nervous system disorders Stroke	5.0% 1/20 • Number of events 1 • Baseline through 6 months post-treatment.	0.00% 0/14 • Baseline through 6 months post-treatment.	0.00% 0/12 • Baseline through 6 months post-treatment.	0.00% 0/15 • Baseline through 6 months post-treatment.
Gastrointestinal disorders Choking Episode	0.00% 0/20 • Baseline through 6 months post-treatment.	7.1% 1/14 • Number of events 1 • Baseline through 6 months post-treatment.	0.00% 0/12 • Baseline through 6 months post-treatment.	0.00% 0/15 • Baseline through 6 months post-treatment.
Musculoskeletal and connective tissue disorders Fall	0.00% 0/20 • Baseline through 6 months post-treatment.	0.00% 0/14 • Baseline through 6 months post-treatment.	0.00% 0/12 • Baseline through 6 months post-treatment.	6.7% 1/15 • Number of events 1 • Baseline through 6 months post-treatment.

Other adverse events

Additional Information

Dr. Alvaro Pascual-Leone

Beth Israel Deaconess Medical Center

Phone: (617) 667-0203

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Double rTMS n=20 participants at risk High frequency rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	M1 Active rTMS + DLPFC Sham rTMS n=14 participants at risk High frequency stimulation of the primary motor cortex (M1) and sham stimulation of the dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	DLPFC Active rTMS + M1 Sham rTMS n=12 participants at risk High frequency stimulation of the dorsolateral prefrontal cortex (DLPFC) and sham stimulation of the primary motor cortex (M1). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.	Double Sham rTMS n=15 participants at risk Sham rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS): DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.
Psychiatric disorders Worsened Depression	5.0% 1/20 • Number of events 1 • Baseline through 6 months post-treatment.	0.00% 0/14 • Baseline through 6 months post-treatment.	0.00% 0/12 • Baseline through 6 months post-treatment.	0.00% 0/15 • Baseline through 6 months post-treatment.
Gastrointestinal disorders Worsened Constipation	5.0% 1/20 • Number of events 1 • Baseline through 6 months post-treatment.	0.00% 0/14 • Baseline through 6 months post-treatment.	0.00% 0/12 • Baseline through 6 months post-treatment.	0.00% 0/15 • Baseline through 6 months post-treatment.
General disorders Hospitlization	5.0% 1/20 • Number of events 1 • Baseline through 6 months post-treatment.	0.00% 0/14 • Baseline through 6 months post-treatment.	0.00% 0/12 • Baseline through 6 months post-treatment.	0.00% 0/15 • Baseline through 6 months post-treatment.
Cardiac disorders Atrial Fibrillation	5.0% 1/20 • Number of events 1 • Baseline through 6 months post-treatment.	0.00% 0/14 • Baseline through 6 months post-treatment.	0.00% 0/12 • Baseline through 6 months post-treatment.	0.00% 0/15 • Baseline through 6 months post-treatment.
Musculoskeletal and connective tissue disorders Neck Pain	5.0% 1/20 • Number of events 1 • Baseline through 6 months post-treatment.	14.3% 2/14 • Number of events 4 • Baseline through 6 months post-treatment.	0.00% 0/12 • Baseline through 6 months post-treatment.	0.00% 0/15 • Baseline through 6 months post-treatment.
Gastrointestinal disorders Heart Burn	5.0% 1/20 • Number of events 1 • Baseline through 6 months post-treatment.	0.00% 0/14 • Baseline through 6 months post-treatment.	0.00% 0/12 • Baseline through 6 months post-treatment.	0.00% 0/15 • Baseline through 6 months post-treatment.
General disorders Right-Sided Soreness	5.0% 1/20 • Number of events 1 • Baseline through 6 months post-treatment.	0.00% 0/14 • Baseline through 6 months post-treatment.	0.00% 0/12 • Baseline through 6 months post-treatment.	0.00% 0/15 • Baseline through 6 months post-treatment.
Musculoskeletal and connective tissue disorders Fall	5.0% 1/20 • Number of events 1 • Baseline through 6 months post-treatment.	0.00% 0/14 • Baseline through 6 months post-treatment.	8.3% 1/12 • Number of events 1 • Baseline through 6 months post-treatment.	0.00% 0/15 • Baseline through 6 months post-treatment.
Nervous system disorders Headache	15.0% 3/20 • Number of events 5 • Baseline through 6 months post-treatment.	14.3% 2/14 • Number of events 3 • Baseline through 6 months post-treatment.	0.00% 0/12 • Baseline through 6 months post-treatment.	0.00% 0/15 • Baseline through 6 months post-treatment.
Musculoskeletal and connective tissue disorders Left Hip Ache	5.0% 1/20 • Number of events 1 • Baseline through 6 months post-treatment.	0.00% 0/14 • Baseline through 6 months post-treatment.	0.00% 0/12 • Baseline through 6 months post-treatment.	0.00% 0/15 • Baseline through 6 months post-treatment.
Skin and subcutaneous tissue disorders Scalp Pain	5.0% 1/20 • Number of events 2 • Baseline through 6 months post-treatment.	0.00% 0/14 • Baseline through 6 months post-treatment.	0.00% 0/12 • Baseline through 6 months post-treatment.	0.00% 0/15 • Baseline through 6 months post-treatment.
Musculoskeletal and connective tissue disorders Left Shoulder Pain	5.0% 1/20 • Number of events 1 • Baseline through 6 months post-treatment.	0.00% 0/14 • Baseline through 6 months post-treatment.	0.00% 0/12 • Baseline through 6 months post-treatment.	0.00% 0/15 • Baseline through 6 months post-treatment.
Nervous system disorders Dizziness	0.00% 0/20 • Baseline through 6 months post-treatment.	7.1% 1/14 • Number of events 1 • Baseline through 6 months post-treatment.	0.00% 0/12 • Baseline through 6 months post-treatment.	0.00% 0/15 • Baseline through 6 months post-treatment.
Gastrointestinal disorders Nausea	0.00% 0/20 • Baseline through 6 months post-treatment.	14.3% 2/14 • Number of events 3 • Baseline through 6 months post-treatment.	0.00% 0/12 • Baseline through 6 months post-treatment.	0.00% 0/15 • Baseline through 6 months post-treatment.
Musculoskeletal and connective tissue disorders Worsening Dyskinesia	0.00% 0/20 • Baseline through 6 months post-treatment.	7.1% 1/14 • Number of events 1 • Baseline through 6 months post-treatment.	0.00% 0/12 • Baseline through 6 months post-treatment.	0.00% 0/15 • Baseline through 6 months post-treatment.
Musculoskeletal and connective tissue disorders Torn Ligament of R Lower Extremity	0.00% 0/20 • Baseline through 6 months post-treatment.	7.1% 1/14 • Number of events 1 • Baseline through 6 months post-treatment.	0.00% 0/12 • Baseline through 6 months post-treatment.	0.00% 0/15 • Baseline through 6 months post-treatment.