Repetitive Transcranial MAgnetic STimulation (rTMS) for MotoR and Mood Symptoms of Parkinson's Disease (MASTER-PD), a Multicenter Clinical Trial

Depression Clinical Trial

— MASTER-PD  

Official title:

Repetitive Transcranial MAgnetic STimulation (rTMS) for MotoR and Mood Symptoms of Parkinson's Disease (MASTER-PD), a Multicenter Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01080794
• Other study ID #: 2010P-000002
• Status: Completed
• Phase: Phase 2
• First received: March 3, 2010
• Last updated: February 13, 2015
• Start date: May 2010
• Est. completion date: June 2014

Study information

• Verified date: February 2015
• Source: Beth Israel Deaconess Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine if repetitive transcranial magnetic stimulation (rTMS), a method of noninvasive brain stimulation) is effective in the treatment of the motor (movement) and mood symptoms due to Parkinson's disease (PD).

Description:

Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive means of brain stimulation which can produce changes to brain excitability. Following a series of daily rTMS sessions, this modulation of neural circuits and other distant effects may help some of the motor and neuropsychiatric symptoms of PD for months at a time. Recently, the FDA approved daily rTMS over the prefrontal cortex as a treatment for medication-refractory depression after demonstration of efficacy in sham-controlled trials and its safety profile. Among several small and pilot studies of rTMS in PD patients, rTMS over either the motor cortex or prefrontal cortex has been reported to show beneficial effects on motor and mood (depression) symptoms with no serious adverse events. However, the relative effectiveness of rTMS over motor, prefrontal, or both regions on both mood and motor symptoms, has yet to be established in PD patients.

We propose to conduct a four-center, blinded, sham-controlled, randomized, parallel-group study of fixed-dose, high-frequency rTMS in 160 PD patients who are experiencing depressive symptoms despite an adequate trial of at least one antidepressant. Subjects will be randomized to receive rTMS over either motor cortex, prefrontal cortex, both, or neither (sham-rTMS). Subjects will receive rTMS for 25 minutes over either the prefrontal cortex (the brain region associated with mood and depression), and/or primary motor cortex (associated with motor control), and/or sham-rTMS. After 10 days of rTMS (or sham) treatment over a 2-week period, all subjects will undergo a comprehensive assessment of motor, mood, cognition and quality of life on the first working day after the last rTMS treatment, and after 1, 3 and 6 months post-treatment. This study directly addresses the expansion of rTMS as an alternative treatment for depression in the PD population and will provide evidence as to whether motor cortex stimulation will provide additional and/or separate benefit to motor symptoms.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 85
• Est. completion date: June 2014
• Est. primary completion date: June 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 21 Years to 85 Years

Eligibility

Inclusion Criteria:

• Diagnosis of PD according to the UK Brain Bank Criteria, confirmed by a neurologist with expertise in movement disorders.

• Minimum of 3 years since the formal diagnosis of PD, and requiring dopaminergic therapy (at a minimum, on levodopa and/or dopamine agonist therapy).

• Minimum baseline OFF score on the motor UPDRS of 15 points of more.

• Lack of features suggestive of atypical parkinsonism, such as early prominent cerebellar, pyramidal, or autonomic dysfunction; supranuclear gaze palsy; falls within the first year of symptoms; hallucinations prior to initiating a dopaminergic agent.

• No history of neuroleptics or other drugs that induce parkinsonism in the past 60 days.

• Currently optimally treated with medications and, in the view of the treating neurologist, will unlikely be requiring anti-PD medication adjustments in the next 6 months.

• On a stable dose of all medications for 30 days (except anti-depressants— which should be stable for at least 90 days).

• Lack of dementia such that, in the view of the enrolling investigator, the patient is able to give proper informed consent. In addition, all patients must score at least a 26 out of 30 on the screening MMSE.

• HAM-D score > 12 on the first 17 questions of the scale, despite the current use of antidepressant(s) for at least 90 days, or documentation of adequate trial of antidepressants (i.e. at least 6 weeks on an optimal dose), or documentation of intolerability to antidepressants.

• Untreated depression or on a stable dose of antidepressants for 90 days (untreated patients need to have tried at least one antidepressant in the past).

• Age 21 years or older.

• Patient meets the criteria for a depressive disorder based on either the MINI interview (major depression) or SCID (minor depression, or dysthymia).

Exclusion Criteria:

• Intracranial metallic bodies (e.g. from prior neurosurgical procedure).

• Signs or symptoms of increased intracranial pressure.

• Implanted pacemaker, medication pump, vagal stimulator, deep brain stimulator, TENS unit or ventriculoperitoneal shunt.

• History of seizures or unexplained loss of consciousness.

• Possible pregnancy.

• Family history of medication refractory epilepsy.

• History of substance abuse within the last 6 months.

• History of known structural brain abnormality.

• History of exposure to repetitive TMS in the past (to minimizing risk of unblinding sham condition).

• History of exposure to ECT in the past.

• Patients with suicidal ideation deemed by the investigator to be significant enough to render the individual a suicidal risk.

• Patients with a history of hospitalization for suicidal ideation/attempts.

• Patients requiring hospitalization for their depression within the past six months will not be allowed in the study. If a participating subject's depression worsens during the study to a degree that hospitalization is deemed necessary, or if the subject develops significant suicidal ideation, he/she will be withdrawn from the study and referred to a psychiatrist for treatment.

• Patients with bipolar affective disorder and those whose depression is characterized by psychotic features.

• Patients with a history of spontaneous hallucinations or delusions as well as those with other underlying psychotic disorders (e.g., schizophrenia, schizoaffective disorder, delusional disorder). The presence of visual illusions or hallucinations deemed by the enrolling physician to be clearly related to antiparkinsonian medications will be allowed but only if the enrolling physician believes that they are stable and unlikely to require changes in medication (i.e., addition of an antipsychotic or reduction in antiparkinsonian drug dosage). Patients with delusions will be excluded.

• Subjects judged by the clinician investigator to have dementia (by DSM-IV and MMSE criteria) will be excluded.

• Subjects judged by the clinician investigator to have dementia (by MoCA criteria) will be excluded.

• Subjects with unstable medical condition such as diabetes, cardiac disease, and hypertension.

• Subjects with brittle or severe motor fluctuation that will cause severe discomfort during OFF medication testing at Baseline, immediately post-TMS, and at Months 1, 3, and 6.

• Excessive alcohol use or taking one of the following exclusionary medications:

Imipramine, Amitriptyline, Doxepin, Nortriptyline, Maprotiline, Chlorpromazine, Clozapine, Foscarnet, Ganciclovir, Ritonavir, Amphetamines (MDMA, ecstasy), cocaine, phencyclidine (PCP, angel's dust), ketamine, gamma-hydroxybutyrate (GHB), theophylline, and haloperidol.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Depression
• Parkinson Disease
• Parkinson's Disease

Intervention

Device:
• 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.

Locations

Country	Name	City	State
Canada	University Health Network	Toronto	Ontario
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	The Cleveland Clinic	Cleveland	Ohio
United States	University of Florida	Gainesville	Florida
United States	University of California Los Angeles	Los Angeles	California
United States	Oregon Health and Science University	Portland	Oregon

Sponsors (6)

Lead Sponsor	Collaborator
Beth Israel Deaconess Medical Center	Michael J. Fox Foundation for Parkinson's Research, The Cleveland Clinic, University Health Network, Toronto, University of California, Los Angeles, University of Florida

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (91)

Aarsland D, Cummings JL. Depression in Parkinson's disease. Acta Psychiatr Scand. 2002 Sep;106(3):161-2. — View Citation

Adler CH. Nonmotor complications in Parkinson's disease. Mov Disord. 2005;20 Suppl 11:S23-9. Review. — View Citation

BECK AT, WARD CH, MENDELSON M, MOCK J, ERBAUGH J. An inventory for measuring depression. Arch Gen Psychiatry. 1961 Jun;4:561-71. — View Citation

Benabid AL, Chabardès S, Seigneuret E. Deep-brain stimulation in Parkinson's disease: long-term efficacy and safety - What happened this year? Curr Opin Neurol. 2005 Dec;18(6):623-30. Review. — View Citation

Börnke Ch, Schulte T, Przuntek H, Müller T. Clinical effects of repetitive transcranial magnetic stimulation versus acute levodopa challenge in Parkinson's disease. J Neural Transm Suppl. 2004;(68):61-7. — View Citation

Brusa L, Versace V, Koch G, Iani C, Stanzione P, Bernardi G, Centonze D. Low frequency rTMS of the SMA transiently ameliorates peak-dose LID in Parkinson's disease. Clin Neurophysiol. 2006 Sep;117(9):1917-21. Epub 2006 Aug 1. — View Citation

Buhmann C, Gorsler A, Bäumer T, Hidding U, Demiralay C, Hinkelmann K, Weiller C, Siebner HR, Münchau A. Abnormal excitability of premotor-motor connections in de novo Parkinson's disease. Brain. 2004 Dec;127(Pt 12):2732-46. Epub 2004 Oct 27. — View Citation

Burn DJ, Tröster AI. Neuropsychiatric complications of medical and surgical therapies for Parkinson's disease. J Geriatr Psychiatry Neurol. 2004 Sep;17(3):172-80. Review. — View Citation

Burt T, Lisanby SH, Sackeim HA. Neuropsychiatric applications of transcranial magnetic stimulation: a meta analysis. Int J Neuropsychopharmacol. 2002 Mar;5(1):73-103. — View Citation

Cantello R. Applications of transcranial magnetic stimulation in movement disorders. J Clin Neurophysiol. 2002 Aug;19(4):272-93. Review. — View Citation

Cardoso EF, Fregni F, Martins Maia F, Boggio PS, Luis Myczkowski M, Coracini K, Lopes Vieira A, Melo LM, Sato JR, Antonio Marcolin M, Rigonatti SP, Cruz AC Jr, Reis Barbosa E, Amaro E Jr. rTMS treatment for depression in Parkinson's disease increases BOLD responses in the left prefrontal cortex. Int J Neuropsychopharmacol. 2008 Mar;11(2):173-83. Epub 2007 Aug 21. — View Citation

Chaudhuri KR, Healy DG, Schapira AH; National Institute for Clinical Excellence. Non-motor symptoms of Parkinson's disease: diagnosis and management. Lancet Neurol. 2006 Mar;5(3):235-45. Review. — View Citation

Conca A, Koppi S, König P, Swoboda E, Krecke N. Transcranial magnetic stimulation: a novel antidepressive strategy? Neuropsychobiology. 1996;34(4):204-7. — View Citation

Crow TJ, Johnstone EC. Controlled trials of electroconvulsive therapy. Ann N Y Acad Sci. 1986;462:12-29. Review. — View Citation

del Olmo MF, Bello O, Cudeiro J. Transcranial magnetic stimulation over dorsolateral prefrontal cortex in Parkinson's disease. Clin Neurophysiol. 2007 Jan;118(1):131-9. Epub 2006 Nov 9. — View Citation

Dias AE, Barbosa ER, Coracini K, Maia F, Marcolin MA, Fregni F. Effects of repetitive transcranial magnetic stimulation on voice and speech in Parkinson's disease. Acta Neurol Scand. 2006 Feb;113(2):92-9. — View Citation

Dragasevic N, Potrebic A, Damjanovic A, Stefanova E, Kostic VS. Therapeutic efficacy of bilateral prefrontal slow repetitive transcranial magnetic stimulation in depressed patients with Parkinson's disease: an open study. Mov Disord. 2002 May;17(3):528-32. — View Citation

Elahi B, Elahi B, Chen R. Effect of transcranial magnetic stimulation on Parkinson motor function--systematic review of controlled clinical trials. Mov Disord. 2009 Feb 15;24(3):357-63. doi: 10.1002/mds.22364. Review. — View Citation

Epstein CM, Evatt ML, Funk A, Girard-Siqueira L, Lupei N, Slaughter L, Athar S, Green J, McDonald W, DeLong MR. An open study of repetitive transcranial magnetic stimulation in treatment-resistant depression with Parkinson's disease. Clin Neurophysiol. 2007 Oct;118(10):2189-94. Epub 2007 Aug 21. — View Citation

Epstein CM. Transcranial magnetic stimulation: language function. J Clin Neurophysiol. 1998 Jul;15(4):325-32. Review. — View Citation

Fahn S, Cohen G. The oxidant stress hypothesis in Parkinson's disease: evidence supporting it. Ann Neurol. 1992 Dec;32(6):804-12. Review. — View Citation

Fernandez HH, See RH, Gary MF, Bowers D, Rodriguez RL, Jacobson C 4th, Okun MS. Depressive symptoms in Parkinson disease correlate with impaired global and specific cognitive performance. J Geriatr Psychiatry Neurol. 2009 Dec;22(4):223-7. doi: 10.1177/0891988709335792. Epub 2009 May 8. — View Citation

Fernandez HH, Tabamo RE, David RR, Friedman JH. Predictors of depressive symptoms among spouse caregivers in Parkinson's disease. Mov Disord. 2001 Nov;16(6):1123-5. — View Citation

Figiel GS, Epstein C, McDonald WM, Amazon-Leece J, Figiel L, Saldivia A, Glover S. The use of rapid-rate transcranial magnetic stimulation (rTMS) in refractory depressed patients. J Neuropsychiatry Clin Neurosci. 1998 Winter;10(1):20-5. — View Citation

Flint AJ. Epidemiology and comorbidity of anxiety disorders in the elderly. Am J Psychiatry. 1994 May;151(5):640-9. Review. — View Citation

Fregni F, Santos CM, Myczkowski ML, Rigolino R, Gallucci-Neto J, Barbosa ER, Valente KD, Pascual-Leone A, Marcolin MA. Repetitive transcranial magnetic stimulation is as effective as fluoxetine in the treatment of depression in patients with Parkinson's disease. J Neurol Neurosurg Psychiatry. 2004 Aug;75(8):1171-4. — View Citation

Fregni F, Simon DK, Wu A, Pascual-Leone A. Non-invasive brain stimulation for Parkinson's disease: a systematic review and meta-analysis of the literature. J Neurol Neurosurg Psychiatry. 2005 Dec;76(12):1614-23. Review. — View Citation

Friedman JH, Fernandez HH. The nonmotor problems of Parkinson's Disease. The Neurologist 6(1): 18-27, 2000.

George MS, Wassermann EM, Kimbrell TA, Little JT, Williams WE, Danielson AL, Greenberg BD, Hallett M, Post RM. Mood improvement following daily left prefrontal repetitive transcranial magnetic stimulation in patients with depression: a placebo-controlled crossover trial. Am J Psychiatry. 1997 Dec;154(12):1752-6. — View Citation

George MS, Wassermann EM, Williams WA, Callahan A, Ketter TA, Basser P, Hallett M, Post RM. Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression. Neuroreport. 1995 Oct 2;6(14):1853-6. — View Citation

Gershon AA, Dannon PN, Grunhaus L. Transcranial magnetic stimulation in the treatment of depression. Am J Psychiatry. 2003 May;160(5):835-45. Review. — View Citation

Ghabra MB, Hallett M, Wassermann EM. Simultaneous repetitive transcranial magnetic stimulation does not speed fine movement in PD. Neurology. 1999 Mar 10;52(4):768-70. — View Citation

Gill DJ, Freshman A, Blender JA, Ravina B. The Montreal cognitive assessment as a screening tool for cognitive impairment in Parkinson's disease. Mov Disord. 2008 May 15;23(7):1043-6. doi: 10.1002/mds.22017. — View Citation

Grafton ST. Contributions of functional imaging to understanding parkinsonian symptoms. Curr Opin Neurobiol. 2004 Dec;14(6):715-9. Review. — View Citation

Ikeguchi M, Touge T, Nishiyama Y, Takeuchi H, Kuriyama S, Ohkawa M. Effects of successive repetitive transcranial magnetic stimulation on motor performances and brain perfusion in idiopathic Parkinson's disease. J Neurol Sci. 2003 May 15;209(1-2):41-6. — View Citation

Khedr EM, Farweez HM, Islam H. Therapeutic effect of repetitive transcranial magnetic stimulation on motor function in Parkinson's disease patients. Eur J Neurol. 2003 Sep;10(5):567-72. — View Citation

Khedr EM, Rothwell JC, Ahmed MA, Shawky OA, Farouk M. Modulation of motor cortical excitability following rapid-rate transcranial magnetic stimulation. Clin Neurophysiol. 2007 Jan;118(1):140-5. Epub 2006 Nov 9. — View Citation

Kirsch-Darrow L, Fernandez HH, Marsiske M, Okun MS, Bowers D. Dissociating apathy and depression in Parkinson disease. Neurology. 2006 Jul 11;67(1):33-8. Erratum in: Neurology. 2006 Oct 10;67(7):1315. Fernandez, H F [corrected to Fernandez, HH]. — View Citation

Kostíc VS, Filipovic SR, Lecic D, Momcilovic D, Sokic D, Sternic N. Effect of age at onset on frequency of depression in Parkinson's disease. J Neurol Neurosurg Psychiatry. 1994 Oct;57(10):1265-7. — View Citation

Krings T, Buchbinder BR, Butler WE, Chiappa KH, Jiang HJ, Cosgrove GR, Rosen BR. Functional magnetic resonance imaging and transcranial magnetic stimulation: complementary approaches in the evaluation of cortical motor function. Neurology. 1997 May;48(5):1406-16. — View Citation

Lang AE, Obeso JA. Challenges in Parkinson's disease: restoration of the nigrostriatal dopamine system is not enough. Lancet Neurol. 2004 May;3(5):309-16. Review. — View Citation

Leentjens AF, Scholtissen B, Vreeling FW, Verhey FR. The serotonergic hypothesis for depression in Parkinson's disease: an experimental approach. Neuropsychopharmacology. 2006 May;31(5):1009-15. — View Citation

Leentjens AF. Depression in Parkinson's disease: conceptual issues and clinical challenges. J Geriatr Psychiatry Neurol. 2004 Sep;17(3):120-6. Review. — View Citation

Lefaucheur JP, Drouot X, Von Raison F, Ménard-Lefaucheur I, Cesaro P, Nguyen JP. Improvement of motor performance and modulation of cortical excitability by repetitive transcranial magnetic stimulation of the motor cortex in Parkinson's disease. Clin Neurophysiol. 2004 Nov;115(11):2530-41. — View Citation

Lemke MR, Fuchs G, Gemende I, Herting B, Oehlwein C, Reichmann H, Rieke J, Volkmann J. Depression and Parkinson's disease. J Neurol. 2004 Sep;251 Suppl 6:VI/24-7. Review. — View Citation

Levin BE, Llabre MM, Weiner WJ. Parkinson's disease and depression: psychometric properties of the Beck Depression Inventory. J Neurol Neurosurg Psychiatry. 1988 Nov;51(11):1401-4. — View Citation

Lieberman MD, Eisenberger NI, Crockett MJ, Tom SM, Pfeifer JH, Way BM. Putting feelings into words: affect labeling disrupts amygdala activity in response to affective stimuli. Psychol Sci. 2007 May;18(5):421-8. — View Citation

Liu CY, Wang SJ, Fuh JL, Lin CH, Yang YY, Liu HC. The correlation of depression with functional activity in Parkinson's disease. J Neurol. 1997 Aug;244(8):493-8. — View Citation

Lomarev MP, Kanchana S, Bara-Jimenez W, Iyer M, Wassermann EM, Hallett M. Placebo-controlled study of rTMS for the treatment of Parkinson's disease. Mov Disord. 2006 Mar;21(3):325-31. — View Citation

Maeda F, Chang VY, Mazziotta J, Iacoboni M. Experience-dependent modulation of motor corticospinal excitability during action observation. Exp Brain Res. 2001 Sep;140(2):241-4. Retraction in: Iacoboni M, Mazziotta J, Chang VY. Exp Brain Res. 2002 Sep;146(1):127. — View Citation

Maeda F, Keenan JP, Tormos JM, Topka H, Pascual-Leone A. Interindividual variability of the modulatory effects of repetitive transcranial magnetic stimulation on cortical excitability. Exp Brain Res. 2000 Aug;133(4):425-30. — View Citation

Málly J, Farkas R, Tóthfalusi L, Stone TW. Long-term follow-up study with repetitive transcranial magnetic stimulation (rTMS) in Parkinson's disease. Brain Res Bull. 2004 Sep 30;64(3):259-63. — View Citation

Marin RS. Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci. 1991 Summer;3(3):243-54. Review. — View Citation

Mayeux R, Sano M, Chen J, Tatemichi T, Stern Y. Risk of dementia in first-degree relatives of patients with Alzheimer's disease and related disorders. Arch Neurol. 1991 Mar;48(3):269-73. — View Citation

Mayeux R, Stern Y, Cote L, Williams JB. Altered serotonin metabolism in depressed patients with parkinson's disease. Neurology. 1984 May;34(5):642-6. — View Citation

Mayeux R, Stern Y, Williams JB, Cote L, Frantz A, Dyrenfurth I. Clinical and biochemical features of depression in Parkinson's disease. Am J Psychiatry. 1986 Jun;143(6):756-9. — View Citation

Mennemeier M, Triggs W, Chelette K, Woods A, Kimbrell T, Dornhoffer J. Sham Transcranial Magnetic Stimulation Using Electrical Stimulation of the Scalp. Brain Stimul. 2009 Jul 1;2(3):168-173. — View Citation

Miller KM, Okun MS, Fernandez HF, Jacobson CE 4th, Rodriguez RL, Bowers D. Depression symptoms in movement disorders: comparing Parkinson's disease, dystonia, and essential tremor. Mov Disord. 2007 Apr 15;22(5):666-72. — View Citation

Mir P, Matsunaga K, Gilio F, Quinn NP, Siebner HR, Rothwell JC. Dopaminergic drugs restore facilitatory premotor-motor interactions in Parkinson disease. Neurology. 2005 Jun 14;64(11):1906-12. — View Citation

Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005 Apr;53(4):695-9. — View Citation

O'Reardon JP, Solvason HB, Janicak PG, Sampson S, Isenberg KE, Nahas Z, McDonald WM, Avery D, Fitzgerald PB, Loo C, Demitrack MA, George MS, Sackeim HA. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007 Dec 1;62(11):1208-16. Epub 2007 Jun 14. — View Citation

Okabe S, Ugawa Y, Kanazawa I; Effectiveness of rTMS on Parkinson's Disease Study Group. 0.2-Hz repetitive transcranial magnetic stimulation has no add-on effects as compared to a realistic sham stimulation in Parkinson's disease. Mov Disord. 2003 Apr;18(4):382-8. — View Citation

Pascual-Leone A, Rubio B, Pallardó F, Catalá MD. Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression. Lancet. 1996 Jul 27;348(9022):233-7. — View Citation

Pascual-Leone A, Valls-Solé J, Brasil-Neto JP, Cammarota A, Grafman J, Hallett M. Akinesia in Parkinson's disease. II. Effects of subthreshold repetitive transcranial motor cortex stimulation. Neurology. 1994 May;44(5):892-8. — View Citation

Paus T, Castro-Alamancos MA, Petrides M. Cortico-cortical connectivity of the human mid-dorsolateral frontal cortex and its modulation by repetitive transcranial magnetic stimulation. Eur J Neurosci. 2001 Oct;14(8):1405-11. — View Citation

Piasecki SD, Jefferson JW. Psychiatric complications of deep brain stimulation for Parkinson's disease. J Clin Psychiatry. 2004 Jun;65(6):845-9. Review. — View Citation

Rickards H. Depression in neurological disorders: Parkinson's disease, multiple sclerosis, and stroke. J Neurol Neurosurg Psychiatry. 2005 Mar;76 Suppl 1:i48-52. Review. — View Citation

Robertson EM, Théoret H, Pascual-Leone A. Studies in cognition: the problems solved and created by transcranial magnetic stimulation. J Cogn Neurosci. 2003 Oct 1;15(7):948-60. — View Citation

Sackheim HA. The cognitive effectsd of electroconvulsive therapy. Cognitive Disorders: Pathophysiology and Treatment. Moos WH and Gamzu ER. New York, Marcel Decker: 183-228, 1992.

Sawabini KA, Watts RL. Treatment of depression in Parkinson's disease. Parkinsonism Relat Disord. 2004 May;10 Suppl 1:S37-41. Review. — View Citation

Schiffer RB, Kurlan R, Rubin A, Boer S. Evidence for atypical depression in Parkinson's disease. Am J Psychiatry. 1988 Aug;145(8):1020-2. — View Citation

Siebner HR, Filipovic SR, Rowe JB, Cordivari C, Gerschlager W, Rothwell JC, Frackowiak RS, Bhatia KP. Patients with focal arm dystonia have increased sensitivity to slow-frequency repetitive TMS of the dorsal premotor cortex. Brain. 2003 Dec;126(Pt 12):2710-25. Epub 2003 Aug 22. — View Citation

Siebner HR, Mentschel C, Auer C, Conrad B. Repetitive transcranial magnetic stimulation has a beneficial effect on bradykinesia in Parkinson's disease. Neuroreport. 1999 Feb 25;10(3):589-94. — View Citation

Siebner HR. Simultaneous repetitive transcranial magnetic stimulation does not speed fine movement in PD. Neurology. 2000 Jan 11;54(1):272; author reply 273. — View Citation

Snaith RP, Baugh SJ, Clayden AD, Husain A, Sipple MA. The Clinical Anxiety Scale: an instrument derived from the Hamilton Anxiety Scale. Br J Psychiatry. 1982 Nov;141:518-23. — View Citation

Squire LR, Zouzounis JA. Self-ratings of memory dysfunction: different findings in depression and amnesia. J Clin Exp Neuropsychol. 1988 Dec;10(6):727-38. — View Citation

Stallings LE, Speer AM, et al. Combining SPECT and repetitive transcranial magnetic stimulation (rTMS)-left prefrontal stimulation decreases relative perfusion locally in a dose dependent manner. Neuroimage 5: S521 Abstract, 1997.

Starkstein SE, Mayberg HS, Preziosi TJ, Andrezejewski P, Leiguarda R, Robinson RG. Reliability, validity, and clinical correlates of apathy in Parkinson's disease. J Neuropsychiatry Clin Neurosci. 1992 Spring;4(2):134-9. — View Citation

Starkstein SE, Preziosi TJ, Forrester AW, Robinson RG. Specificity of affective and autonomic symptoms of depression in Parkinson's disease. J Neurol Neurosurg Psychiatry. 1990 Oct;53(10):869-73. — View Citation

Strafella AP, Paus T, Barrett J, Dagher A. Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus. J Neurosci. 2001 Aug 1;21(15):RC157. — View Citation

Strafella AP, Paus T, Fraraccio M, Dagher A. Striatal dopamine release induced by repetitive transcranial magnetic stimulation of the human motor cortex. Brain. 2003 Dec;126(Pt 12):2609-15. Epub 2003 Aug 22. — View Citation

Talairach J, Tournoux P. Co-planar Stereotaxic Atlas of the Human Brain. New York, Thieme Medical Publishers, Inc. 1988.

Tergau F, Wanschura V, Canelo M, Wischer S, Wassermann EM, Ziemann U, Paulus W. Complete suppression of voluntary motor drive during the silent period after transcranial magnetic stimulation. Exp Brain Res. 1999 Feb;124(4):447-54. — View Citation

Tergau F, Wassermann EM, Paulus W, Ziemann U. Lack of clinical improvement in patients with Parkinson's disease after low and high frequency repetitive transcranial magnetic stimulation. Electroencephalogr Clin Neurophysiol Suppl. 1999;51:281-8. — View Citation

Tormos JM, Catala MD, et al. Effects of repetitive transcranial magnetic stimulation (rTMS) on EEG. Neurology 50: A317-A318 Abstract, 1998.

Triggs WJ, McCoy KJ, Greer R, Rossi F, Bowers D, Kortenkamp S, Nadeau SE, Heilman KM, Goodman WK. Effects of left frontal transcranial magnetic stimulation on depressed mood, cognition, and corticomotor threshold. Biol Psychiatry. 1999 Jun 1;45(11):1440-6. — View Citation

Valero-Cabré A, Payne BR, Rushmore J, Lomber SG, Pascual-Leone A. Impact of repetitive transcranial magnetic stimulation of the parietal cortex on metabolic brain activity: a 14C-2DG tracing study in the cat. Exp Brain Res. 2005 May;163(1):1-12. Epub 2005 Feb 2. — View Citation

Veazey C, Aki SO, Cook KF, Lai EC, Kunik ME. Prevalence and treatment of depression in Parkinson's disease. J Neuropsychiatry Clin Neurosci. 2005 Summer;17(3):310-23. Review. — View Citation

Wassermann EM, Wang B, Zeffiro TA, Sadato N, Pascual-Leone A, Toro C, Hallett M. Locating the motor cortex on the MRI with transcranial magnetic stimulation and PET. Neuroimage. 1996 Feb;3(1):1-9. — View Citation

Wu AD, Fregni F, Simon DK, Deblieck C, Pascual-Leone A. Noninvasive brain stimulation for Parkinson's disease and dystonia. Neurotherapeutics. 2008 Apr;5(2):345-61. doi: 10.1016/j.nurt.2008.02.002. Review. — View Citation

Ziemssen T, Reichmann H. Non-motor dysfunction in Parkinson's disease. Parkinsonism Relat Disord. 2007 Aug;13(6):323-32. Epub 2007 Mar 8. Review. — View Citation

* Note: There are 91 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Motor subscale of the Unified Parkinson's Disease Rating Scale (UPDRS Part III)	To evaluate the motor symptoms in PD.	pre-treatment; 0,1,3, and 6 months post-treatment	No
Primary	Hamilton Depression Scale (HAM-D)	To evaluate the mood symptoms in PD.	pre-treatment; 0,1,3 and 6 months post-treatment	No
Secondary	Clinical Anxiety Scale (CAS)	To evaluate anxiety in PD.	pre-treatment; 0,1,3, and 6 months post-treatment	No
Secondary	Apathy Evaluation Scale (AES)	To evaluate apathy in PD.	pre-treatment; 0,1,3, and 6 months post-treatment	No
Secondary	Parkinson's Disease Questionnaire 39 (PDQ-39)	To assess the quality of life (QOL) in PD.	pre-treatment; 0,1,3, and 6 months post-treatment	No
Secondary	Montreal Cognitive Assessment (MoCA)	To screen and follow cognitive function in PD.	pre-treatment; 0,1,3, and 6 months post-treatment	No
Secondary	Unified Parkinson's Disease Rating Scale (UPDRS) Parts I, II, and IV	To assess apathy, cognition, depression, activities of daily living (ADL), quality of life (QOL), and motor symptoms in PD.	pre-treatment; 0,1,3, and 6 months post-treatment	No
Secondary	Beck Depression Inventory (BDI-II)	To assess mood symptoms in PD.	pre-treatment; 0,1,3, and 6 months post-treatment	No
Secondary	Global Impression Scales		0,1,3, and 6 months post-treatment	No
Secondary	The number and severity of akk types of adverse events (i.e., serious, treatment-emergent, adverse events of interest, total adverse events)	To establish the safety and tolerability of rTMS in PD.	Baseline through Month 6	Yes