Transcranial Magnetic Stimulation (TMS) for Individuals With Tourette's Syndrome
TMS
1 other identifier
interventional
20
1 country
2
Brief Summary
This study will evaluate the clinical efficacy of 1 Hz repetitive transcranial magnetic stimulation (rTMS) applied to the supplementary motor area (SMA) in Tourette's Syndrome (TS) patients who have not fully responded to conventional therapies. The investigators will collect TMS measures of motor cortex excitability to test whether rTMS restores normal levels of intracortical inhibition found to be deficient in TS. The investigators will administer neuropsychological tests to demonstrate that SMA targeted rTMS can be administered safely without significant impairments of cognitive or motor functioning. The investigators hypothesize that:
- 1.Compared to sham (placebo), active rTMS will improve symptoms of TS as assessed with the Yale Global Tic Severity Scale (Y-GTSS) and Clinical Global Impression (CGI).
- 2.Active (but not sham) rTMS will normalize levels of motor cortex excitability, as reflected by increased intracortical inhibition, motor threshold, and cortical silent period, and by decreased intracortical facilitation, relative to pre-treatment baseline.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for phase_2
Started Jul 2007
Typical duration for phase_2
2 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
Study Start
First participant enrolled
July 1, 2007
CompletedFirst Submitted
Initial submission to the registry
September 13, 2007
CompletedFirst Posted
Study publicly available on registry
September 14, 2007
CompletedPrimary Completion
Last participant's last visit for primary outcome
July 1, 2011
CompletedStudy Completion
Last participant's last visit for all outcomes
July 1, 2011
CompletedResults Posted
Study results publicly available
February 15, 2013
CompletedFebruary 21, 2019
February 1, 2019
4 years
September 13, 2007
November 13, 2012
February 4, 2019
Conditions
Keywords
Outcome Measures
Primary Outcomes (5)
Yale Global Tic Severity Scale (Y-GTSS)
Y-GTSS is a clinician-rated scale used to assess tic severity. Motor and phonic tics are rated separately from 0 to 5 on several scales including number, frequency, intensity, complexity, and interference. Thus Motor and Phonic Tic scores can range from 0 to 25; the combined Total Tic Score ranges from 0 to 50. There is also an Impairment score that rates the overall burden due to tics. The Impairment scale yields a single score from 0 to 50 with higher scores indicating higher levels of overall impairment associated with tics.
3 weeks
Motor Cortex Excitability Normalization-Right Motor Threshold
Motor Threshold (MT) is thought to be a measure of membrane excitability in pyramidal neurons. MT is defined as the minimum magnetic flux needed to elicit a threshold EMG response (50 µV in peak to peak amplitude) in a resting target muscle in 5 out of 10 trials using single pulse TMS administered to the contralateral primary motor cortex. MT for both right and left hand are determined, and the lowest is used to select the intensity for rTMS.
3 weeks
Number of Patients With "Much Improved or Very Much Improved" on Clinical Global Impression-Improvement (CGI) Scale
The CGI-I is a clinician-rated scales that have been used in clinical trials for over 25 years. Clinicians rate patient improvement compared to baseline. By convention, 4 = No Change; scores of 5, 6, and 7 move in the direction of worsening; scores of 3, 2, and 1 correspond to "Minimal Improvement," "Much Improved" or "Very Much Improved," respectively. CGI-I ratings of "Much" or "Very Much Improved" at post-treatment are used to identify treatment responders.
3 weeks
Motor Cortex Excitability Normalization-Left Motor Threshold
Motor Threshold (MT) is thought to be a measure of membrane excitability in pyramidal neurons. MT is defined as the minimum magnetic flux needed to elicit a threshold EMG response (50 µV in peak to peak amplitude) in a resting target muscle in 5 out of 10 trials using single pulse TMS administered to the contralateral primary motor cortex. MT for both right and left hand are determined, and the lowest is used to select the intensity for rTMS.
3 weeks
Number of Patients With "Improved or Minimally Improved" in Clinical Global Impression-Improvement (CGI) Scale
The CGI-I is a clinician-rated scales that have been used in clinical trials for over 25 years. Clinicians rate patient improvement compared to baseline. By convention, 4 = No Change; scores of 5, 6, and 7 move in the direction of worsening; scores of 3, 2, and 1 correspond to "Minimal Improvement," "Much Improved" or "Very Much Improved," respectively. CGI-I ratings of "Much" or "Very Much Improved" at post-treatment are used to identify treatment responders.
3 weeks
Study Arms (2)
Active
ACTIVE COMPARATORSham
SHAM COMPARATORInterventions
Magstim Rapid2 stimulator with Air Film Coil at 110% motor threshold at 1Hz for 30 minutes.
Magstim Rapid2 stimulator with Sham Air Film Coil at 110% motor threshold at 1Hz for 30 minutes.
Eligibility Criteria
You may qualify if:
- Primary diagnosis of Tourette's Syndrome, as confirmed by the DSM-IV-TR criteria
- Residual TS symptoms, defined as a total Y-GTSS total motor tic or phonic tic score \> 20, despite treatment with an adequate trial of medications (defined as a failure to respond to a trial of commonly used medications for TS such as clonidine, guanfacine, or neuroleptic medications, given at recommended dosage and duration based on the clinician's judgment)
- Persistent high level of tic severity for 4 months despite efforts to control the tics using medications, or the presence of self injurious tics
- Duration of the index episode of at least a year
- Individuals who cannot tolerate medications of class and dose at the specified duration as described above will also be included
- Patients currently on medication must be at the same stable dose(s) for one month prior to enrollment and be willing to continue at the same dose(s) through the duration of the study
You may not qualify if:
- Individuals diagnosed with major depressive disorder (current) of moderate or severe intensity (CGI ≥ 4), bipolar disorder (lifetime), any psychotic disorder (lifetime), or an Axis II personality disorder; with a history of substance abuse or dependence within the past year (except nicotine and caffeine); or at significant acute suicide risk will be excluded
- Individuals with a clinically defined neurological disorder, with an increased risk of seizure for any reason, with a history of treatment with TMS, deep brain stimulation for any disorder will be excluded
- Patients with cardiac pacemakers, implanted medication pumps, intracardiac lines, or acute, unstable cardiac disease, with intracranial implants (e.g. aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed will be excluded
- Current use of any investigational drug, any medications with proconvulsive action, such as bupropion, maprotiline, tricyclic antidepressant, clomipramine, classical antipsychotics, and daily use of any medications with a known inhibitory effect on cortical excitability measures (e.g., anticonvulsants, standing doses of benzodiazepines, sedative/hypnotics, and atypical antipsychotics) will not be permitted
- If participating in psychotherapy, patients must have been in stable treatment for at least three months prior to entry into the study, with no anticipation of change in frequency therapeutic sessions, or the therapeutic focus over the duration of the TMS trial
- Finally, current significant laboratory abnormality, known or suspected pregnancy, women who are breast-feeding or women of childbearing potential not using a medically accepted form of contraception when engaging in sexual intercourse will also be excluded.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Yale Universitylead
- Tourette Association of Americacollaborator
Study Sites (2)
Yale University School of Medicine
New Haven, Connecticut, 06520, United States
New York State Psychiatric Institute
New York, New York, 10032, United States
Related Publications (47)
Alexander GE, Crutcher MD, DeLong MR. Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, "prefrontal" and "limbic" functions. Prog Brain Res. 1990;85:119-46.
PMID: 2094891BACKGROUNDAllison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, Weiden PJ. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999 Nov;156(11):1686-96. doi: 10.1176/ajp.156.11.1686.
PMID: 10553730BACKGROUNDArtola A, Brocher S, Singer W. Different voltage-dependent thresholds for inducing long-term depression and long-term potentiation in slices of rat visual cortex. Nature. 1990 Sep 6;347(6288):69-72. doi: 10.1038/347069a0.
PMID: 1975639BACKGROUNDBliss TV, Gardner-Medwin AR. Long-lasting potentiation of synaptic transmission in the dentate area of the unanaestetized rabbit following stimulation of the perforant path. J Physiol. 1973 Jul;232(2):357-74. doi: 10.1113/jphysiol.1973.sp010274.
PMID: 4727085BACKGROUNDBruggeman R, van der Linden C, Buitelaar JK, Gericke GS, Hawkridge SM, Temlett JA. Risperidone versus pimozide in Tourette's disorder: a comparative double-blind parallel-group study. J Clin Psychiatry. 2001 Jan;62(1):50-6. doi: 10.4088/jcp.v62n0111.
PMID: 11235929BACKGROUNDChen R, Classen J, Gerloff C, Celnik P, Wassermann EM, Hallett M, Cohen LG. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology. 1997 May;48(5):1398-403. doi: 10.1212/wnl.48.5.1398.
PMID: 9153480BACKGROUNDElwood RW. The California Verbal Learning Test: psychometric characteristics and clinical application. Neuropsychol Rev. 1995 Sep;5(3):173-201. doi: 10.1007/BF02214761.
PMID: 8653108BACKGROUNDGreenberg BD, Ziemann U, Cora-Locatelli G, Harmon A, Murphy DL, Keel JC, Wassermann EM. Altered cortical excitability in obsessive-compulsive disorder. Neurology. 2000 Jan 11;54(1):142-7. doi: 10.1212/wnl.54.1.142.
PMID: 10636140BACKGROUNDHoffman RE, Cavus I. Slow transcranial magnetic stimulation, long-term depotentiation, and brain hyperexcitability disorders. Am J Psychiatry. 2002 Jul;159(7):1093-102. doi: 10.1176/appi.ajp.159.7.1093.
PMID: 12091184BACKGROUNDKirkwood A, Dudek SM, Gold JT, Aizenman CD, Bear MF. Common forms of synaptic plasticity in the hippocampus and neocortex in vitro. Science. 1993 Jun 4;260(5113):1518-21. doi: 10.1126/science.8502997.
PMID: 8502997BACKGROUNDLeckman JF. Tourette's syndrome. Lancet. 2002 Nov 16;360(9345):1577-86. doi: 10.1016/S0140-6736(02)11526-1.
PMID: 12443611BACKGROUNDLeckman JF, Hardin MT, Riddle MA, Stevenson J, Ort SI, Cohen DJ. Clonidine treatment of Gilles de la Tourette's syndrome. Arch Gen Psychiatry. 1991 Apr;48(4):324-8. doi: 10.1001/archpsyc.1991.01810280040006.
PMID: 2009034BACKGROUNDLeckman JF, Vaccarino FM, Kalanithi PS, Rothenberger A. Annotation: Tourette syndrome: a relentless drumbeat--driven by misguided brain oscillations. J Child Psychol Psychiatry. 2006 Jun;47(6):537-50. doi: 10.1111/j.1469-7610.2006.01620.x.
PMID: 16712630BACKGROUNDMarsh R, Alexander GM, Packard MG, Zhu H, Wingard JC, Quackenbush G, Peterson BS. Habit learning in Tourette syndrome: a translational neuroscience approach to a developmental psychopathology. Arch Gen Psychiatry. 2004 Dec;61(12):1259-68. doi: 10.1001/archpsyc.61.12.1259.
PMID: 15583117BACKGROUNDMoll GH, Heinrich H, Gevensleben H, Rothenberger A. Tic distribution and inhibitory processes in the sensorimotor circuit during adolescence: a cross-sectional TMS study. Neurosci Lett. 2006 Jul 31;403(1-2):96-9. doi: 10.1016/j.neulet.2006.04.021. Epub 2006 May 9.
PMID: 16690208BACKGROUNDPeterson BS, Leckman JF. The temporal dynamics of tics in Gilles de la Tourette syndrome. Biol Psychiatry. 1998 Dec 15;44(12):1337-48. doi: 10.1016/s0006-3223(98)00176-0.
PMID: 9861477BACKGROUNDPeterson BS, Skudlarski P, Anderson AW, Zhang H, Gatenby JC, Lacadie CM, Leckman JF, Gore JC. A functional magnetic resonance imaging study of tic suppression in Tourette syndrome. Arch Gen Psychiatry. 1998 Apr;55(4):326-33. doi: 10.1001/archpsyc.55.4.326.
PMID: 9554428BACKGROUNDPeterson BS, Staib L, Scahill L, Zhang H, Anderson C, Leckman JF, Cohen DJ, Gore JC, Albert J, Webster R. Regional brain and ventricular volumes in Tourette syndrome. Arch Gen Psychiatry. 2001 May;58(5):427-40. doi: 10.1001/archpsyc.58.5.427.
PMID: 11343521BACKGROUNDPeterson BS, Thomas P, Kane MJ, Scahill L, Zhang H, Bronen R, King RA, Leckman JF, Staib L. Basal Ganglia volumes in patients with Gilles de la Tourette syndrome. Arch Gen Psychiatry. 2003 Apr;60(4):415-24. doi: 10.1001/archpsyc.60.4.415.
PMID: 12695320BACKGROUNDPiacentini J, Chang S. Behavioral treatments for Tourette syndrome and tic disorders: state of the art. Adv Neurol. 2001;85:319-31. No abstract available.
PMID: 11530440BACKGROUNDQuintana H. Transcranial magnetic stimulation in persons younger than the age of 18. J ECT. 2005 Jun;21(2):88-95. doi: 10.1097/01.yct.0000162556.02720.58.
PMID: 15905749BACKGROUNDRossi S, Pasqualetti P, Rossini PM, Feige B, Ulivelli M, Glocker FX, Battistini N, Lucking CH, Kristeva-Feige R. Effects of repetitive transcranial magnetic stimulation on movement-related cortical activity in humans. Cereb Cortex. 2000 Aug;10(8):802-8. doi: 10.1093/cercor/10.8.802.
PMID: 10920051BACKGROUNDSallee FR, Kurlan R, Goetz CG, Singer H, Scahill L, Law G, Dittman VM, Chappell PB. Ziprasidone treatment of children and adolescents with Tourette's syndrome: a pilot study. J Am Acad Child Adolesc Psychiatry. 2000 Mar;39(3):292-9. doi: 10.1097/00004583-200003000-00010.
PMID: 10714048BACKGROUNDSallee FR, Nesbitt L, Jackson C, Sine L, Sethuraman G. Relative efficacy of haloperidol and pimozide in children and adolescents with Tourette's disorder. Am J Psychiatry. 1997 Aug;154(8):1057-62. doi: 10.1176/ajp.154.8.1057.
PMID: 9247389BACKGROUNDScahill L, Chappell PB, Kim YS, Schultz RT, Katsovich L, Shepherd E, Arnsten AF, Cohen DJ, Leckman JF. A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. Am J Psychiatry. 2001 Jul;158(7):1067-74. doi: 10.1176/appi.ajp.158.7.1067.
PMID: 11431228BACKGROUNDScahill L, Leckman JF, Schultz RT, Katsovich L, Peterson BS. A placebo-controlled trial of risperidone in Tourette syndrome. Neurology. 2003 Apr 8;60(7):1130-5. doi: 10.1212/01.wnl.0000055434.39968.67.
PMID: 12682319BACKGROUNDScahill L, Riddle MA, King RA, Hardin MT, Rasmusson A, Makuch RW, Leckman JF. Fluoxetine has no marked effect on tic symptoms in patients with Tourette's syndrome: a double-blind placebo-controlled study. J Child Adolesc Psychopharmacol. 1997 Summer;7(2):75-85. doi: 10.1089/cap.1997.7.75.
PMID: 9334893BACKGROUNDSchultz RT, Carter AS, Gladstone M, Scahill L, Leckman JF, Peterson BS, Zhang H, Cohen DJ, Pauls D. Visual-motor integration functioning in children with Tourette syndrome. Neuropsychology. 1998 Jan;12(1):134-145. doi: 10.1037//0894-4105.12.1.134.
PMID: 9460741BACKGROUNDShapiro E, Shapiro AK, Fulop G, Hubbard M, Mandeli J, Nordlie J, Phillips RA. Controlled study of haloperidol, pimozide and placebo for the treatment of Gilles de la Tourette's syndrome. Arch Gen Psychiatry. 1989 Aug;46(8):722-30. doi: 10.1001/archpsyc.1989.01810080052006.
PMID: 2665687BACKGROUNDSpeer AM, Willis MW, Herscovitch P, Daube-Witherspoon M, Shelton JR, Benson BE, Post RM, Wassermann EM. Intensity-dependent regional cerebral blood flow during 1-Hz repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers studied with H215O positron emission tomography: II. Effects of prefrontal cortex rTMS. Biol Psychiatry. 2003 Oct 15;54(8):826-32. doi: 10.1016/s0006-3223(03)00324-x.
PMID: 14550682BACKGROUNDStanton PK, Sejnowski TJ. Associative long-term depression in the hippocampus induced by hebbian covariance. Nature. 1989 May 18;339(6221):215-8. doi: 10.1038/339215a0.
PMID: 2716848BACKGROUNDWirshing DA, Boyd JA, Meng LR, Ballon JS, Marder SR, Wirshing WC. The effects of novel antipsychotics on glucose and lipid levels. J Clin Psychiatry. 2002 Oct;63(10):856-65. doi: 10.4088/jcp.v63n1002.
PMID: 12416594BACKGROUNDZiemann U, Paulus W, Rothenberger A. Decreased motor inhibition in Tourette's disorder: evidence from transcranial magnetic stimulation. Am J Psychiatry. 1997 Sep;154(9):1277-84. doi: 10.1176/ajp.154.9.1277.
PMID: 9286189BACKGROUNDParent A, Hazrati LN. Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop. Brain Res Brain Res Rev. 1995 Jan;20(1):91-127. doi: 10.1016/0165-0173(94)00007-c.
PMID: 7711769BACKGROUNDCohen LG, Roth BJ, Nilsson J, Dang N, Panizza M, Bandinelli S, Friauf W, Hallett M. Effects of coil design on delivery of focal magnetic stimulation. Technical considerations. Electroencephalogr Clin Neurophysiol. 1990 Apr;75(4):350-7. doi: 10.1016/0013-4694(90)90113-x.
PMID: 1691084BACKGROUNDWassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Electroencephalogr Clin Neurophysiol. 1998 Jan;108(1):1-16. doi: 10.1016/s0168-5597(97)00096-8.
PMID: 9474057BACKGROUNDOrth M, Kirby R, Richardson MP, Snijders AH, Rothwell JC, Trimble MR, Robertson MM, Munchau A. Subthreshold rTMS over pre-motor cortex has no effect on tics in patients with Gilles de la Tourette syndrome. Clin Neurophysiol. 2005 Apr;116(4):764-8. doi: 10.1016/j.clinph.2004.10.003. Epub 2004 Nov 25.
PMID: 15792884BACKGROUNDWilhelm S, Deckersbach T, Coffey BJ, Bohne A, Peterson AL, Baer L. Habit reversal versus supportive psychotherapy for Tourette's disorder: a randomized controlled trial. Am J Psychiatry. 2003 Jun;160(6):1175-7. doi: 10.1176/appi.ajp.160.6.1175.
PMID: 12777279BACKGROUNDBloch MH, Leckman JF, Zhu H, Peterson BS. Caudate volumes in childhood predict symptom severity in adults with Tourette syndrome. Neurology. 2005 Oct 25;65(8):1253-8. doi: 10.1212/01.wnl.0000180957.98702.69.
PMID: 16247053BACKGROUNDChae JH, Nahas Z, Wassermann E, Li X, Sethuraman G, Gilbert D, Sallee FR, George MS. A pilot safety study of repetitive transcranial magnetic stimulation (rTMS) in Tourette's syndrome. Cogn Behav Neurol. 2004 Jun;17(2):109-17. doi: 10.1097/01.wnn.0000116253.78804.3a.
PMID: 15453520BACKGROUNDDavis KK, Davis JS, Dowler L. In motion, out of place: the public space(s) of Tourette Syndrome. Soc Sci Med. 2004 Jul;59(1):103-12. doi: 10.1016/j.socscimed.2003.10.008.
PMID: 15087147BACKGROUNDFried I, Katz A, McCarthy G, Sass KJ, Williamson P, Spencer SS, Spencer DD. Functional organization of human supplementary motor cortex studied by electrical stimulation. J Neurosci. 1991 Nov;11(11):3656-66. doi: 10.1523/JNEUROSCI.11-11-03656.1991.
PMID: 1941101BACKGROUNDKaradenizli D, Dilbaz N, Bayam G. Gilles de la Tourette syndrome: response to electroconvulsive therapy. J ECT. 2005 Dec;21(4):246-8. doi: 10.1097/01.yct.0000184618.00661.72.
PMID: 16301887BACKGROUNDKnowlton BJ, Mangels JA, Squire LR. A neostriatal habit learning system in humans. Science. 1996 Sep 6;273(5280):1399-402. doi: 10.1126/science.273.5280.1399.
PMID: 8703077BACKGROUNDMantovani A, Lisanby SH, Pieraccini F, Ulivelli M, Castrogiovanni P, Rossi S. Repetitive transcranial magnetic stimulation (rTMS) in the treatment of obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS). Int J Neuropsychopharmacol. 2006 Feb;9(1):95-100. doi: 10.1017/S1461145705005729. Epub 2005 Jun 28.
PMID: 15982444BACKGROUNDMunchau A, Bloem BR, Thilo KV, Trimble MR, Rothwell JC, Robertson MM. Repetitive transcranial magnetic stimulation for Tourette syndrome. Neurology. 2002 Dec 10;59(11):1789-91. doi: 10.1212/01.wnl.0000036615.25044.50.
PMID: 12473773BACKGROUNDLanderos-Weisenberger A, Mantovani A, Motlagh MG, de Alvarenga PG, Katsovich L, Leckman JF, Lisanby SH. Randomized Sham Controlled Double-blind Trial of Repetitive Transcranial Magnetic Stimulation for Adults With Severe Tourette Syndrome. Brain Stimul. 2015 May-Jun;8(3):574-81. doi: 10.1016/j.brs.2014.11.015. Epub 2014 Dec 3.
PMID: 25912296DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Dr. Angeli Landeros-Weisenberger
- Organization
- Yale University
Study Officials
- PRINCIPAL INVESTIGATOR
Antonio Mantovani, MD
New York State Psychiatric Institute
Publication Agreements
- PI is Sponsor Employee
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- DOUBLE
- Who Masked
- PARTICIPANT, OUTCOMES ASSESSOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Principal Investigator
Study Record Dates
First Submitted
September 13, 2007
First Posted
September 14, 2007
Study Start
July 1, 2007
Primary Completion
July 1, 2011
Study Completion
July 1, 2011
Last Updated
February 21, 2019
Results First Posted
February 15, 2013
Record last verified: 2019-02