Tourette Syndrome
Conditions
Keywords
Tourette, Tourette's
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.
Detailed description
This study tests the efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) in the treatment of Tourette's Syndrome (TS). It also examines measures of brain function to study the brain basis underlying TS. Despite major advances in the study and treatment of TS, patients often do not experience full remission from pharmacotherapy or behavioral therapy (Leckman 2002). rTMS is a non-invasive procedure that stimulates the brain using magnetic fields. This pilot study reported that rTMS may reduce TS symptoms (Mantovani et al., 2006). While promising, prior research has several limitations (e.g., relatively small sample sizes, and lack of sham \[placebo\] comparison). This study addresses the drawbacks of prior work, and will provide data that will help to determine whether rTMS can be useful for TS patients resistant to conventional therapies. 25 outpatients with TS who have been only partially responsive to conventional therapies will be randomly assigned to either active low frequency (1 Hz) rTMS or sham (placebo) stimulation. The active or sham stimulation will be applied to the supplementary motor area (SMA) daily for three weeks. If rTMS will be added onto ongoing pharmacotherapy, the doses must have been stable for four weeks prior to study entry. The SMA was selected because of its connections with brain areas implicated in TS. Pilot work indicates that stimulation of SMA with low frequency rTMS is beneficial in TS patients. Low frequency rTMS has the added benefit of a better safety profile (i.e. no risk of seizure) than high frequency rTMS. Rating scales for symptom change will be obtained at baseline, during the rTMS course, and at the end of three weeks of treatment. Patients will then be offered an open-label cross-over phase for an additional three weeks of daily active rTMS treatment. Patients who meet remission criteria in either phase or response criteria following the cross-over phase will continue routine clinical care under the supervision of their treating psychiatrist and will be invited back for assessment at 1, 3, and 6 months to determine the persistence of benefit. Excitability of the motor cortex has been reported to be abnormal in TS, and may relate to dysfunction in motor pathways. We will collect measures of motor cortex excitability (with single and paired-pulse TMS) at baseline and after each phase to study whether changes in these measures may be correlated with clinical improvement.
Interventions
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.
Sponsors
Tourette Association of America
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* 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
Exclusion criteria
* 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 Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Yale Global Tic Severity Scale (Y-GTSS) | 3 weeks | 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. |
| Motor Cortex Excitability Normalization-Right Motor Threshold | 3 weeks | 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. |
| Number of Patients With Much Improved or Very Much Improved on Clinical Global Impression-Improvement (CGI) Scale | 3 weeks | 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. |
| Motor Cortex Excitability Normalization-Left Motor Threshold | 3 weeks | 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. |
| Number of Patients With Improved or Minimally Improved in Clinical Global Impression-Improvement (CGI) Scale | 3 weeks | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Active Magstim Rapid2 stimulator with Air Film Coil at 110% motor threshold at 1Hz for 30 minutes. | 9 |
| Sham Magstim Rapid2 stimulator with Sham Air Film Coil at 110% motor threshold at 1Hz for 30 minutes. | 11 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Active | Sham | Total |
|---|---|---|---|
| Age, Continuous | 29.1 years STANDARD_DEVIATION 7.4 | 39.0 years STANDARD_DEVIATION 16.1 | 33.7 years STANDARD_DEVIATION 12.1 |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 7 Participants | 9 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 8 | 9 / 10 |
| serious Total, serious adverse events | 0 / 8 | 0 / 10 |
Outcome results
Primary
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.
Time frame: 3 weeks
Population: This data was only available for the subjects at the Yale site only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active | Motor Cortex Excitability Normalization-Left Motor Threshold | 56.5 µV | Standard Deviation 12.8 |
| Sham | Motor Cortex Excitability Normalization-Left Motor Threshold | 63.8 µV | Standard Deviation 16.3 |
Primary
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.
Time frame: 3 weeks
Population: This data was only available for the subjects at the Yale site only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active | Motor Cortex Excitability Normalization-Right Motor Threshold | 56 µV | Standard Deviation 16.3 |
| Sham | Motor Cortex Excitability Normalization-Right Motor Threshold | 59.8 µV | Standard Deviation 16.3 |
Primary
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.
Time frame: 3 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Active | Number of Patients With Improved or Minimally Improved in Clinical Global Impression-Improvement (CGI) Scale | 2 participants |
| Sham | Number of Patients With Improved or Minimally Improved in Clinical Global Impression-Improvement (CGI) Scale | 8 participants |
Primary
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.
Time frame: 3 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Active | Number of Patients With Much Improved or Very Much Improved on Clinical Global Impression-Improvement (CGI) Scale | 1 participants |
| Sham | Number of Patients With Much Improved or Very Much Improved on Clinical Global Impression-Improvement (CGI) Scale | 0 participants |
Primary
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.
Time frame: 3 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active | Yale Global Tic Severity Scale (Y-GTSS) | 29.5 units on a scale | Standard Deviation 11.9 |
| Sham | Yale Global Tic Severity Scale (Y-GTSS) | 31.5 units on a scale | Standard Deviation 8.1 |