Transcranial Magnetic Stimulation (TMS) for Individuals With Tourette's Syndrome

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.

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 exclusion criteria include those common to every TMS protocol:

- 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.