Theta-burst Transcranial Magnetic Stimulation

Testing will occur at three identical visits, with escalating stimulation intensity at each
visit. Initial screening will be performed by telephone or in clinic and final screening will
be performed and informed consent will be signed at the start of the first study visit.
Initial set-up and calibration of the magnetic stimulation device will require 10-20 minutes.
Theta-burst stimulation requires 40 seconds. Hand and arm function will be tested immediately
before and during the one hour following the TBS. Therefore, each visit should occupy 90-120
minutes. Each visit will be at least 2 days after the previous visit and a telephone call
will be placed one week after the third visit.

Testing of limb function will be performed according to standard clinical rating scales,
including the modified Ashworth spasticity scale and the Barry-Albright Dystonia rating
scale. Electrophysiological testing of hand function will involve moving finger muscles
against resistance while surface electromyographic signals (EMG) are monitored for the
ability to activate one finger at a time while minimizing muscle co-contraction and overflow.
Testing of arm function will involve measurement of the ability to relax the biceps and
triceps and the resistance of the elbow to passive movement by the examiner.

Testing of cortical function will occur both before and after theta-burst stimulation, and
will involve a standard protocol using suprathreshold single and paired-pulse magnetic
stimulation with measurement of the induced motor evoked potential (MEP) in the hand and arm
muscles. The resting MEP threshold and input-output curve will be measured for the first
dorsal interosseus muscle. Paired-pulse inhibition of the MEP will be tested using a
subthreshold pulse (80% of resting motor threshold) followed by a suprathreshold pulse at
2.5msec interval. Paired-pulse facilitation will be tested using a 12msec interval. Silent
period duration in response to a pulse at 120% of resting motor threshold will be measured.

Theta-burst stimulation will be performed according to the standard protocols developed by
Rothwell and co-workers with NIH and European consortium safety guidelines stringently
enforced. Active motor threshold and resting motor threshold will be determined by
single-pulse stimulation while monitoring electromyographic (EMG) activity at the first
dorsal interosseus (FDI) muscle according to standard published protocols using commercially
available surface EMG electrodes (DelSys Inc.). Stimulation will be performed using the
commercially-available Magstim Rapid 2 (Magstim, Inc., Wales UK) with a standard figure-eight
coil held by a member of the research team. Biphasic stimulation pulses will be given
according to the standard included driver software. Single pulse, paired pulse, and
theta-burst rapid stimulation protocols are directly available through standard user options
on this device.

Threshold determination and stimulation location will be performed using each subject's most
affected hand, or the non-dominant hand if both hands are affected. The location of lowest
threshold for stimulation of the FDI will be determined by gradual movement of the
stimulation coil over the surface of the contralateral scalp, in the region of the standard
"C3" or "C4" electrode position (determined by international 10-20 EEG electrode placement
convention). The handle of the stimulation coil will be pointed backward and 45 degrees from
the sagittal plane so as to be approximately perpendicular to the rolandic fissure. The
location of minimum threshold will be marked with a washable non-permanent marker on the
subject's scalp in order to ensure consistency of stimulation.

For assessment of active motor threshold, subjects will be asked to contract the FDI muscle
against resistance while being given biofeedback to maintain average integrated EMG at 20% of
maximal voluntary isometric EMG. For assessment of resting motor threshold, EMG of the FDI
must be less than 5% of maximal prior to stimulation. Single-pulses at increasing intensity
will be used to determine the intensity at which 5 out of 10 pulses evoke an EMG response
greater than 200mV (active threshold) or 50mV (resting threshold) above baseline. (Active
motor threshold is virtually always less than the resting motor threshold. If this is not the
case in a subject, then stimulation will be adjusted so that intensity never exceeds 80% of
the resting motor threshold.) Thresholds will be assessed both before and after theta-burst
stimulation, and these thresholds will be used for the cortical excitability testing as
described above.

Stimulation intensity for theta burst will be set at 60% active motor threshold (visit 1),
80% active motor threshold (visit 2), and 80% resting motor threshold (visit 3). All
stimulation is subthreshold, and thus not expected to produce muscle activity. To ensure this
is the case, muscle activity will be continuously monitored from the FDI and stimulation will
be aborted if any muscle activity during the TBS is detected.

Set-up of theta-burst stimulation will involve the same Magstim Rapid 2 device in which the
handle of the stimulation coil (same standard figure-eight coil) will be pointed backward and
45 degrees from the sagittal plane so as to be approximately perpendicular to the rolandic
fissure. We will use a continuous (cTBS) pattern of delivery for magnetic stimulation and
pulses will occur in sets of three at 20msec intervals (50hz burst rate), with each burst of
three pulses separated by 200msec (5hz inter-burst rate). Thus there are 15 pulses per
second, divided into 5 bursts of three pulses. Each burst of three pulses will be the same.
Stimulation will continue for 40 seconds, for a total of 600 pulses. The subject will be
instructed to maintain all muscles relaxed, and relaxation relevant to stimulation will be
monitored using EMG of the FDI muscle. After the initial TBS treatment, single and
paired-pulse magnetic stimulation will be performed again to test cortical function and MEP
threshold. These pulses will be applied in the same manner as before TBS treatment (described
in previous paragraph).

The stimulation pulses can produce a loud clicking noise, and subjects will be provided with
earplugs or sound isolating ear cuffs if the sound intensity becomes uncomfortable or exceeds
normal speech volume.

Inclusion Criteria:1. Dystonia affecting one or both hands or arms, and/or spasticity
affecting one or both hands/arms 2. Age 2 years to 29 years 3. Sufficient cognitive
function to attempt isolated finger movements

Exclusion Criteria:1. any metallic implants in the head or neck 2. seizure within 2 years
of study entry, or prior history of status epilepticus outside the newborn period.

3. deep-brain stimulator, vagal nerve stimulator, pacemaker, intrathecal baclofen pump, or
other implanted electrical device.

4. prior neurosurgical procedure 5. migraine disorder 6. known cardiac arrhythmia, or
history of syncope 7. use of tricyclic antidepressants or neuroleptic medications during
the study 8. use or requirement for medications to treat seizures