Theta-burst Transcranial Magnetic Stimulation
Condition: Dystonia
MeSH terms: Dystonia; Dystonic Disorders
Study type: Interventional

Summary: 
      Theta-burst transcranial magnetic stimulation (TBS) is a type of repetitive transcranial
      magnetic stimulation (rTMS) method that reduces the excitability of a small region of brain
      for less than one hour. Since dystonia and spasticity may be associated with increased
      excitability of motor cortex, we expect that by reducing the excitability of motor cortex
      with TBS we will temporarily improve these symptoms and hopefully open avenues in the future
      for the use of TBS as a new, non-invasive therapeutic intervention to aid in physical therapy
      and symptom amelioration of dystonia and spasticity. We will test for motor improvement
      during the hour immediately following TBS using tests of muscle function and quality of limb
      movement.
    

Detailed description: 
      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.
    

Intervention name(s): Transcranial magnetic stimulation
Intervention type(s): Device
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic