iTBS Methods and Motor Cortex Excitability
Condition: Motor Activity
Study type: Interventional
Phase: Early Phase 1

Summary: 
      In a recent publication by Gamboa et al. 20108 it was shown that extended theta-burst
      stimulation duration might have reverse effects on cortical excitability when compared to the
      original Huang et al. 2005 publication. While the post treatment effects of the original
      Huang et al. 2005 protocol were successfully replicated, when continuous theta burst
      stimulation (cTBS) protocols were doubled to 1200 pulses over 80 seconds and the iTBS
      protocols were doubled to 1200 pulses over 390 seconds, there was increased facilitation
      after the prolonged cTBS and decreased excitability after prolonged iTBS. Currently there is
      an interest in optimizing repetitive transcranial magnetic stimulation (rTMS) protocols and
      in particular theta burst stimulation as both a therapeutic and an investigational tool. In
      Hanlon et al. 2015, a novel theta burst paradigm is described in which two trains of 1800
      pulses of cTBS were administered, each train separated by a one-minute interval. In this
      study 11-cocaine dependent individuals underwent cTBS over the medial prefrontal cortex
      (MPFC) and showed attenuated craving as well as decreases in activity of the striatum and
      anterior insula. This study aims to replicate the findings of the Gamboa and Huang protocols
      as well as investigate how novel theta burst stimulation paradigms such as those described in
      Hanlon et al. 2015, which are currently being explored as therapeutic methods in addiction
      may change cortical excitability.
    

Detailed description: 
      rTMS is a method of non-invasive neuromodulation. Although TMS (transcranial magnetic
      stimulation) has widely been used as a research method to better understand brain
      neurophysiology, rTMS protocols have been shown to be clinically beneficial to patients
      suffering from neurological disorders such as Parkinson's Disease and stroke as well as
      psychiatric diseases such as major depression. In October of 2008 the FDA approved 10 Hertz
      (Hz) dorsolateral prefrontal cortex (DLPFC) stimulation for patients with medication
      resistant depression. The typical duration of a single rTMS treatment for depression lasts
      for about 30 minutes, but must be repeated daily over several weeks. The decision to use
      DLPFC stimulation was due in part to imaging studies, which suggested depressed patients had
      decreased activity in the region. Thus, rTMS could be used to reverse those behavioral
      effects of depression by increasing activity in the DLPFC. Traditionally 5 Hertz (Hz)
      stimulation and upward has been shown to be excitatory while stimulation of 0.2-1 Hertz (Hz)
      has been shown to have inhibitory effects on the cortex. Although these parameters appear to
      be efficacious the development of new rTMS methods are still being explored.

      Theta burst stimulation (TBS) is a method with the potential of providing excitatory or
      inhibitory effects on the cortex, which are as powerful as traditional rTMS methods yet more
      efficient in duration and intensity required. Evidence from previous studies looking at theta
      burst as a treatment for depression has highlighted the importance of the method's
      development. One study indicated that theta-burst stimulation over the dorsomedial prefrontal
      cortex (DMPFC) for a duration of just 6 minutes can produce comparable anti-depressant
      effects to traditional 10Hz stimulation over 30 minutes. Theta burst stimulation effects were
      first empirically tested on the human motor cortex by Huang et al. 2005. The effects of
      stimulation (80% of active motor threshold) over the motor cortex were measured pre and post
      treatment with electromyography (EMG) recordings of motor evoked potentials (MEPs) on a small
      contralateral hand muscle in response to single pulses of TMS. Two protocols showed changes
      in excitability of the corticospinal tract, including cTBS defined as three burst stimuli at
      50 Hz with 20ms between stimuli repeated every 200ms at 5Hz and iTBS defined as a 2s train of
      TBS repeated every 10 seconds. Although both protocols deliver a total of 600 pulses, the
      cTBS protocols lasts for 40 seconds while the iTBS protocol lasts for 190 seconds. Huang et
      al. 2005 determined that cTBS over motor cortex decreased excitability while iTBS increased
      excitability which were present an hour following treatment.

      The excitability of the motor cortex may be modulated differently depending on the type of
      theta burst stimulation protocol utilized. iTBS was originally described by Huang et al. 2005
      resulting in an excitatory effects (LTP like) on the cortex. Gamboa et al. 2010 later
      confirmed this finding but showed that there was a decrease in excitability (LTD-like) when
      the protocol is doubled. Both of these protocols are to be replicated and in addition 2 new
      protocols. In order to investigate how cortical excitability changes as a function of
      protocol, MEPs will be recorded using EMG on the hand muscle contralateral to the stimulated
      cortex. Baseline MEPs will be obtained pretreatment, followed by one of the four theta burst
      protocols, or a sham treatment. Theta burst protocols are to be administered to each
      participant in randomized order. After theta burst is administered 20 MEPs will be collected
      at 0, 10, 20, 30, 40, 50 and 60 minutes.

      Specific Aim 1: To determine the long-term potentiation (LTP) like and long-term depression
      (LTD) like effects of four different theta burst stimulation protocols on motor cortex
      excitability.
    

Intervention name(s): Real iTBS; Sham iTBS
Intervention type(s): Device; Device
Intervention description(s): This will be delivered with the Magventure Magpro system; pulses are delivered with the active coil (double blinded using the Universal Serial Bus key); This will be delivered with the Magventure Magpro system; pulses are delivered with the sham coil (double blinded using the Universal Serial Bus key). The MagVenture MagPro system has an integrated active sham that passes current through two surface electrodes placed on the skin beneath the B60 coil.
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: 30 healthy controls will undergo four Active TMS treatment sessions (separated by at least 24 hrs), along with a Sham TMS treatment session. The theta-burst treatments will be counterbalanced across participants.
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: TMS; Motor Cortex; Excitability; LTP; LTD