Repeated iTBS Cycloserine Motor Plasticity
Condition: Motor Activity
Study type: Interventional
Phase: Phase 2

Summary: 
      Repetitive transcranial magnetic stimulation (rTMS) is a modality for probing and altering
      brain function in humans non-invasively. The technology relies on the principles of
      electromagnetic induction, whereby magnetic fields have an associated electrical field. By
      intersecting two magnetic fields safely generated outside the head, one can induce a focal
      electrical current where the magnetic fields intersect in the brain, and this can depolarize
      cell membranes and impact brain activity.

      A well investigated phenomenon in neuroscience is the principle of long term potentiation
      (LTP), and its converse long term depression (LTD), referring to the ability of neurons to
      increase or decrease their connection strength in an activity dependent manner. They do this
      through modifications to their electrochemical junctions, the synapses. We have previously
      used the motor system as a model system to study the impact D-Cycloserine, an NMDA receptor
      partial agonist, on synaptic plasticity after TMS.

      Conventional therapeutic TMS is delivered once daily, however it is increasingly being
      delivered multiple times per day in an effort to speed treatment effects. It is unclear how
      adjunctive agents would impact these repeated stimulation designs.

      Research Question:

      Does the N-methyl-D-aspartate receptor partial agonist D-Cycloserine stabilize motor
      plasticity across multiple daily sessions of TMS?
    

Detailed description: 
      Objectives:

        1. To recruit 20 participants into a cross-over trial. These participants will complete two
           study phases (active and placebo), and will not know whether they are taking a low-dose
           d-cycloserine capsule (100mg) or a placebo capsule at each of these phases.

        2. To measure motor evoked potentials (MEP) in the hand in relation to magnetic stimulation
           of the motor cortex responsible for this muscle. These will be measured at baseline, and
           after receiving rTMS over the motor cortex.

        3. To deliver intermittent theta-burst rTMS stimulation (TBS) to the FDI region of the
           motor cortex.

        4. To measure the magnitude (and associated change from baseline) of the MEPs after rTMS at
           a fixed stimulus intensity, and using a range of stimuli to generate a stimulus response
           curve.

        5. To repeat iTBS one hour later and measure the impact on MEPs.

        6. To measure changes in performance on computerized cognitive tasks following ingestion of
           the blinded capsule.

      Methods:

      D-Cycloserine will be purchased from Parsolex and repackaged into 100mg placebo-controlled
      capsules by Script Pharmacy in Calgary.

        1. We will recruit 20 participants aged 18-65 through community advertisement, carefully
           screened for exclusion factors related to rTMS and DCS.

        2. Participants will be randomly assigned by random number sequence with allocation
           concealment to one of two first arms of the crossover study: a) placebo-DCS 100mg and b)
           DCS 100mg-placebo.

        3. Participants will complete the QIDS-SR (Quick Inventory of Depressive Symptoms-Self
           Report), the BAI (Beck Anxiety Inventory), and the STAI (State Trait Anxiety Inventory).

        4. Participants will take their blinded capsule at least 1 hour prior to TBS. (we
           anticipate that it will take approximately 30 minutes to do steps 5-7)

        5. Electromyographic (EMG) electrodes will be positioned over the first dorsal interosseous
           (FDI) bilaterally. These are non-invasive electrodes that use an adhesive to stick to
           the skin.

        6. Using neuronavigation in conjunction with an atlas brain, the M1 hand strip will be
           localized using single pulse TMS (MagPro X100).

        7. Motor evoked potentials are measurements of muscle activation, in this case in response
           to TMS stimulation of the brain. We will use single pulse TMS to record the magnitude of
           responses. As a baseline, we will collect twenty single-pulse (120% resting motor
           threshold (RMT), 0.25Hz) MEPs every 5 minutes for the 15 minutes preceding TBS rTMS. We
           will also characterize the stimulus response curve at baseline by delivering single
           pulse TMS at stimulus intensities ranging from 100-150% resting motor threshold
           presented in random order.

        8. TBS rTMS will be applied to the FDI 'hotspot'. TBS consists of 2s trains every 10s.
           Trains are composed of 3 pulses at 50Hz, 200ms intervals, 80% RMT. Total time 190s and
           600 pulses.

        9. After TBS, twenty MEPs will be acquired (single pulse, 120% RMT, 0.25Hz) every 5 minutes
           for the first 15 minutes after iTBS. A stimulus response curve will be acquired at 30
           minutes and 60 minutes post iTBS.

       10. One hour following TBS, a second train of TBS rTMS will be applied to the FDI 'hotspot'.
           TBS consists of 2s trains every 10s. Trains are composed of 3 pulses at 50Hz, 200ms
           intervals, 80% RMT. Total time 190s and 600 pulses.

       11. After TBS, twenty MEPs will be acquired (single pulse, 120% RMT, 0.25Hz) every 5 minutes
           for the first 15 minutes after iTBS. A stimulus response curve will be acquired at 30
           minutes and 60 minutes post iTBS.

       12. During one of the breaks in the stimulation procedure, a brief, computerized
           neurocognitive assessment will take place after ingestion of the blinded capsule.

       13. Participants will be asked if they believe they received the study medication or placebo
           in this first phase of the crossover trial.

      This is study involves a crossover design, therefore after a minimum of 7 days the experiment
      will be repeated with the second blinded capsule.
    

Intervention name(s): Transcranial Magnetic Stimulation; Cycloserine; Placebo Oral Tablet
Intervention type(s): Device; Drug; Drug
Intervention description(s): Single-pulse transcranial magnetic stimulation and theta-burst stimulation; Cycloserine 100mg; Placebo capsule matched to cycloserine capsule
Intervention MeSH terms: Cycloserine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science