Repetitive transcranial magnetic stimulation (rTMS) uses a magnetic field to non-invasively induce electrical function within the brain. Stimulation allows brain cells to change the way that they adapt and communicate with each other, known as 'synaptic plasticity'. It is thought that alterations in these adaptive brain changes underlie the ability of rTMS to treat mental illnesses like depression. The regulation of synaptic plasticity is complex, and involves multiple interacting factors and redundant systems to ensure that plasticity is carefully regulated. To date, studies attempting to alter impact synaptic plasticity have done so using pharmacological adjuncts that target extracellular contributions to plasticity. Here, we propose the first proof of principle study targeting intracellular regulation of plasticity by using a pharmacological adjunct targeting Phosphodiesterase 4 (PDE4), a key regulator a cyclic AMP gradients in brain cells. We will pair TMS with electromyography (EMG) to measure activity dependent changes in the motor cortex following rTMS to test the ability of a PDE4 inhibition to enhance synaptic plasticity after rTMS.
This study will employ a randomized, placebo-controlled single-blind crossover trial of adjunctive roflumilast with intermittent or continuous theta burst (iTBS/cTBS) TMS to the primary motor cortex. Participants will complete a screen visit to determine eligibility based on the inclusion/exclusion criteria. If the participants are not eligible, no further study procedures will be conducted. Randomization with allocation concealment of eligible patients to begin with either the study medication or placebo arm of the study will involve a random number sequence generated a priori with atmospheric noise, with single-blind random condition assignment and allocation concealment. Baseline corticospinal excitability will be quantified. One hour following ingestion of the blinded capsule iTBS/cTBS will be applied to the primary motor cortex, and the response will be quantified through a combination of motor evoked potentials (MEPs) at a fixed stimulus intensity, cortical silent period, and a range of stimuli to generate stimulus response curves (SRCs). The duration of each arm is up to 2.5 hours, and they will be separated by at least 1 week. All participants will complete a questionnaire to assess any side effects (emotional and physical) following each rTMS session.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
DOUBLE
Enrollment
20
Participants will ingest either a placebo or roflumilast 500mg in a single blind crossover study and receive transcranial magnetic stimulation to the primary motor cortex.
Participants will ingest either a placebo or roflumilast 500mg in a single blind crossover study and receive transcranial magnetic stimulation to the primary motor cortex.
Intermittent theta-burst stimulation consists of 2 second trains every 10 seconds. Each train is composed of 3 pulses at 50Hz, 200 milliseconds intervals given at 80% resting motor threshold. The total time for this treatment stimulus is 600 pulses over 190 seconds.
Continuous theta-burst stimulation consists of 2 second trains every 10 seconds. Each train is composed of 3 pulses at 50Hz, 200 milliseconds intervals given at 80% resting motor threshold. The total time for this treatment stimulus is 600 pulses over 40 seconds.
University of Calgary
Calgary, Alberta, Canada
Motor evoked potential amplitude
Motor evoked potentials will be measured using surface electrodes placed over the first dorsal interosseous muscle of the hand to a single stimulus intensity of 120% of resting motor threshold.
Time frame: -5 minutes, -10minutes, -5 minutes, and immediately prior to theta-burst stimulation, then +5 minutes, +10 minutes, +15 minutes, +20 minutes, +25 minutes, +30 minutes, +45 minutes and +60 minutes after theta-burst stimulation.
Motor evoked potential stimulus response curve
Motor evoked potentials will be measured using surface electrodes placed over the first dorsal interosseous muscle to varying stimulus intensities.
Time frame: Baseline, 30 minutes following theta-burst stimulation, 60 minutes following theta-burst stimulation.
Cortical silent period
Motor evoked potentials will be measured using surface electrodes placed over the first dorsal interosseous muscle while participants maintain a light contracture of the muscle.
Time frame: Baseline, 30 minutes following theta-burst stimulation, 60 minutes following theta-burst stimulation.
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