Roflumilast TMS-EEG Plasticity

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. rTMS is a Health Canada approved treatment for depression, however, 2/3rds of people fail to show meaningful improvement. This highlights the need for more effective therapeutic means. The purpose of the present study is to augment the therapeutic abilities of rTMS through the conjunctive use of a medication that also increases synaptic plasticity. We will pair TMS with an electroencephalograph (EEG) to measure activity dependent changes in the frontal cortex following rTMS.

This randomized, placebo-controlled, crossover trial will enroll 20 healthy participants. In one arm of the study, participants will randomly receive either 250mcg of roflumilast (a phosphodiesterase-4 inhibitor), or a placebo capsule, and participants will receive the other intervention one week later.

1. The investigators will recruit 20 healthy participants through community advertisement, carefully screened for exclusion factors related to rTMS and roflumilast.
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-roflumilast 250mcg and b) roflumilast 250mcg-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).

   Participants will report their perception of physical symptoms (potential side effects) in the 7 days before participating in the study taking the randomized capsule (Toronto Side Effects Scale - 1 Week).
4. Participants will take their blinded capsule at least 30 minutes prior to TBS (theta-burst stimulation).
5. The resting motor threshold of participants will be determined using electromyographic electrodes (EMG). EMG electrodes will be positioned over the first dorsal interosseous (FDI) muscle on the right hand. These electrodes are non-invasive and use an adhesive to stick to the skin.
6. The M1 hand strip will be localized using single pulse TMS (MagPro X100) in conjunction with neuronavigation and an atlas brain.
7. Muscle activation in response to TMS will be measured through motor evoked potentials (MEP). The strength of MEPs in response to differing strengths of single pulse TMS will be used to determine a participants resting motor threshold (RMT). The RMT is the lowest TMS setting at which the FDI muscle responds to TMS stimulus. 80% of the RMT will then be the strength at which TBS protocol will be applied to the DLPFC.
8. Two baselines of TMS Evoked Potentials (TEPs) will be collected via one hundred single-pulse (120% RMT), 0.25Hz) over the F3 site. Each baseline will occur 10 minutes apart.
9. TBS-rTMS will be applied to the DLPFC site. TBS consists of 2s trains every 10s. Each train is composed of 3 pulses at 50Hz, 200ms intervals given at 80% RMT. The total time for this treatment stimulus is 600 pulses over 190s.
10. Following TBS, one hundred TEPs over the F3 site will again be acquired at 10, 20, and 30 minutes after treatment (single pulse, 120%RMT, 0.25Hz).

As this is a cross-over study, participants will return 1 week later to repeat the second arm of the protocol (steps 3-10).

Eligibility Criteria:
Inclusion Criteria:

1. Healthy individuals (no chronic medical conditions).
2. Aged 18-60 years.

Exclusion Criteria:

1. Pregnancy
2. Lactation
3. Epilepsy
4. Previous stroke
5. Current Renal Disease
6. Current Liver Disease
7. Allergy to roflumilast or any of its non-medicinal ingredients
8. Current psychiatric concerns
9. Currently taking any medications that interact with roflumilast
10. Intracranial metallic objects (dental hardware is not an exclusionary criterion)
11. Substance use disorder
12. The inability to refrain from alcohol use for 24 hours prior to stimulation