The goal of this clinical trial is to explore the effects of non-invasive brain stimulation protocols using intermittent theta-burst stimulation (iTBS) on brain plasticity in healthy, right-handed individuals aged 18 to 50 years. Brain plasticity is the brain's ability to change through growth or reorganization. iTBS is a form of transcranial magnetic stimulation (TMS), where magnetic pulses are applied to the scalp using a coil. These pulses pass through the scalp, and can alter brain activity in the area underneath the coil. Based on previous research conducted in animals and humans, researchers believe that iTBS can strengthen the connections between cells in the brain, leading to improved brain plasticity.

This trial will compare the effects of the compressed iTBS (iTBS-c) protocol, which is commonly used to treat depression, and the spaced iTBS (iTBS-s) protocol. Researchers want to find out which protocol is better able to produce changes in brain plasticity. Sham iTBS (iTBS-sh) will be used as a control to make the results of the study more reliable.

Participants will complete 5 study visits within the span of 3 months, including:

• Screening assessments to determine eligibility (Visit 1);
• Calibration iTBS session (Visit 2) to assess tolerability of brain stimulation;
• Three experimental iTBS sessions (iTBS-s, iTBS-c, and iTBS-sh) in a randomized order (Visits 3-5), each separated by at least 72 hours. During each session, the study team will stimulate the motor cortex and record the muscle activity of your hand to measure changes in brain plasticity.

Major Depressive Disorder (MDD) is a mental illness affecting millions of individuals worldwide and in Canada, and is a leading cause of morbidity, mortality, and disability. While antidepressant medications are effective in treating MDD, their efficacy is moderate and systemic side-effects persist, such as sexual dysfunction, drowsiness, weight gain, and dry mouth. Thus, more effective treatments are needed for MDD.

Neuroimaging techniques have implicated the dysregulation of brain plasticity in depression. In particular, long-term potentiation (LTP)-like activity in the dorsolateral prefrontal cortex (DLPFC) and the motor cortex is known to be impaired in MDD. As such, transcranial magnetic stimulation (TMS)-based interventions, which aim to modify underlying cortical activity, are now established treatments of depression. Intermittent theta-burst stimulation (iTBS), a novel form of repetitive TMS approved by the US Food and Drug Administration (FDA) for the treatment of depression, delivers intermittent, high-frequency theta bursts. It has been demonstrated to induce sustained plasticity in the DLPFC and the motor cortex. Although iTBS is approved for the treatment of depression, response and remission rates for MDD are still relatively low.

Based on promising research conducted in the hippocampus of rodents, the investigators believe that modifying some parameters of the iTBS protocol may be more effective in inducing plasticity than the currently used iTBS protocol. Thus, in this trial researchers aim to optimize iTBS and its effects on cortical plasticity as a first step towards optimizing it for the treatment of depression.

The primary and secondary objectives and hypotheses of the study are as follows:

Objective 1: To compare the effect of compressed iTBS (iTBS-c) to spaced iTBS (iTBS-s) on LTP-like activity (referred to hereafter as iTBS-LTP) as measured using motor evoked potentials (MEPs) recorded from the right abductor pollicis brevis (APB), abductor digiti minimi (ADM), and first dorsal interosseous (FDI) muscles.

Hypothesis 1: iTBS-s will elicit larger iTBS-LTP post-iTBS as compared to iTBS-c.

Objective 2: To compare the effect of iTBS-c and iTBS-s on iTBS-LTP relative to iTBS-sh.

Hypothesis 2: iTBS-c and iTBS-s will elicit larger iTBS-LTP post-iTBS as compared to iTBS-sh.

Inclusion Criteria:

1. Age 18 years or above, and less than 51 years.
2. Right handedness, assessed using the Edinburgh Handedness Inventory (EHI).
3. Sufficiently proficient in English to complete the required study assessments, as per investigator judgement.
4. Willingness and capacity to provide informed consent.
5. Willingness to comply with all study procedures.

Exclusion Criteria:

1. Age 17 years or less, or greater than 51 years, as brain plasticity is known to be affected by age.
2. Current use of any psychotropic medications (e.g. anti-depressants, anti-convulsants, anti-psychotics, etc.).
3. Contraindications to transcranial magnetic stimulation (TMS), as per investigator judgment.
4. Lifetime history of any Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnosis, assessed using the Structured Clinical Interview for DSM-5 (SCID-5), except simple phobias.
5. Left handed or ambidextrous, assessed using the EHI, to minimize the heterogeneity in cortical excitability and plasticity.
6. Self-reported history of seizures and/or other major neurological conditions, as per investigator judgement, due to the risk of seizures associated with TMS in individuals with a heightened risk.

This clinical trial is a single-blinded study. Participants will be blinded to the iTBS condition they are receiving in Visits 2-5. The individual administering iTBS (i.e., the interventionist) will not be blinded to the iTBS condition being administered. To maintain participant blinding, each of the three iTBS interventions (iTBS-c, iTBS-s, and iTBS-sh) were designed to be similar in length and structure.