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 and depression severity in depressed individuals aged 18 to 50 years old. 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 and improve symptoms of depression among individuals diagnosed with Major Depressive Disorder (MDD). In this trial, participants will be randomized to receive 3 sessions of iTBS-s or iTBS-c, undergo a washout period of at least 2 weeks, then complete 3 sessions of the opposite iTBS intervention.

Participants will complete 5 study visits within the span of 2-3 months, including:

• Screening assessments to determine eligibility & 1 sham iTBS (iTBS-sh) session to assess tolerability of the brain stimulation (Visit 1);
• 1 Magnetic Resonance Imaging (MRI) brain scan and randomization (Visit 2);
• Safety and clinical assessments, iTBS-s or iTBS-c intervention, TMS evoked electroencephalography (TMS-EEG) measurements, and post-iTBS questionnaires (Visits 3-5) followed by a washout period of at least 2 weeks;
• Safety and clinical assessments, the opposite iTBS-s or iTBS-c intervention originally randomized to, TMS-EEG measurements, and post-iTBS questionnaires (Visits 6-8).

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 (rTMS) 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. Studies have shown that iTBS is equally effective as conventional rTMS in terms of response rates, and its adverse effects are comparable to iTBS-sh and active rTMS. One key advantage of iTBS over rTMS is its time efficiency, with each session lasting approximately 3 min compared to up to 40 min with rTMS. Notwithstanding its efficiency, systematic reviews of RCTs indicate no significant difference in remission rates - defined as a reduction in symptoms below a threshold indicating euthymic state - between iTBS (~26%) and iTBS-sh (~19%), or between iTBS (32%) and rTMS (27%). Thus, while iTBS is well tolerated, efficient and effective in reducing symptoms of MDD, its efficacy is still far from optimal as is the case for other treatments of depression.

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 determine whether an optimized iTBS protocol will result in better LTP-like activity in the DLPFC of adults with MDD.

The objectives and hypotheses of the study are as follows:

Objective 1: To compare the ability of iTBS-c vs. iTBS-s to induce DLPFC LTP-like activity in depressed adults as measured using TMS-electroencephalography (EEG).

Hypothesis 1a: iTBS-s will induce stronger DLPFC LTP-like activity compared to iTBS-c.

Hypothesis 1b: iTBS-s will induce longer-lasting DLPFC LTP-like activity compared to iTBS-c.

Objective 2: To evaluate the relationship between DLPFC LTP-like activity and changes in depression severity, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS).

Hypothesis 2a: DLPFC LTP-like activity will be inversely associated with baseline depressive symptoms.

Hypothesis 2b: DLPFC LTP-like activity will be associated with improvement in depressive symptoms on Visits 3 to 5.

Objective 3: To compare the effect of iTBS-c vs. iTBS-c within-subjects on DLPFC LTP-like activity in depressed adults as measured using TMS-EEG during the cross-over phase of the study.

Hypothesis 3: iTBS-s will induce stronger DLPFC LTP-like activity compared to iTBS-c within-subjects.

Inclusion Criteria:

• Aged 18-50 years old;
• Must meet criteria for a current Major Depressive Episode (MDE) as ascertained using the Structured Clinical Interview for DSM 5 (SCID-5);
• Hamilton Rating Scale for Depression (HRSD-17) score > 7;
• Must be on a stable antidepressant regimen for a minimum of 4 weeks prior to enrollment, if currently taking antidepressants;
• Right handed or ambidextrous, assessed using the Edinburgh Handedness Inventory (EHI);
• Sufficiently proficient in English to complete the required study assessments, as per investigator judgement;
• Willingness and capacity to provide informed consent;
• Willingness to comply with all study procedures.

Exclusion Criteria:

• Age 17 years or less, or greater than 51 years old, as brain plasticity is known to be affected by age;
• Presence of any DSM-5 diagnosis (other than MDD), known to be associated with prefrontal cortical dysfunction, including lifetime diagnoses of bipolar disorder, intellectual disability, or a psychotic disorder, assessed using the SCID-5 and as per investigator judgement;
• Presence of acute suicidal intent, as determined by the Scale for Suicidal Ideation (SSI);
• Contradictions to MRI or TMS (e.g., cardiac pacemaker, acoustic device, history of seizures, pregnancy), assessed using the MRI Safety Form and TMS Adult Safety Screen (TASS) and as per investigator judgement;
• Left handed, assessed using the EHI, to minimize the heterogeneity in cortical excitability and plasticity;
• Current antipsychotic, antiepileptic, or benzodiazepine use given their potential effects on cortical plasticity, as ascertained through a medication review. An exception will be made if they are taking gabapentin or pregabalin prescribed only for chronic pain, and if the dose had been stable for at least 4 weeks prior to study enrollment.

The study will be completed under double-blind conditions: (1) Participants will be blind to the hypothesis and potential differences in outcomes between iTBS-c and iTBS-s; (2) The research staff conducting the clinical and TMS-EEG assessments will be blind to group assignment.

Trained personnel administering iTBS (i.e., the interventionist) will not be blinded to the iTBS condition being administered. Therefore, trained personnel who administer iTBS will not be permitted to complete any study assessments following the intervention.