Neural Mechanisms of Intermittent Theta Burst Stimulation in the Core Depression Network

Repetitive Transcranial magnetic stimulation (TMS) uses magnetic fields to modulate brain activity. A novel form of repetitive TMS (rTMS), intermittent theta burst stimulation (iTBS), has emerged as a promising new treatment for depression. This technique may be advantageous due to its very short duration and potentially stronger effect on brain activity in comparison with standard rTMS. However, the exact effect of iTBS on the activity of the brain in clinical populations remains poorly understood. This project aims to improve understanding of the mechanisms of action of iTBS by comparing its neuronal effect to sham treatment in 22 individuals with a diagnosis of major depressive episode, using positron emission tomography (PET) and magnetic resonance imaging (MRI) in a double-blind cross-over experiment, followed by a 6-week daily treatment course of iTBS.

Repetitive transcranial magnetic stimulation (rTMS) is a Health Canada approved treatment for major depression. Typical clinical rTMS treatment is delivered on the left dorsolateral prefrontal cortex (DLPFC) at a 10 Hz frequency for 30-45 minutes to increase cortical excitability which will outlast the duration of stimulation. The treatment involves daily sessions that are applied over a four to six-week period. Intermittent theta burst stimulation (iTBS) is a novel refinement of conventional rTMS. iTBS consists of bursts of 3 stimulations at 50 Hz at theta frequency (5 Hz). However, instead of 30-min treatment sessions, iTBS has comparable clinical efficacy with only 3 minutes treatment sessions. Because iTBS is a novel technique, much of its effects on the brain are currently unknown. However, since it is a modified rTMS protocol, it is assumed that its neuronal effects are comparable.

Therapeutic effects of rTMS are thought to be related to its effects on the subgenual anterior cingulate cortex (sgACC; Broadman area 25). In depression, metabolic activity of the sgACC is increased (measured as increase of 18F-labeled fluorodeoxyglucose (\[18F\]FDG) uptake with positron emission tomography (PET)). Importantly, the metabolic activity of the sgACC appears to be a general marker for treatment response, e.g. \[18F\]FDG uptake is decreased in response to antidepressant medications or deep brain stimulation. In addition to resting state functional MRI, diffusion weighted imaging has been used to study TMS targets, but this technique has never been used for testing targets for treating depression.

Currently, the system level mechanisms of action of iTBS in depression patients are completely unexplored. Based on prior research the investigators hypothesize that 1) a single session of iTBS will decrease \[18F\]FDG uptake in the sgACC and 2) the magnitude of decrease is related to the connectivity between the target site and the sgACC. This study will establish the system level mechanisms of action of iTBS, paving a way to improve clinical treatment. This study will also develop connectivity measures that can be used to improve iTBS targeting (i.e. choose iTBS target based on sgACC connectivity) and predict treatment response (i.e. predict iTBS treatment response in patients based on sgACC connectivity).

Eligibility Criteria:
Inclusion Criteria:

* Men or women aged 18 to 55 years of age
* Mini-International Neuropsychiatric Interview-confirmed diagnosis of MDD, as a single or recurring episode
* Symptoms of MDD have not improved after ≥ 1 but ≤ 7 adequate dose(s) of antidepressant trial(s) in the current depressive episode
* A baseline score of ≥ 15 on the 17-item Hamilton Rating Scale for Depression (HRSD-17)
* Have received a stable antidepressant regimen for at least four weeks prior to entering trial
* Are voluntary and competent to consent to study
* Can speak and read English

Exclusion Criteria:

* Current or past (\< 3 months) substance (including nicotine) or alcohol abuse/dependence, as defined in DSM-5 criteria
* Positive urine test for illegal substances, cannabis, or cotinine
* Suicide attempt in the past three months and/or active suicidal intent
* Pregnancy (confirmed by urine test) and/or lactation
* Psychotic features in the current episode
* Any comorbid mental health disorders (including, but not limited to lifetime history of psychotic disorders, OCD, PTSD and/or bipolar I or II disorder) with the exception of anxiety/panic disorders and ADHD
* Significant unstable medical or neurologic illness confirmed by medical history and blood test at baseline (e.g. uncontrolled diabetes, or renal dysfunction)
* Organic cause to the depressive symptoms (e.g. thyroid dysfunctions), as ruled out by the referring physician
* Contraindication for TMS (e.g., personal history of epilepsy or convulsion, metallic head implant, pacemaker)
* Contraindication for MRI (e.g. metallic implant, claustrophobia)
* Have undergone a prior PET or SPECT research study
* ECT or rTMS treatment in the current depressive episode
* Benzodiazepine use
* Have a body mass index (BMI) higher then 35 or lower then 18
* Any other condition that, in the opinion of the investigators, would adversely affect the participant's ability to complete the study