The proposed project will investigate the neurobiological mechanisms of accelerated intermittent Theta Burst Stimulation (iTBS) in major depressive disorder (MDD) using an advanced multimodal imaging approach. This single-arm, within-subject study will deliver one week of accelerated iTBS and use pre-/post-treatment PET/MRI to quantify changes in synaptic density, functional connectivity, and microstructural integrity. We will combine \[¹⁸F\]SynVesT-1 PET with functional, neurochemical and anatomical MRI, such as resting-state fMRI, magnetic resonance spectroscopy (MRS) and neurite orientation dispersion and density imaging (NODDI), to capture treatment-related plasticity. This integrated design will link molecular and network-level mechanisms to clinical improvement, providing an unprecedented mechanistic map of how accelerated iTBS restores brain function in depression.
18 to 55 years old.
Competent to provide voluntary informed consent.
English comprehension and verbal communication (participants must be able to both understand and speak English sufficiently to follow study procedures and be understood by study personnel
Referred by their treating physician.
Any comorbid mental health disorders (including, but not limited to lifetime history of psychotic disorders, OCD, and/or bipolar I or II disorder) with the exception of anxiety/panic disorders, posttraumatic stress disorder and ADHD
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.
Significant unstable medical or neurologic illness confirmed by medical history (e.g. uncontrolled diabetes, or renal dysfunction).
Single group
repetitive Transcranial Magnetic Stimulation
DeviceRepetitive transcranial magnetic stimulation (rTMS) is a Health Canada approved treatment for major depression. Typical treatments involve 30 to 45 minutes daily sessions delivered over 4 to 6 weeks. Recent technical advances allowed the development of theta burst stimulation (TBS), a novel rTMS paradigm that reduces daily sessions to 3 to 4 minutes while maintaining the same clinical efficacy. This study will specifically be administering intermittent TBS (iTBS), which is a novel refinement of conventional rTMS and consists of bursts of 3 stimulations at 50 Hz at theta frequency (5 Hz).
Change in Synaptic Density Following iTBS Measured by [¹⁸F]SynVesT-1 PET
We will quantify changes in synaptic density (expressed as non-displaceable binding potential (BPND)) within (a) the sgACC (primary ROI) and (b) the stimulated DLPFC (secondary ROI), with exploratory analyses in frontal, parietal and cerebellar regions identified in the seed dataset.
Change in Resting-State Functional Connectivity Following accelerated iTBS
Resting-state functional MRI (rs-fMRI) will be used to assess changes in functional connectivity (Fisher z-transformed correlation coefficients) within fronto-limbic networks following accelerated iTBS.
Change in Cortical Neurochemistry Following iTBS
Magnetic resonance spectroscopy (MRS) will be used to assess changes in cortical neurochemical metabolite concentrations or metabolite ratios (e.g., Glx, GABA+/Cr) following accelerated iTBS.
Change in Cerebral Perfusion Following iTBS
Arterial spin labelling (ASL) MRI will be used to assess changes in regional cerebral blood flow levels following accelerated iTBS.
Change in Neurite Microstructure Following iTBS
Neurite Orientation Dispersion and Density Imaging (NODDI) will be used to assess changes in neurite microstructure following accelerated iTBS, as measured by changes in neurite density index (NDI) and orientation dispersion index (ODI).
Incidence of Treatment-Emergent Adverse Events
Adverse events will be tracked and recorded.
Side Effects
Side effects will be tracked and recorded on any TMS visits, using the TMS side effects questionnaire.
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