Comparing Outcomes of Theta Burst Stimulation in Depression Using Advanced PET Imaging

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.

Inclusion Criteria For inclusion in the study, participants must fulfill all the following criteria: 1. 18 to 55 years old. 2. Competent to provide voluntary informed consent. 3. 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 4. Referred by their treating physician. 5. Mini-International Neuropsychiatric Interview-confirmed diagnosis of MDD, as a single or recurring episode. 6. Symptoms of MDD have not improved after ≥ 1 adequate antidepressant medication trial in the current depressive episode29. 7. Baseline score of ≥18 on the 17-item Hamilton Rating Scale for Depression (HRSD-17). 8. Maintained a stable treatment regimen for at least four weeks prior to entering the study, defined as being on a stable antidepressant regimen, a stable psychotherapy regimen, both, or neither (i.e., no treatment), with no changes during this period. Exclusion Criteria Participants fulfilling any of the following criteria will be excluded from the study: 1. 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 2. Current or past (\< 3 months) substance (including nicotine) or alcohol abuse/dependence, as defined in DSM-5 criteria. 3. Positive urine test for illegal substances, cannabis, or cotinine. 4. Significant unstable medical or neurologic illness confirmed by medical history (e.g. uncontrolled diabetes, or renal dysfunction). 5. Breastfeeding or pregnant (confirmed via urine test). 6. BMI \> 30 or BMI \< 18. 7. Contraindication for TMS (e.g., personal history of epilepsy or convulsion, metallic head implant, pacemaker). 8. Contraindication for MRI (e.g. metallic implant, claustrophobia). 9. Have received a cumulative radioactivity dose \> 15.2mSv during the last 12 months. 10. Have active malignancies (due to high chance of undergoing radiation therapy). 11. Suicide attempt in the past three months and/or active suicidal intent. 12. Failed (non-response) course of ECT or rTMS treatment in the current depressive episode. 13. Benzodiazepine or lithium use. Other psychotropic medications (e.g. ADHD medications) are permitted, if stable in the 4 weeks prior to and during the treatment course) 14. Any other condition that, in the opinion of the investigators, would adversely affect the participant's ability to complete the study.