Individualized Functional Connectivity Targeting in aiTBS for Depression

The goal of this clinical trial is to estimate the importance of neuroimaging in accelerated intermittent theta burst stimulation (aiTBS) for depression. Participants will receive aiTBS treatment, but they will not know if their treatment spot was found with neuroimaging or head measurements.

Inclusion Criteria:English proficiency sufficient for informed consent, questionnaires/tasks, and treatmentPrimary diagnosis of major depressive disorder per Diagnostic and Statistical Manual (DSM)-V criteria (MINI International Neuropsychiatric Interview)>20 on BDI>20 on the MADRS 10, 11Moderate to severe level of treatment resistance (Maudsley Staging Method)Stable antidepressant medication regimen, or remain medication free, for 4 weeks prior to treatment and to remain on this regimen throughout the study (including all follow-up assessments after the 5-day treatment protocol).Primary clinician responsible for psychiatric care before, during, and after the trialAgreement to lifestyle considerationsAbstain from becoming pregnant from screening through end of treatmentContinue usual intake patterns of caffeine- or xanthine-containing products (e.g., coffee, tea, soft drinks, chocolate) throughout treatmentAbstain from alcohol for at least 24 hours before the start of each MRI and TMS sessionAbstain from tobacco products during treatment dayExclusion Criteria:Active pregnancy as determined by a urine pregnancy testPrimary psychiatric diagnosis other than major depressive disorder requiring treatment other than comorbid anxiety disorderThose who did not respond to electroconvulsive therapy (ECT) after 8 sessionsRecent (within 4 weeks) or concurrent use of rapid acting antidepressant agent (ketamine/esketamine/ECT)History of:Prior exposure to TMSNeurosurgical intervention for depressionAutism spectrum disorderIntellectual disabilitySevere cognitive impairmentSignificant neurological illness (e.g., dementia, Parkinson's, Huntington's, brain tumor, seizure disorder, subdural hematoma, multiple sclerosis, brain lesion)Untreated or insufficiently treated endocrine disorderTreatment with investigational drug or intervention during the study periodDepth-adjusted TMS treatment dose > 65% maximum stimulator output≥ 30% change in MADRS score between screening and baselineAnyone presenting with:Mania or hypomaniaPsychosisActive suicidal ideation or a suicide attempt (defined by C-SSRS) within the past yearNeurological lesionContraindications to either TMS or MRI (e.g., metallic implants, severe insomnia > 4 hours per night with hypnotic, etc.).Current moderate or severe substance use disorder or demonstrating signs of acute substance withdrawalPositive urine drug screen for illicit substancesSevere borderline personality disorderAny other condition deemed by the PI to interfere with the study or increase risk to the participant