Individualized Functional Connectivity Targeting in aiTBS for Depression (AINT)

Inclusion Criteria: English proficiency sufficient for informed consent, questionnaires/tasks, and treatment Primary 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, 11 Moderate 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 trial Agreement to lifestyle considerations Abstain from becoming pregnant from screening through end of treatment Continue usual intake patterns of caffeine- or xanthine-containing products (e.g., coffee, tea, soft drinks, chocolate) throughout treatment Abstain from alcohol for at least 24 hours before the start of each MRI and TMS session Abstain from tobacco products during treatment day Exclusion Criteria: Active pregnancy as determined by a urine pregnancy test Primary psychiatric diagnosis other than major depressive disorder requiring treatment other than comorbid anxiety disorder Those who did not respond to electroconvulsive therapy (ECT) after 8 sessions Recent (within 4 weeks) or concurrent use of rapid acting antidepressant agent (ketamine/esketamine/ECT) History of: Prior exposure to TMS Neurosurgical intervention for depression Autism spectrum disorder Intellectual disability Severe cognitive impairment Significant neurological illness (e.g., dementia, Parkinson's, Huntington's, brain tumor, seizure disorder, subdural hematoma, multiple sclerosis, brain lesion) Untreated or insufficiently treated endocrine disorder Treatment with investigational drug or intervention during the study period Depth-adjusted TMS treatment dose > 65% maximum stimulator output ≥ 30% change in MADRS score between screening and baseline Anyone presenting with: Mania or hypomania Psychosis Active suicidal ideation or a suicide attempt (defined by C-SSRS) within the past year Neurological lesion Contraindications 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 withdrawal Positive urine drug screen for illicit substances Severe borderline personality disorder Any other condition deemed by the PI to interfere with the study or increase risk to the participant