rTMS to Target Neural Connectivity and Rumination in Treatment-Resistant Depression

Inclusion Criteria:

• Diagnosis of unipolar major depressive disorder without psychotic features by theMini-International Neuropsychiatric Interview (MINI) and confirmed by studypsychiatrist

• First depressive episode prior to age 50

• Current moderate to severe depression, Hamilton Depression Rating Scale (HDRS) ≥17)

• Failure to respond to ≥1 antidepressant medication at adequate dose and duration inthe current depressive episode; (note: this criterion is designed to be consistentwith the original 2008 FDA-labeled indication for TMS in Major Depressive Disorder,that specifies failure to respond to "one prior medication at or above the minimaleffective dose and duration in the current episode" (https://www.accessdata.fda.gov/cdrh_docs/pdf8/K083538.pdf). ))

• Off psychotropic medications OR on a stable dose of medication(s) for 6 weeks, andwilling to remain on stable medication dosage throughout the study

• Capacity to consent

• Ability to safely receive MRI

Exclusion Criteria:

• Actively/imminently suicidal, Quick Inventory of Depressive Symptomatology (QIDS)item 12 score >2)

• Current depressive episode duration > 5 years

• Presence of clinically significant psychiatric diagnoses other than unipolar,non-psychotic major depression, such as post-traumatic stress disorder (PTSD) orobsessive-compulsive disorder (OCD)

• Evidence of cognitive impairment, Montreal Cognitive Assessment (MOCA) < 23)

• Significant substance use disorder within past 6 months

• New-onset psychotherapy and/or somatic therapy (e.g., light therapy) within 6 weeksof screening

• Prior exposure to any form of TMS

• Have participated in any clinical trial with an investigational drug or devicewithin the past 6 weeks prior to screening

• Failure to respond to Electroconvulsive therapy (ECT)

• Any history of neurosurgery to treat a neurologic or psychiatric disorder (e.g.Vagus nerve stimulation, cortical stimulation, deep brain stimulation, or ablativesurgery)

• Unstable medical illness

• Evidence or history of significant neurological disorder, including moderate-severehead trauma, stroke, Parkinson's disease or other movement disorder (except benignessential tremor)

• Epilepsy

• History of seizures (except juvenile febrile seizures or provoked seizures at thePI's discretion) or any condition/concurrent medication that could notably lowerseizure threshold

• Pregnancy or planned pregnancy during the study

• Presence of cardiac pacemaker, cochlear implant, or other implanted electronicdevice

• Any vision problem that will prevent them from seeing the adjectives presentedinside the MRI scanner without glasses