This study is a stratified, parallel-group, single-center study utilizing multimodal imaging techniques to identify biomarkers for Major Depressive Disorder (MDD). The study goal is to identify biomarkers for MDD and treatment response that can be implemented in clinical diagnosis and care as valid and reliable measures, through monitoring neurophysiological and electrophysiological changes across the course of transcranial magnetic stimulation (TMS) treatment.

First, the study will examine the replicability and prognostic utility of two previously identified potential biomarkers for MDD using resting state imaging. Second, investigators will conduct an exploratory, whole brain analysis combining EEG and imaging techniques to identify new potential biomarkers for MDD and treatment response as participants complete a course of TMS treatment. It is the hope to shed new light on the mechanisms underlying depression and relapse, which may allow for a more effective, personalized selection of treatment course.

Participants will complete initial screening and baseline evaluation, along with resting-state functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI) and electroencephalography (EEG) scans prior to the initial TMS treatment. Participants will complete 30-36 TMS sessions and a post-treatment evaluation, along with mid- and post-treatment fMRI, DTI and EEG scans.

It is anticipated that participants with MDD have a specific set of neural features that can classify with high precision patients with MDD from those who do not, and that align with clinical diagnoses. This set of neural features will change across the course of treatment. Further, investigators expect that improvement as rated by a common MDD measure is modulated by time of treatment.

Inclusion Criteria:

• Age 18-70
• Meet Diagnostic and Statistical Manual-V (DSM-V) diagnostic criteria for Major Depressive Disorder in a current major depressive episode, without psychotic features.
• Has Montgomery-Asberg Depressive Rating Scale (MADRS) of > 19 at baseline, corresponding with moderate to severe depression.
• Demonstrate a moderate level of resistance to antidepressant treatment in the current episode, defined as a failure of 1-4 adequate medication trials.
• If participant is on a regimen of psychotropic medication, no changes in this regimen should be made during the period between the time at which pre-treatment and post-treatment scans are taken.
• Willing and able to undergo non-invasive brain stimulation
• Willing and able to attend research visits for approximately 8 weeks
• Willing and able to provide informed consent
• Ability to speak and read English

Exclusion Criteria:

• Diagnosed with acute or chronic psychotic symptoms of disorders (e.g. schizophrenia, schizophreniform, schizoaffective disorder) in the current depressive episode.
• Has neurological conditions including epilepsy, cerebrovascular disease, dementia, increased intracranial pressure, having a history of repetitive or severe head trauma, or with primary or secondary tumors in the central nervous system.
• Presence of an implanted magnetic-sensitive medical device in or near the head, including but not limited to pacemaker, vagus nerve stimulator, or metal aneurysm clips or coils, staples, or stents.
• Generalized anxiety disorder as the primary DSM-V disorder during the current MDD episode.
• Meets criteria for alcohol or substance abuse or dependence (other than caffeine) in previous 6 months, as determined by the SCID
• History of seizures
• Implantable hardware not compatible with MRI or with the study
• Inability to comply with study daily visits
• Women who are pregnant, plan to become pregnant, or breast feeding
• Inability to speak and/or read English
• Inability to give consent
• Any active suicidal intent or plan during the current depressive episode, as determined by a score of 3 on Question #9 of Beck's Depression Inventory (scores reviewed daily by study team members versed in scoring clinical scales), or as by a subjective determination by a study clinician during any study visit.

A third party assessor will conduct a biweekly MADRS clinician rating to assess depression symptoms.