The goal of this project is to guide rTMS using functional magnetic resonance imaging (fMRI) in individuals with depression who did not respond to standard TMS treatment to evaluate whether targeted TMS using individualized functional MRI scans produce outcome superior to that of conventional approaches. The study team also plans to scan patients with Major Depression Disorder (MDD) patients prescribed to receive standard TMS for the first time before and after which they will have resting-state Functional Magnetic Resonance Imaging (rs-FMRI) scan in order to see if we can predict their responsiveness based on the functional connectivity maps.

Significance: There are few therapeutic options for individuals with treatment resistant depression (TRD). One recently developed approach is rTMS over left dorsolateral prefrontal cortex. Recent studies have demonstrated overall antidepressant benefit of rTMS in patients who fail to respond to a trial of antidepressant medication (1, 2, 3). Nevertheless, for many patients the response is incomplete, suggesting the need for further optimization. One potential cause of heterogeneous response might relate to individual differences in brain anatomy and connectivity patterns. At present, the rTMS stimulation site across subjects is based upon fixed location relative to motor cortex. Potentially, however, the approach could be optimized by stimulating based upon individual brain functional connectivity pattern. The present project will collect pre- and post-treatment brain functional connectivity measures in a group of patients who will be receiving independent clinical rTMS for resistant depression, a connectivity-based targeting approach will be applied at the single-subject level to individualize therapy in those patients who do not respond to standard approaches.

Patients will be divided in 2 groups. Group 1 (N=30) will be depressed patients undergoing standard TMS for the first time. Group 2 (N=30) constitutes those who have previously demonstrated that they do not respond to standard TMS. MDD patients prescribed to receive standard TMS for the first time (group 1) will have resting-state FMRI in order to see if their responsiveness based on the functional connectivity maps can be predicted. Non-responders to standard TMS approaches (Group 2) will be randomized (3:2) to either receive targeted (N=18) or standard (N=12) repetitive TMS (rTMS) treatments. A connectivity-based targeting strategy will be used on patients undergoing targeted rTMS to optimize target for focal brain stimulation. Raters and patients in group 2 will be kept blinded to the treatment assignment. All patients referred from the ongoing treatment study will be assessed by 3 tesla brain MRI, Magnetic Resonance Spectroscopy (MRS) and Cerebral Blood Flow/Volume (CBF/CBV) procedures at baseline and immediately following the final treatment.

General Inclusion Criteria:

1. Male or female outpatients, 18 to 60 years of age.
2. Primary diagnosis of Major Depressive Disorder as confirmed by the Structured Clinical Interview for Diagnostic and Statistical Manual (DSM-IV-TR) Disorders (SCID-IV-TR).
3. Duration of the index episode of at least 1 month.
4. MDD symptoms, defined as a total HDRS-17 score ≥ 18 despite treatment with an adequate trial of a serotonin reuptake inhibitor (SRI).
5. Individuals who cannot tolerate medications.
6. Patients currently on medication must be at the same stable dose(s) for 1 month prior to enrollment and be willing to continue at the same dose(s) through the duration of the study.
7. Capable and willing to provide informed consent.
8. Signed HIPAA authorization.
9. Right-handed.
10. Willingness to undergo research fMRI scan (3T).
11. Willingness to undergo randomization to either treatment arm.

General Exclusion Criteria:

1. Investigators, and their immediate families (defined as a spouse, parent, child or sibling, whether by birth or legal adoption).
2. Individuals diagnosed by the investigators with the following conditions: Bipolar Disorder (lifetime), any Psychotic Disorder (lifetime), history of substance abuse or dependence within the past year (except nicotine and caffeine).
3. Behavior, which in the judgment of the investigator may hinder the patient in completing the procedures required by the study protocol.
4. Individuals with a clinically defined neurological disorder including, but not limited to: tics, space occupying brain lesion; any history of seizures except those therapeutically induced by electroconvulsive therapy (ECT); history of cerebrovascular accident; history of fainting; transient ischemic attack within two years; cerebral aneurysm, Dementia; Parkinson's Disease; Huntington chorea; Multiple Sclerosis.
5. Increased risk of seizure for any reason, including prior diagnosis of increased intracranial pressure (such as after large infarctions or trauma), or history of significant head trauma with loss of consciousness for ≥ 5 minutes.
6. Use of any investigational drug within 12 weeks of the randomization visit.
7. Significant acute suicide risk, defined as follow: suicide attempt within the previous 6 months that required medical treatment; or ≥ 2 suicide attempts in the past 12 months; or in the investigator's opinion, has significant risk for suicide based on the current state or recent history.
8. Cardiac pacemakers, implanted medication pumps, intracardiac lines, or acute, unstable cardiac disease.
9. Intracranial implants (e.g. aneurysms clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed.
10. Current illicit drug use (cannabinoid, phencyclidine, amphetamines, barbiturates, cocaine, methadone, and opiates), defined as drug use during the 6 months before screening.
11. Known or suspected pregnancy. Urine pregnancy test Women who are breast-feeding.
12. Women of childbearing potential not using a medically accepted form of contraception when engaging in sexual intercourse.
13. Medicinal patch, unless removed prior to the magnetic resonance (MR) scan.
14. MDD patients with very severe depression, defined as a total HDRS-17 score ≥ 23, will be excluded and referred to immediate treatment.
15. Risks related to seizures, such as substance abuse or sleep disruptions/insomnia.

SpecificExclusion criteria (group 1):

History of treatment with rTMS therapy for any disorder.

Specific Inclusion criteria (group 2):

History of non-response to rTMS in this depressive episode.

6 weeks