This study utilizes resting state fMRI, arterial spin labelling imaging, diffusion tensor imaging, structural MR-imaging, and MR-spectroscopy of GABA and Glutamate to probe the antidepressant mechanisms of repetitive transcranial magnetic stimulation (rTMS). The above imaging modalities will be acquired before and after an open-label 5 week course of rTMS for depression in currently depressed individuals with treatment resistant depression. Changes in functional, structural, and neurochemical markers will be investigated in rTMS responders and nonresponders to elucidate mechanisms of plasticity that correlate with treatment response. Additionally, functional, structural, and neurochemical signatures at baseline that correlate with subsequent treatment response will be investigated.

Repetitive Transcranial Magnetic Stimulation (rTMS) applied over the left dorsolateral prefrontal cortex (DLPFC) alleviates mood in major depression. This treatment received FDA approval in 2009 and is now in routine clinical use for the treatment of major depression. A recently published sham-controlled study showed a response rate of 14% in real rTMS compared to 5% in sham rTMS. The response, defined by a greater than 50% reduction in the Hamilton Depression Rating Scale from pre-treatment to post-treatment, was also found to be 14% in one recent meta-analysis. The inclusion criteria in these studies admitted a broad spectrum of participants, ranging from subjects having a first major depressive episode, to those having failed multiple medication trials, suggesting that a subgroup with a more robust response may be masked by an unresponsive group. Abnormal function of the left frontal lobe accompanies major depression and this may be normalized by rTMS Cerebral blood flow measured with SPECT imaging was reduced in the left DLPFC of depressed subjects and was increased during and after a course of rTMS over the left DLPFC. Decreased blood flow was found in a broader region of frontal and paralimbic regions in depressed individuals and treatment success was associated with decreased blood flow in the inferior frontal lobes both pre- and post- treatment. Greater post-treatment vs. pre-treatment BOLD activation of left frontal regions was demonstrated using fMRI in a planning task that engages the frontal lobes. Left prefrontal myo-inositol is reduced in depressed subjects and this is normalized by rTMS. The above functional abnormalities view the frontal lobe in isolation. However, recent work has demonstrated a network-based structural marker of risk for familial depression consisting of decreased cortical and white mater volume. Resting state fMRI (rs-fMRI) tests cross-regional temporal coherence in low frequency oscillations in brain responses (~0.1 Hz) that are believed to represent spontaneous neural activity. Correlated spontaneous fluctuations are understood to reflect functional connections between brain regions that arise through a history of co-activation across one's lifetime. Previous work has shown that depressed patients exhibit altered functional connectivity patterns as gauged by rs-fMRI, and some studies suggest that these differences may be mitigated by treatment with antidepressant medications. However, whether and how TMS may affect functional connectivity is unknown. I propose to acquire the several described MRI types both before and after rTMS treatment in a search for predictive markers of rTMS treatment success as well as markers of treatment-induced change. Arterial spin labeling will be acquired to measure the blood flow distribution throughout the brain, both to confirm the SPECT results already reported and to test for additional regions of change. Resting state fMRI will be collected and DTI will be used to explore the structural basis of functional network changes. Structural MRI will be collected to measure cortical thickness and white matter volumes that may be predictive of rTMS response. Magnetic resonance spectroscopy will be collected to confirm the previously reported finding of rTMS-induced myo-inositol changes, as well as to consider the Glutamate/Glutamine and GABA spectra, given the importance of these neurotransmitters in theories of depression.

Inclusion Criteria:

1. A history of major depressive disorder by the Structured Clinical Interview for DSM-IV (SCID)
2. Failure to respond to at least two previous antidepressant trials at adequate doses for 8 weeks (for current or prior major depressive episodes)
3. A minimum 17-item Hamilton depression rating scale of 17 on both the screening day and the treatment day #1
4. Age 18-70
5. Participants may be taking antidepressants, antipsychotics, or low-dose mood stabilizers during the study
6. Participants may be in psychotherapy during the study

Exclusion Criteria:

1. Participants with metal implants (Will use the NY Presbyterian Hospital MRI Checklist)
2. Prior exposure to TMS
3. Pregnant women
4. Lactating women
5. Bipolar disorder (on the Structured Clinical Interview for DSM-IV (SCID)
6. Current depressive episode longer than 3 years
7. Active suicidal ideation with plan or intent
8. Borderline personality disorder (on the Structured Clinical Interview for DSM-IV (SCID)
9. Substance abuse or dependence with the past 3 years
10. Current urine drug screen positive for any drugs of abuse
11. Current symptoms of psychosis
12. History of seizure disorder
13. History of closed head injury with loss of consciousness
14. History of brain surgery

Five weeks (25 days)