Interleaved TMS-fMRI to Evaluate Intermittent Theta-burst and Dorsolateral Prefrontal Circuit Engagement in Ultra-treatment Resistant Depression

The objective of this study is to assess plasticity in both whole brain connectivity and a mood/affective circuit involving the dorsolateral prefrontal cortex (DLPFC) in individuals undergoing repetitive transcranial magnetic stimulation (rTMS) for treatment of ultra-treatment resistant depression. Our second aim is to explore how these markers predict response to rTMS. The DLPFC is a brain region known to support mood regulation and has functional brain activity that is altered in depression. Past evidence from healthy controls suggests that rTMS increases coupling of the DLPFC network with another functional brain network involved in reward. Using sophisticated neuroimaging techniques that concurrently capture functional MRI while patients are being stimulated with rTMS, the investigators will identify patterns of brain activity associated with depressed mood and measure the coupling of the DLPFC mood circuit with a reward network prior to an acute course of rTMS. Following baseline imaging, all patients will then undergo an accelerated rTMS protocol over the course of five days, using the pre-treatment imaging to localize the brain region (circuit) targeted by the TMS coil. The investigators will also use questionnaires to assess mood and function before, during and after rTMS treatment. Two comparison groups will be included in this study: 1) patients with depression who have ultra-treatment resistant depression and have been referred for consideration of neurosurgical neuromodulation for depression, and 2) persons with milder treatment resistant depression who are referred to the Harquail Centre for rTMS treatment of depression. This research will help us better understand the mechanisms of how rTMS modulates brain activity, improve TMS targeting in depression, and identify pre-treatment imaging that predict response to rTMS with potentially far-reaching clinical implications.