Orbitofrontal Cortex Repetitive Transcranial Magnetic Stimulation for the Treatment of Major Depressive Disorder

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that is a safe and efficacious treatment for major depressive disorder (MDD). Conventional rTMS in MDD targets the dorsolateral prefrontal cortex (DLPFC) or the dorsomedial prefrontal cortex (DMPFC). However, many patients do not respond to DLPFC-rTMS or DMPFC-rTMS. Recent evidence suggests that the right lateral orbitofrontal cortex (OFC) plays a key role in ‘non-reward’ functions and shows hyperconnectivity in MDD. An initial case study by our group demonstrated that inhibitory OFC-rTMS was able to achieve remission in an MDD case nonresponsive to DLPFC- and DMPFC-rTMS. The aim of this thesis was to assess the safety, tolerability, and efficacy of inhibitory OFC-rTMS in the MDD population. Furthermore, we aimed to characterize the functional predictors and correlates of OFC-rTMS with functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). OFC-rTMS was found to be both safe and tolerable for MDD patients and led to significant reductions in depressive symptoms in a case series (N=42) and a randomized crossover trial (N=32). A crossover effect was not found for the primary outcome measure following OFC-rTMS. With respect to fMRI predictors and correlates of treatment outcome, abnormally increased functional connectivity between key nodes of the reward and non-reward circuitry was found to be related to future improvement, while disrupting reward circuitry connectivity was found to be the mechanism. With respect to EEG, increased frontal theta was found to be weakly, albeit non-significantly, predictive of future improvement. Improvement following OFC-rTMS was significantly correlated with decreases in frontal theta power. The findings of this thesis suggest that OFC-rTMS may be a promising treatment option for patients who present as non-responsive to traditional rTMS targets. Future work must be done in order to establish OFC-rTMS as a treatment for patients characterized by reward or non-reward circuitry dysfunction.Ph.D