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Functional connectivity changes with rapid remission from severe major depressive disorder

Major depressive disorder (MDD) is prevalent and debilitating, and development of improved treatments is limited by insufficient understanding of the neurological changes associated with disease remission. In turn, efforts to elucidate these changes have been challenging due to disease heterogeneity as well as limited effectiveness, delayed onset, and significant off-target effects of treatments. We recently developed a form of repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex (lDLPFC) that induces remission from MDD in 90% of individuals in 1-5 days (Stanford Accelerated Intelligent Neuromodulation Therapy, SAINT). This provides a new tool to begin exploring the functional connectivity (FC) changes associated with MDD remission. Herein, we report our investigation of the FC changes that occur following SAINT. Resting-state fMRI scans were performed before and after SAINT in 18 participants with severe, treatment-resistant MDD. FC was determined between regions of interest defined a priori by well-described roles in emotion regulation. Following SAINT, FC was significantly decreased between subgenual cingulate cortex (sgACC) and 3 of 4 default mode network (DMN) nodes. Significant reductions in FC were also observed between the following: DLPFC-striatum, DLPFC-amygdala, DMN-amygdala, DMN-striatum, and amygdala-striatum. Greater clinical improvements were correlated with larger decreases in FC between DLPFC-amygdala and DLPFC-insula, as well as smaller decreases in FC between sgACC-DMN. Greater clinical improvements were correlated with lower baseline FC between DMN-DLPFC, DMN-striatum, and DMN-ventrolateral prefrontal cortex. The multiple, significant reductions in FC we observed following SAINT and remission from depression support the hypothesis that MDD is a state of hyper-connectivity within these networks, and rapid decoupling of network nodes may lead to rapid remission from depression. Significance statement Major depressive disorder is common and debilitating. It has been difficult to study the brain changes associated with recovery from depression, because treatments take weeks-to-months to become effective, and symptoms fail to resolve in many people. We recently developed a type of magnetic brain stimulation called SAINT. SAINT leads to full remission from depression in 90% of people within 5 days. We used SAINT and functional magnetic resonance imaging to determine how the brain changes with rapid remission from depression. We found changes in areas of the brain associated with emotion regulation. This provides a significantly clearer picture of how the non-depressed brain differs from the depressed brain, which can be used to develop rapid and effective treatments for depression.