Functional Connectivity Changes with Rapid Remission from Moderate-to-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 developed a form of repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex (lDLPFC) that in an open-label study was associated with remission from MDD in 90% of individuals in 1-5 days (Stanford Accelerated Intelligent Neuromodulation Therapy, SAINT). This provides a tool to begin exploring the functional connectivity (FC) changes associated with MDD remission. Resting-state fMRI scans were performed before and after SAINT in 18 participants with moderate-to-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.### Competing Interest StatementDr. Bentzley receives consulting payments from Owl Insights.* AI : anterior insula BLA : basolateral amygdala CMA : centromedian amygdala dACC : dorsal anterior cingulate cortex DLPFC : dorsolateral prefrontal cortex DMN : default mode network exeS : executive striatum FC : functional connectivity HAMD : Hamilton Depression Rating Scale Ins : insula limS : limbic striatum MADRS : Montgomery Asberg Depression Rating Scale MDD : major depressive disorder SA : superficial amygdala sgACC : subgenual anterior cingulate cortex SN : salience network VLPFC : ventrolateral prefrontal cortex. Preceding r : right preceding l : left.