Neurobiological Mechanism and Treatment Targets of Magnetic Seizure Therapy for Resolution of Suicidal Ideation in Treatment-Resistant Depression

Background: Major depressive disorder affects 16% of the general population and is associated with increased risk of suicidal ideation. Up to 40% depression patients do not respond to two or more antidepressant trials and are referred to as having treatment-resistant depression (TRD). Magnetic Seizure Therapy (MST) is a promising intervention for TRD patients and may be effective at targeting their suicidal ideation. Methods: To better understand the mechanism of MST and to identify potential biomarkers, TRD patients were recruited from an open label MST trial and assessed before and after the treatment course with measures of transcranial magnetic stimulation and electroencephalography (TMS-EEG) in the dorsolateral prefrontal cortex (DLPFC). Objectives/Hypotheses: 1) To evaluate if higher GABAergic inhibition (measure: N100 peak and long-interval cortical inhibition (LICI)) at baseline is effective at predicting suicidal ideation resolution (SI-resolution) after MST; 2) To determine if MST produces neuroplasticity (measure: cortical evoked activity) while decreasing GABAergic inhibition (measure: LICI); 3) To check if MST works by decreasing the strength of the DLPFC to subgenual cingulate (SGC) connection (measure: significant current scatter). Results: 1) Higher prefrontal GABAergic inhibition at baseline predicted SI-resolution after MST with 89% accuracy. 2) MST produced neuroplasticity in tandem with individual specific reductions in GABAergic inhibition that are indicative of SI-resolution after treatment. 3) Stronger DLPFC to SGC connection at baseline was able to predict SI-resolution with 83% accuracy, while the connectivity was significantly decreased after the treatment course. Conclusion: MST works by producing neuroplasticity in TRD patients with individual variations in suicidal ideation reduction governed by differences in GABAergic inhibition, both at baseline and in the process of treatment. The neuroplasticity produced by MST involved a neural circuit component part of the limbic-cortical network, specifically the DLPFC to SGC connection, which determined the efficacy of MST at baseline and is modified by the seizure treatments.Ph.D.2019-12-19 00:00:0