PROJECT SUMMARY / ABSTRACT Over 700,000 individuals across the world die by suicide annually. Most individuals who complete suicide suffer from psychiatric illness, of which major depressive disorder (MDD) is most common. Suicidal ideation (SI) is more prevalent in individuals with treatment-resistant depression (TRD) compared to those who respond to treatment. Given treatment limitations of SI in TRD, novel interventions paired with an improved understanding of the neurobiology of SI are needed. Repetitive transcranial magnetic stimulation (rTMS) is efficacious for TRD. Evidence suggests that bilateral rTMS (i.e., targeting both the right and left prefrontal cortex) may be more efficacious for SI in TRD compared to unilateral rTMS, and bilateral brain disturbances are evident from neuroimaging studies in individuals with SI. Recent advances in rTMS delivery have greatly decreased treatment duration: accelerated intermittent theta burst stimulation (aiTBS) condenses 6-weeks of standard rTMS into 1- week. In fact, a unilateral form of aiTBS, the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) System, was recently approved by the FDA for the treatment of TRD. Given the efficacy of bilateral rTMS for SI, and recent advances in accelerated treatment paradigms, investigation of bilateral accelerated TBS (aTBS) for the treatment of SI in TRD is warranted. Compelling evidence suggests that SI in TRD is related to aberrant cortical inhibition bilaterally in the dorsolateral prefrontal cortex (DLPFC) and that rTMS may modulate inhibitory neurotransmission. Mechanistically, cortical inhibition is closely associated with γ-aminobutyric acid (GABA) signaling. Therefore, investigating cortical inhibition in the bilateral DLPFC in conjunction with bilateral aTBS treatment may be key to understanding treatment response. We propose to use transcranial magnetic stimulation combined with simultaneous electroencephalography (TMS-EEG) to investigate cortical inhibition as a biological target of treatment in this study (Aim 1). A randomized double-blind clinical trial will be conducted to test the hypothesis of superiority of bilateral aTBS to unilateral aiTBS on SI in TRD (Aim 2). Seventy-six participants will be recruited over 5 years. The applicant serves as Medical Director of the Interventional Psychiatry Program at UC San Diego Health, and he will facilitate appropriate recruitment of participants into this study. The career development objectives for the applicant are: 1) develop independence as a clinical trialist with relevant statistical approaches; 2) gain expertise in the conduct and analysis of TMS-EEG; and 3) establish working knowledge in MRI functional connectivity analysis to guide future rTMS protocols. The applicant’s primary mentor is the Chair of the Department of Psychiatry at UCSD, neurophysiology and clinical trial expert, Dr. Jeff Daskalakis. Dr. Greg Appelbaum, Research Director of the Interventional Psychiatry Program will ...