Therapeutic Efficacy of Reward Circuit-Targeted Transcranial Magnetic Stimulation (TMS) on Suicidal Ideation in Depressed Patients: A Sham-Controlled Trial of Two TMS Protocols

Background: Suicide is one of the leading causes of premature death, and dysfunctional reward processing may serve as a potential mechanism. However, effective treatment targeting reward circuits is rarely reported.Objective: The present study investigated the therapeutic efficacy of two individualized protocols, repetitive transcranial magnetic stimulation (rTMS) and intermittent theta burst stimulation (iTBS), targeting the left dorsolateral prefrontal cortex (lDLPFC)-nucleus accumbens (NAcc) circuit on suicidal ideation among patients with major depressive disorder (MDD).Methods: Here, 40 healthy controls (HCs) and 70 MDD patients (MDDs) were recruited for this double-blinded, sham-controlled clinical trial. The reward learning process during the Iowa gambling task (IGT) was initially measured at the baseline. Further, 62 MDDs were assigned to receive 15 daily sessions of individualized rTMS (n = 25), iTBS (n = 15), or sham treatment (n = 22) to the site of strongest lDLPFC-NAcc connectivity.Results: We found MDDs demonstrated abnormalities in both IGT performance and reward-associated event-related potential (ERP) components compared to HCs. MDDs in the rTMS and iTBS groups showed significant improvements in suicidal ideation and anhedonia symptoms compared to the sham group. The rTMS group also exhibited a more negative-going N170 and feedback-related negativity (FRN) after treatment, and the increase in N170 absolute amplitude posttreatment showed a trend of correlation with improved Temporal Experience Pleasure Scales (TEPSs) and TEPS-anticipatory (TEPS-ant) scores.Conclusion: The current study indicates that reward circuit-based rTMS and iTBS showed comparable antisuicidal effects in depressive patients, suggesting that the lDLPFC-NAcc pathway may serve as a potential treatment target.Trial Registration: ClinicalTrials.gov identifier: