Blunted anterior midcingulate response to reward in opioid users is normalized by prefrontal transcranial magnetic stimulation

Abnormalities in goal-directed behavior, mediated by mesocorticolimbic reward system, contribute to worse clinical outcomes including higher risk of treatment dropout and drug relapse in opioid users (OU). Despite efforts to counteract such neural alterations, brain-based interventions for this disorder remain ineffective. In this sham-controlled randomized study, we report the initial results on the efficacy of transcranial magnetic stimulus (TMS) in normalizing reward functioning in this population. During a reward-based choice task, we applied robot-assisted 10-Hz TMS to the prefrontal cortex in OU (Active = 16, Sham = 18) and matched healthy controls (HC, Active = 22, Sham = 24) while we recorded the reward positivity - an electrophysiological signal believed to index sensitivity of the anterior midcingulate cortex (MCC) to rewards. A robotic arm positioned a TMS coil over a prefrontal cortex target, and 50 pulses were delivered at 10-Hz before every 10 trials (2000 pulses, 400 trials). Our results revealed an interaction between TMS (Active vs Sham) and Group (OU vs HC) (F_1,72 = 6.9, p = 0.01, η² = 0.09). First, in the Sham TMS condition, OU exhibited a blunted reward positivity compared to HC (p = 0.01, d = 0.84). Second, OU receiving active TMS displayed a larger reward positivity compared to OU receiving sham (p = 0. 003, d = 0.98), and no differences were observed between OU and HC (p = 0.42, d = 0.17) or HC receiving sham (p = 0.48, d = 0.11). We envision that targeting a specific frontal-cingulate reward pathway is an important first step to maintain long-terms effect of TMS on MCC reward function, which may enhance treatment success through the maintenance of treatment goals.