FMRI-guided focal transcranial magnetic stimulation of anterior cingulate cortex reduces opioid seeking and restores connectivity

Relapse remains a major challenge in opioid addiction treatment. Transcranial magnetic stimulation (TMS) has emerged as a potential therapeutic strategy for addiction, yet results had been mixed due to empirically selected stimulation targets and limited knowledge of neural circuit engagement. Here, we used a focal rat TMS platform to test whether high-density theta-burst stimulation (hdTBS) of the anterior cingulate cortex (ACC), a corticostriatal node implicated in opioid relapse by prior causal and longitudinal functional MRI studies, decreases relapse-like oxycodone seeking and associated circuit dysfunction. Male rats self-administered oxycodone intravenously for 14 d and then underwent 13 d of electric barrier-induced abstinence, a procedure that suppresses drug taking while preserving drug availability and drug-associated context. During abstinence, the rats received seven daily sessions of sham stimulation or ACC-targeted hdTBS, with relapse tests and longitudinal functional MRI acquired during early and late abstinence to assess the behavioral and circuit-level effects of stimulation. Sham-treated rats showed a time-dependent increase (incubation) in oxycodone seeking and reduced ACC connectivity with dorsal and ventral striatum. In contrast, ACC-targeted hdTBS prevented incubation of oxycodone seeking and reversed abstinence-associated ACC-striatal connectivity reductions. Stimulation-sensitive functional circuits showed spatial correspondence with tracer-defined ACC projection patterns, suggesting that anatomical connectivity is critical to the circuit-level effects of focal stimulation. These findings support ACC-centered corticostriatal circuits as mechanistically informed targets for neuromodulation in opioid addiction and introduce a preclinical framework for linking stimulation, behavior, and longitudinal circuit remodeling.