Left frontal pole theta burst stimulation decreases orbitofrontal and insula activity in cocaine users and alcohol users

Background. Preclinical research has demonstrated a causal relationship between medial prefrontal cortex activity and cocaine self-administration. As a step towards translating those data to a neural circuit-based intervention for patients, this study sought to determine if continuous theta burst stimulation (cTBS) to the left frontal pole (FP), would attenuate frontal-striatal activity in two substance-dependent populations. Methods: Forty-nine substance dependent individuals (25 cocaine, 24 alcohol) completed a single-blind, sham controlled, crossover study wherein they received 6 trains of real or sham cTBS (110% resting motor threshold, FP1) each visit. Baseline evoked BOLD signal was measured immediately before and after real and sham cTBS (interleaved TMS/BOLD imaging: single pulses to left FP; scalp-to-cortex distance covariate, FWE correction p < 0.05) Results: Among cocaine users, real cTBS significantly decreased evoked BOLD signal in the caudate, accumbens, anterior cingulate, orbitofrontal (OFC) and parietal cortex relative to sham cTBS. Among alcohol users, real cTBS significantly decreased evoked BOLD signal in left OFC, insula, and lateral sensorimotor cortex. There was no significant difference between the groups. Conclusions: These data suggest that 6 trains of left FP cTBS delivered in a single day decreases TMS-evoked BOLD signal in the OFC and several cortical nodes which regulate salience and are typically activated by drug cues. The reliability of this pattern across cocaine- and alcohol-dependent individuals suggests that cTBS may be an effective tool to dampen neural circuits typically engaged by salient drug cues. Multiday studies are required to determine it this has a sustainable effect on the brain or drug use behavior.