State-dependent effects of ventromedial prefrontal cortex continuous thetaburst stimulation on cocaine cue reactivity in chronic cocaine users

Cue-induced craving is a significant barrier to obtaining abstinence from cocaine. Neuroimaging research has shown that cocaine cue exposure evokes elevated activity in a network of frontal-striatal brain regions involved in drug craving and drug seeking. Prior research from our laboratory has demonstrated that when targeted at the medial prefrontal cortex (mPFC), continuous theta burst stimulation (cTBS), an inhibitory form of non-invasive brain stimulation, can decrease drug cue-related activity in the striatum in cocaine users and alcohol users. However, it is known that there are individual differences in response to repetitive transcranial magnetic stimulation (rTMS), with some individuals being responders and others non-responders. There is some evidence that state-dependent effects influence response to rTMS, with baseline neural state predicting rTMS treatment outcomes. In this single-blind, active sham-controlled crossover study, we assess the striatum as a biomarker of treatment response by determining if baseline drug cue reactivity in the striatum influences striatal response to mPFC cTBS. The brain response to cocaine cues was measured in 19 cocaine-dependent individuals immediately before and after real and sham cTBS (110% resting motor threshold, 3600 total pulses). Group independent component analysis (ICA) revealed a prominent striatum network comprised of bilateral caudate, putamen, and nucleus accumbens, which was modulated by the cocaine cue reactivity task. Baseline drug cue reactivity in this striatal network was inversely related to change in striatum reactivity after real (vs. sham) cTBS treatment (ρ = -.79; p < .001; R²Adj = .58). Specifically, individuals with a high striatal response to cocaine cues at baseline had significantly attenuated striatal activity after real but not sham cTBS (t9 = -3.76; p ≤ .005). These data demonstrate that the effects of mPFC cTBS on the neural circuitry of craving are not uniform and may depend on an individual's baseline frontal-striatal reactivity to cues. This underscores the importance of assessing individual variability as we develop brain stimulation treatments for addiction.