Cigarette smoking is the leading cause of preventable death in the United States. The nicotine withdrawal syndrome (NWS) remains a barrier to successful smoking cessation; however, current pharmacological treatments minimally impact sustained abstinence. An emerging class of non-invasive neuromodulation devices, such as transcranial direct current stimulation (tDCS), have been proposed as novel therapeutics for smoking cessation. tDCS has the potential to modulate brain circuits by application of weak currents through the scalp; its use builds upon recent advances in mapping the large-scale network organization of the brain. Functional magnetic resonance imaging (fMRI) functional connectivity (FC) studies have identified three networks as particularly vulnerable to disruption in psychopathology: the Executive Control Network (ECN), Salience Network (SN), and Default Mode Network (DMN). The NWS has been hypothesized to be mediated by reduced FC within the ECN, and between ECN–SN; and increased FC within the DMN, and between DMN–SN.

It is hypothesized that tDCS, applied to cortical nodes of the ECN (e.g. dorsolateral prefrontal cortex) and DMN (e.g. ventromedial prefrontal cortex), may remediate NWS network dysregulation. Network effects of tDCS were assessed by simultaneous task-based fMRI. 15 smokers (in sated and withdrawal states) and 28 matched nonsmokers participated in a double-blind, randomized crossover design of three tDCS conditions: anodal left-dlPFC/cathodal right-vmPFC (“An-dlPFC”), polarity reversed (“An-vmPFC”), and Sham. Although single-session (25min, 2mA) tDCS did not evoke task behavior changes, An-dlPFC tDCS robustly suppressed DMN nodes during a working memory task, and enhanced anterior cingulate activity (SN node) during a conflict monitoring task. DMN suppression within smokers was more pronounced during the sated (vs. withdrawn) state. Given that DMN and SN are hypothesized to be dysregulated in nicotine and other addictions, these data quantitatively support the hypothesis that tDCS may modify large-scale circuits implicated in addictive disease. Additionally, the observation of state-dependent tDCS effects in smokers suggests that tDCS may be most efficacious when combined with standard smoking cessation therapies. This work contributes a translational approach to assessment of tDCS, an emerging intervention at the crossroads of basic neuroscience research and clinical therapeutics in addiction and psychiatric disease.