Drug addiction is characterized by disruption in finely balanced brain networks. Over the two decades, the animal models (Shippenberg and Koob, 2002) and human neuroimaging studies (Hu et al., 2015) has facilitated the understanding of neurobiology of addiction. In a recent review, Koob and Volkow have proposed that three domains (motivational “wanting”-incentive salience, emotional “liking”-negative emotional state, and executive control) mediated by three neurocircuits (basal ganglia, extended amygdala, and prefrontal cortex) (Koob and Volkow, 2016). A long stand of human studies had indicated the orbitofrontal cortex (the hub of go circuit) was essential for regulating incentive salience when a drug cue was presented to the drug dependents (Volkow and Fowler, 2000; Clarke et al., 2008; Hart et al., 2014). And evidence from rodent research has demonstrated that drug-related reinstatement involved by stop circuit that links PrL to VS, which correspond with anterior cingulate cortex (ACC) in human (McFarland and Kalivas, 2001). Hu and colleagues have identified the balance of “go-stop” circuit to produce compulsive-like habits by combining the merits of animal model and brain imaging in individuals. However, in the study, animal model could not fully emulate the addiction cycle (e.g., the preoccupation/anticipation stage, which is a pivotal stage of relapse in humans) and complex emotional dysregulation correlated with withdrawal and protracted abstinence (de Wit, 2009; McEwen and Morrison, 2013; Maier et al., 2015) in human. There is also evidence indicating withdrawal from drug can cause fatigue, irritability, insomnia, and psychological symptoms (e.g., depression and anxiety; Koob and Le Moal, 1997). Future study to ascertain the shared and distinct neurocircuit mechanisms between depression/anxiety and addiction would be of interest.

In conclusion, this research has suggested that the imbalance of brain circuits plays an important role in maladaptive behavior in drug dependents (Everitt and Robbins, 2016). These findings have underscored that the balance of resting-state functional connectivity would be a potential neuroimaging biomarker to forecast future addiction relapse, and provide neurocircuit candidate for exploring the genetic basis of endophenotypes related to addiction. Moreover, these results extended previous understanding of fundamental brain circuits involved in addiction cycle and opened for a principled way to develop individualized treatment in SUDs. Prior works from our lab have focused on stimulating the dorsolateral prefrontal cortex (DLPFC), a hub of frontal-striatal circuitry that is dysfunctional in SUD individuals (Liu et al., 2017, 2019; Shen et al., 2017; Zhao et al., 2020). Our results have manifested through either activation of left DLPFC or inhibition of the right DLPFC may reduce craving and alleviate symptoms of depression in methamphetamine dependents (Zhao et al., 2020). Another strand studies from Hanlon lab have suggested that stimulating left frontal areas can induce selective changes in ventromedial prefrontal cortex (VMPFC), the striatum, and ACC thus change drug cue reactivity in cocaine dependent- and alcohol dependent patients (Hanlon et al., 2015, 2016, 2017, 2018). These empirical results showed that it would be possible to attenuate stop circuit through targeting frontal areas or ACC, which may lay a foundation for future clinical trials for treating SUDs.

H-BZ, HZ, YZ, and DZ conceived the idea and wrote the manuscript together. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.