Subsequently, Hong and colleagues (2010) went on to demonstrate that a gene variant of the α5 subunit of nicotinic acetylcholine receptors is associated with a very similar “addiction related circuit”. Specifically, this α5 gene variant, the most replicated genetic marker of smoking (Bierut et al., 2008), now identified a dorsal ACC-ventral striatum/extended amygdala circuit, such that the risk allele was associated with decreased rsFC between these structures. This circuit, representing a “trait-like” biomarker, was impaired in smokers, not altered by nicotine intake, and was anatomically consistent with (although not identical to) that previously shown to predict addiction severity using the phenotypic Fagerström index (Hong et al., 2009). Another independent smoking-related variant in the same gene cluster (α3) (Bierut et al., 2008) was associated with a separate circuit between dorsal ACC and anterior thalamus that was related to recency of smoking but not addiction severity, resembling a “state-like” marker for smoking, perhaps related to craving or withdrawal in these mildly deprived smokers. The results of these initial studies suggest the intriguing possibility that alterations in specific neural circuits may provide systems-level biomarkers of addiction severity that could be leveraged to track cessation treatment trajectories.
