These findings should be interpreted in the context of the study’s strengths and limitations. Strengths include the well-validated alcohol cue-exposure task and well-defined sample of alcohol dependent patients prospectively genotyped to allow for meaningful comparisons across OPRM1 genotype. The use of PPI methods to extend upon whole-brain analyses of the alcohol versus water cues contrast represents a strength of the study. However, the correlative nature of PPI methods limit causal inferences about the directionality of connections between regions, precluding the ability to infer, for example, whether frontal activation occurred prior to striatal activation and vice versa. Study limitations include the relatively small sample size and the lack of a control group. The study sample size may only afford adequate statistical power to detect large effect sizes. Furthermore, the limited power afforded by the sample size precludes further analyses to examine the precise nature of the individual genotype group PPI effects, leaving open the potential for alternative interpretations. The a-priori selection of alcohol dependent patients as well as the prospective genotyping approach was consistent with the study aims of testing OPRM1
