What can case-control comparisons of neural drug cue reactivity tell us about addiction? A neuroimaging meta-analysis

Abstract Neural drug cue reactivity (DCR) is a central paradigm in addiction neuroscience for probing how drug cues acquire excessive motivational salience in substance use disorders (SUDs). However, the field faces challenges in clinical translation, replicability, and within-group designs are susceptible to visual confounding due to stimulus matching. A complementary approach is to examine case-control contrasts to identify SUD-specific neural architecture while mitigating effects of task-design variability. We conducted a systematic literature search and an activation likelihood estimation (ALE) meta-analysis to identify convergence effects in the contrast drug > control cues between SUD and control groups. ALE results were supplemented by assessing behavioural domains, meta-analytic connectivity profiles, robustness to publication bias, and study-level modulators using penalised logistic regression. The ALE analysis revealed one reliable convergence cluster in the ventral anterior cingulate cortex (vACC), associated with reward, reasoning, and social cognition. Penalised logistic regression indicated that contributions to this cluster were less likely in alcohol DCR-studies and were sensitive to matching conditions for human content. vACC DCR effects contrasted with neutral control cues were invariant across abstinence periods, whereas vACC DCR contrasted with natural reward cues declined with longer abstinence. This meta-analysis replicates context-sensitive SUD-specific DCR convergence in vACC regions intersecting reward pathways and the default-mode network, while reliable striatal convergence was not observed. The review recapitulates these results by discussing current challenges in balancing personalisation and standardisation, the use of motivationally inert versus salient comparators, and argues for careful deliberation when inferring evidence for hyperreactive reward responses.