Importance: Heroin addiction is rampant and persistent, with devastating consequences to the public health, necessitating further study into the neurobiological mechanisms of drug cue-reactivity and craving-reducing interventions (e.g., reappraisal and savoring). Objective: To document cortico-striatal reactivity during passive viewing, reappraisal, and savoring, as predictors of heroin craving in individuals with heroin use disorder (iHUD) vs. controls. Design: A cross-sectional study (11/2020-09/2021), with a novel fMRI task in iHUD vs. controls. Setting: iHUD and controls were recruited from treatment facilities and surrounding neighborhoods, respectively. Participants: iHUD (N=32) [40.3(8.8) years; 7 (21.9%) women] and age-/sex-matched controls (N=21) [40.6(10.8) years; 8 (38%) women]. Main Outcomes and Measures: Between-group blood-oxygen-level-dependent signal differences during cue-reactivity/reappraisal/savoring and their direct contrast (reappraisal vs. savoring), and correlations with drug craving in iHUD. Results: Drug cue-reactivity (look drug>neutral) revealed higher nucleus accumbens and ventromedial prefrontal cortical activity in iHUD vs. controls (Z>3.1, p<.05), the latter positively correlated with post-task drug cravings (r2=.47, p<.001). In contrast, controls showed higher dorsolateral prefrontal cortex (dlPFC) and inferior frontal gyrus (IFG) reactivity to food cues (>drug; Z>3.1, p<.05; with the opposite pattern for the iHUD). Both drug-reappraisal and food-savoring (vs. respective passive viewing) showed increased activity in the IFG and supplementary motor area in all participants; the higher the dlPFC/IFG drug reappraisal in iHUD, the lower the post-MRI drug cue-induced craving (Z>3.1, p<.05). A direct comparison (drug-reappraisal vs. food-savoring) revealed higher drug-reappraisal in the ventral caudate and PFC regions in the iHUD (Z>3.1, p<.05), as predicted in the striatum by pre-task drug cravings (Z>2.57, p<.05); in controls, these areas showed instead higher food-savoring (Z>3.1, p<.05). Conclusions and Relevance: We demonstrate upregulated cortico-striatal activity during drug-cue exposure (while passively looking or reappraising) and impaired reactivity during processing (looking or savoring) of non-drug rewards in heroin addiction. These results bolster the impaired response inhibition and salience attribution model of drug addiction, previously supported mostly by results in stimulant addiction. Normalizing cortico-striatal function by reducing drug cue-reactivity (e.g., reappraising drug cues) and enhancing natural reward valuation (e.g., savoring food stimuli) may inform therapeutic mechanisms for reducing drug craving/seeking in heroin addiction.

The authors have declared no competing interest.

This work was supported by R01DA048094 to EG and R01AT010627 to RZG.

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