Cortico-striatal engagement during cue-reactivity, reappraisal, and savoring of drug and non-drug stimuli predicts craving in heroin addiction

Abstract

AbstractImportanceHeroin 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).ObjectiveTo document cortico-striatal reactivity during passive viewing, reappraisal, and savoring, as predictors of heroin craving in individuals with heroin use disorder (iHUD) vs. controls.DesignA cross-sectional study (11/2020-09/2021), with a novel fMRI task in iHUD vs. controls.SettingiHUD and controls were recruited from treatment facilities and surrounding neighborhoods, respectively.ParticipantsiHUD (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 MeasuresBetween-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.ResultsDrug 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 RelevanceWe 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.Key PointsQuestionWhat are the cortico-striatal brain regions driving reactivity to and reappraisal of drug vs. savoring food cues in individuals with heroin use disorder (iHUD); do these activations contribute to self-reported drug cravings?FindingsIn this cross-sectional study, and compared to matched healthy control subjects, iHUD exhibited cortico-striatal reward and self-control regional hyperactivations to drug cues during both passive viewing of pictures and their reappraisal as compared to savoring of alternative reward (images of food); and these activations correlated with drug cravings.MeaningWe identified drug-cue biased processing in cortico-striatal regions in iHUD, providing potential therapeutic biomarkers for neuromodulation and cognitive training in reducing hyper-responsiveness to drug cues and enhancing responses to alternative natural rewards.