Mechanistically Distinct Subtypes of Individuals With Cocaine Use Disorder Identified by Neural Cue Reactivity and...

Drug cue reactivity is a known predictor of relapse in individuals with substance use disorders. However, its robust detection is impeded by interindividual heterogeneity, which remains insufficiently characterized and may reflect divergent neurobiological phenotypes that differentially influence clinical outcomes. Here we investigated neurophysiological heterogeneity during cue-reactivity in individuals with cocaine use disorder (CUD).

Eighty-eight individuals with CUD completed an electroencephalography cue-reactivity task; the final analytic sample included 70 participants (14 female, 55 male, and 1 participant with missing sex information). The late positive potential (LPP) amplitude, a robust neurophysiological marker of drug cue reactivity, was extracted in the 400- to 1000-ms window after cocaine cue onset. Sensor-level LPP topographical heterogeneity was used to identify subtypes, and source-amplitude and beta oscillation analyses were subsequently used to mechanistically characterize subtype differences.

Posterior cue reactors (PCR) (n = 29) and frontal cue reactors (FCR) (n = 41) were determined based on spatially distinct sensor patterns of cue-reactivity LPP maxima. PCR (vs. FCR) showed hypoactivations in lingual, pericalcarine, isthmus cingulate, temporal, frontal, and precentral regions and hyperactivations in postcentral and cuneus regions. PCR (vs. FCR) also showed beta hypoactivations in orbitofrontal and rostral anterior cingulate cortex, with hyperactivations in paracentral and pericalcarine regions. Cue-induced regional activations were associated with clinical outcomes, including craving and withdrawal severity, years of regular use, prospective abstinence, and percent use days.

Results showed that cocaine cue reactivity is heterogeneous and may involve distinct neurobiological subtypes in individuals with CUD. Future research should validate these neurophysiological patterns in independent samples and examine their stability and clinical relevance longitudinally to inform targeted interventions addressing subtype-specific neural circuit disruptions.