Multimodal neuroimaging of cue-induced craving and cortical alterations in etomidate use disorder

Despite the escalating global abuse of etomidate, a GABA A -specific anesthetic, the neurobiological mechanisms underlying craving and structural brain alterations remain poorly understood. This case-control study aimed to identify the neural characteristics of cue-induced craving and cortical brain changes in etomidate use disorder (EUD). Right-hand males aged 18–45 years meeting DSM-5 criteria for EUD and age-matched healthy males for controls (HC) were recruited in Guangzhou, China, between June 2023 and October 2024. Within a cue-reactivity paradigm, spatiotemporal neural dynamics of drug craving were investigated using multimodal neuroimaging, including electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) in independent cohorts. Effective connectivity was analyzed with dynamic causal modeling (DCM), and structural MRI (sMRI) was further employed to assess cortical thickness. EEG analyses demonstrated amplified frontocentral late positive potential (LPP) amplitudes in response to drug cues in the EUD group, which correlated with subjective craving. FMRI analyses revealed cue-induced hyperactivation in the temporoparietal junction (TPJ) and ventrolateral prefrontal cortex (VLPFC). Signed cue-modulated DCM parameters indicated abnormal VLPFC-to-TPJ inhibitory modulation in the EUD group, with weaker inhibitory modulation associated with higher subjective craving. Furthermore, sMRI identified widespread cortical thinning across prefrontal, parietal, occipitotemporal, and limbic regions among EUD individuals. These findings suggest that chronic etomidate exposure is associated with altered VLPFC function, maladaptive top-down inhibition within the VLPFC-TPJ connectivity, and heightened salience attribution to drug cues. These findings highlight the VLPFC-TPJ circuit as a promising neuromodulation target for treating EUD, underscoring its clinical potential in addressing this growing public health issue.