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Previous studies both in laboratory animals and humans have reported that abstinence induces incubation of cue-induced drug craving for nicotine, alcohol, cocaine, and methamphetamine. However, current experimental procedures utilized to study incubation of methamphetamine craving do not incorporate the temporal dynamics of neuropsychological measures and electrophysiological activities associated with this incubation process. This study utilized the high-density electroencephalogram (EEG) signals as a rapid, inexpensive, and noninvasive measure of cue-induced craving potential. A total of 156 male individuals with methamphetamine use disorder (MUD) enrolled in this multisite, cross-sectional study. Structured clinical interview data, self-report questionnaires (cued craving, quality of sleep, impulsivity, anxiety, and depression) and resting-state, eye-closed 128 high-density channel EEG signals were collected at 5 abstinence duration time points (<1, 1–3, 3–6, 6–12, and 12–24 months) to track the neuropsychological and neurophysiological signatures. Cue-induced craving was higher after 1–3 months than after the other time points. This incubation effect was also observed for sleep quality but not for anxiety, depression, and impulsivity symptoms, along with exhibited decreased power spectrum for theta (5.5–8 Hz) and alpha (8–13 Hz), and increased in beta (16.5–26.5 Hz) frequency band. Source reconstructed resting-state EEG analysis showed increased synchronization of medial prefrontal cortex (MPFC) for the beta frequency band in 1–3 months abstinent MUD group, and associated with the incubation of craving. Remarkably, the robust incubation-related abnormalities may be driven by beta-band source space connectivity between MPFC and bilateral orbital gyrus (ORB). Our findings suggest the enhancement of beta activity in the incubation period most likely originates from a dysfunction involving frontal brain regions. This neurophysiological signature of incubation of craving can be used to identify individuals who might be most susceptible to relapse, providing a potential insight into future therapeutic interventions for MUD via neuromodulation of beta activity.

Drug exposure impairs cortical plasticity and motor learning, which underlies the reduced behavioral flexibility in drug addiction. Physical exercise has been used to prevent relapse in drug rehabilitation program. However, the potential benefits and molecular mechanisms of physical exercise on drug-evoked motor-cortical dysfunctions are unknown. Here we report that 1-week treadmill training restores cocaine-induced synaptic deficits, in the form of improved in vivo spine formation, synaptic transmission, and spontaneous activities of cortical pyramidal neurons, as well as motor-learning ability. The synaptic and behavioral benefits relied on de novoprotein synthesis, which are directed by the activation of the mechanistic target of rapamycin (mTOR)-ribosomal protein S6 pathway. These findings establish synaptic functional restoration and mTOR signaling as the critical mechanism supporting physical exercise training in rehabilitating the addicted brain.