Stage-dependent Neural Mechanisms in Human Methamphetamine Abstinence: Insights from the Digital Twin Brain Model.

Background: The reward circuits are crucial in treating human methamphetamine (MA) addiction, while the underlying action mechanisms may vary throughout the intervention process. This gap limits the identification of specific modulation targets and results in a "one-size-fits-all" approach. Demonstrating these specific neural signatures can inform tailored therapy and enhance precision medicine for MA addiction.

Methods: A total of 62 MA addicts (21 females) and 57 healthy controls (16 females) were recruited. Longitudinal data were collected at the early and later stages of MA abstinence. We used probabilistic metastable substates to investigate macro-scale functional changes and established the digital twin brain model to determine key regions in abstinence from a causal, quantitative perspective. Molecular imaging, gene set, and cell-type enrichment analyses were conducted to provide a multi-scale neurobiological explanation. Computational drug repurposing analysis was performed to identify drug candidates with the potential to treat MA addiction.

Results: We observed that brain regions within the reward circuits were crucial throughout the entire abstinence process. Molecular imaging, transcriptomic data, and cell-type analysis independently revealed that metabolic activities may play a more prominent role in early abstinence, while neuroplasticity is essential in both early and later abstinence. Identified putative drugs included approved medications for psychiatric symptoms, AIDS, and cancer.

Conclusions: Our work provides an integrative perspective on understanding the neural underpinnings of human MA abstinence and may inform future tailored therapies. Particularly, these findings support the stage-dependent nature of in-vivo human MA abstinence.