Challenges and Frontiers in Computational Metabolic Psychiatry.

One of the primary challenges in metabolic psychiatry is that the disrupted brain functions that underlie psychiatric conditions arise from a complex set of downstream and feedback processes spanning across multiple spatiotemporal scales. Importantly, the same circuit can have multiple points of failure, each of which results in a different type of dysregulation, and thus elicits distinct cascades downstream that produce divergent signs and symptoms. Here, we illustrate this challenge by examining how subtle differences in circuit perturbations can lead to divergent clinical outcomes. We also discuss how computational models can perform the spatially heterogenous integration and bridge in vitro and in vivo paradigms. By leveraging recent methodological advances and tools, computational models can integrate relevant processes across scales (e.g., TCA-cycle, ion channel, neural microassembly, whole-brain macro-circuit) and across physiological systems (e.g., neural, endocrine, immune, vascular), providing a framework that can unite these mechanistic processes in a manner that goes beyond the conceptual and descriptive, to the quantitative and generative. These hold the potential to sharpen our intuitions towards circuit-based models for personalized diagnostics and treatment.