Chesebro Anthony G, Antal Botond B, Weistuch Corey, Mujica-Parodi Lilianne R
Department of Biomedical Engineering and Laufer Center for Physical and Quantitative Biology, Renaissance School of Medicine, State University of New York at Stony Brook, Stony Brook, New York; Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts.
Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York.
Biol Psychiatry Cogn Neurosci Neuroimaging. 2025 Mar;10(3):258-266. doi: 10.1016/j.bpsc.2024.10.011. Epub 2024 Oct 29.
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 that span 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 heterogeneous 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., tricarboxylic acid cycle, ion channel, neural microassembly, whole-brain macrocircuit) 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 toward circuit-based models for personalized diagnostics and treatment.
代谢精神病学的主要挑战之一在于，构成精神疾病基础的大脑功能紊乱源自一系列复杂的下游和反馈过程，这些过程跨越多个时空尺度。重要的是，同一神经回路可能存在多个故障点，每个故障点都会导致不同类型的失调，进而引发下游不同的级联反应，产生不同的体征和症状。在此，我们通过研究神经回路扰动的细微差异如何导致不同的临床结果来说明这一挑战。我们还将讨论计算模型如何进行空间异质性整合，并在体外和体内范式之间架起桥梁。通过利用最近的方法学进展和工具，计算模型可以整合跨尺度（例如三羧酸循环、离子通道、神经微组件、全脑宏观回路）和跨生理系统（例如神经、内分泌、免疫、血管）的相关过程，提供一个框架，以超越概念性和描述性的方式，将这些机制过程统一到定量和生成性的层面。这些有望增强我们对基于神经回路的个性化诊断和治疗模型的理解。
