Dopamine is known to play a role in the pathogenesis of psychotic symptoms, but the mechanisms driving dopaminergic dysfunction in psychosis remain unclear. Considerable attention has focused on the role of corticostriatothalamic (CST) circuits, given that they regulate and are modulated by the activity of dopaminergic cells in the midbrain. Preclinical studies have proposed multiple models of CST dysfunction in psychosis, each prioritizing different brain regions and pathophysiological mechanisms. A particular challenge is that CST circuits have undergone considerable evolutionary modification across mammals, complicating comparisons across species. Here, we consider preclinical models of CST dysfunction in psychosis and evaluate the degree to which they are supported by evidence from human resting-state functional magnetic resonance imaging studies conducted across the psychosis continuum, ranging from subclinical schizotypy to established schizophrenia. In partial support of some preclinical models, human studies indicate that dorsal CST and hippocampal-striatal functional dysconnectivity are apparent across the psychosis spectrum and may represent a vulnerability marker for psychosis. In contrast, midbrain dysfunction may emerge when symptoms warrant clinical assistance and may thus be a trigger for illness onset. The major difference between clinical and preclinical findings is the strong involvement of the dorsal CST in the former, consistent with an increasing prominence of this circuitry in the primate brain. We close by underscoring the need for high-resolution characterization of phenotypic heterogeneity in psychosis to develop a refined understanding of how the dysfunction of specific circuit elements gives rise to distinct symptom profiles.

已知多巴胺在精神病症状的发病机制中发挥作用，但在精神病中驱动多巴胺能功能障碍的机制仍不清楚。相当多的注意力集中在皮质纹状体丘脑 (CST) 回路的作用上，因为它们调节并受中脑多巴胺能细胞活动的调节。临床前研究提出了精神病中 CST 功能障碍的多种模型，每种模型都优先考虑不同的大脑区域和病理生理机制。一个特别的挑战是 CST 电路在哺乳动物中经历了相当大的进化修改，使跨物种的比较复杂化。这里，我们考虑了精神病中 CST 功能障碍的临床前模型，并评估了这些模型在何种程度上得到了人类静息状态功能磁共振成像研究证据的支持，这些研究跨越精神病连续体进行，范围从亚临床精神分裂症到确定的精神分裂症。在部分支持一些临床前模型的情况下，人类研究表明，背侧 CST 和海马-纹状体功能性连接异常在整个精神病谱中都很明显，并且可能代表精神病的易感性标记。相反，当症状需要临床帮助时，可能会出现中脑功能障碍，因此可能是疾病发作的诱因。临床和临床前发现之间的主要区别是前者背侧 CST 的强烈参与，与灵长类动物大脑中这种回路的日益突出相一致。最后，我们强调需要对精神病表型异质性进行高分辨率表征，以深入了解特定回路元件的功能障碍如何导致不同的症状特征。