Clinical trials of pharmacological candidates targeting the core features of autism have largely failed. This is despite evidence linking differences in multiple neurochemical systems to brain function in autism. While this has in part been explained by the heterogeneity of the autistic population, the field has largely relied upon association studies to link brain chemistry to function. The only way to directly establish that a neurotransmitter or neuromodulator is involved in a candidate brain function is to change it and observe a shift in that function. This experimental approach dominates preclinical neuroscience, but not human studies. There is little direct experimental evidence describing how neurochemical systems modulate information processing in the living human brain. Thus, our understanding of how neurochemical differences contribute to neurodiversity is limited, impeding our ability to translate findings from animal studies into humans. Here, we introduce our ‘shiftability’ paradigm, an approach to bridge the translational gap in autism research. We provide an overview of the guiding principles and methodologies we use to directly test the hypothesis that neurochemical systems function differently in autistic and non-autistic individuals.

中文翻译：

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编辑视角：弥合自闭症转化神经科学差距——“可转移性”范式的发展

针对自闭症核心特征的候选药物的临床试验基本上失败了。尽管有证据表明多种神经化学系统的差异与自闭症患者的大脑功能有关，但情况仍然如此。虽然这在一定程度上可以用自闭症人群的异质性来解释，但该领域在很大程度上依赖于关联研究来将大脑化学与功能联系起来。直接确定神经递质或神经调节剂参与候选大脑功能的唯一方法是改变它并观察该功能的变化。这种实验方法主导了临床前神经科学，但不是人类研究。几乎没有直接的实验证据描述神经化学系统如何调节活人大脑中的信息处理。因此，我们对神经化学差异如何影响神经多样性的理解是有限的，这阻碍了我们将动物研究结果转化为人类的能力。在这里，我们介绍我们的“可转移性”范式，这是一种弥合自闭症研究转化差距的方法。我们概述了我们用来直接检验神经化学系统在自闭症和非自闭症个体中功能不同的假设的指导原则和方法。