Ajram L A, Horder J, Mendez M A, Galanopoulos A, Brennan L P, Wichers R H, Robertson D M, Murphy C M, Zinkstok J, Ivin G, Heasman M, Meek D, Tricklebank M D, Barker G J, Lythgoe D J, Edden R A E, Williams S C, Murphy D G M, McAlonan G M
Department of Forensic and Neurodevelopmental Sciences, The Sackler Centre for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Behavioural and Developmental Psychiatry Clinical Academic Group, South London and Maudsley NHS Trust, London, UK.
Transl Psychiatry. 2017 May 23;7(5):e1137. doi: 10.1038/tp.2017.104.
Currently, there are no effective pharmacologic treatments for the core symptoms of autism spectrum disorder (ASD). There is, nevertheless, potential for progress. For example, recent evidence suggests that the excitatory (E) glutamate and inhibitory (I) GABA systems may be altered in ASD. However, no prior studies of ASD have examined the 'responsivity' of the E-I system to pharmacologic challenge; or whether E-I modulation alters abnormalities in functional connectivity of brain regions implicated in the disorder. Therefore, we used magnetic resonance spectroscopy ([1H]MRS) to measure prefrontal E-I flux in response to the glutamate and GABA acting drug riluzole in adult men with and without ASD. We compared the change in prefrontal 'Inhibitory Index'-the GABA fraction within the pool of glutamate plus GABA metabolites-post riluzole challenge; and the impact of riluzole on differences in resting-state functional connectivity. Despite no baseline differences in E-I balance, there was a significant group difference in response to pharmacologic challenge. Riluzole increased the prefrontal cortex inhibitory index in ASD but decreased it in controls. There was also a significant group difference in prefrontal functional connectivity at baseline, which was abolished by riluzole within the ASD group. Our results also show, for we believe the first time in ASD, that E-I flux can be 'shifted' with a pharmacologic challenge, but that responsivity is significantly different from controls. Further, our initial evidence suggests that abnormalities in functional connectivity can be 'normalised' by targeting E-I, even in adults.
目前，对于自闭症谱系障碍（ASD）的核心症状尚无有效的药物治疗方法。然而，仍有取得进展的潜力。例如，最近的证据表明，ASD患者的兴奋性（E）谷氨酸和抑制性（I）γ-氨基丁酸系统可能发生了改变。然而，此前尚无关于ASD的研究考察E-I系统对药物激发的“反应性”；也未研究E-I调节是否会改变与该疾病相关的脑区功能连接异常。因此，我们使用磁共振波谱（[1H]MRS）来测量成年男性ASD患者和非ASD患者在服用谷氨酸和γ-氨基丁酸作用药物利鲁唑后前额叶的E-I通量。我们比较了利鲁唑激发后前额叶“抑制指数”（即谷氨酸加γ-氨基丁酸代谢物池中γ-氨基丁酸的比例）的变化；以及利鲁唑对静息态功能连接差异的影响。尽管E-I平衡在基线时无差异，但在药物激发反应方面存在显著的组间差异。利鲁唑使ASD患者的前额叶皮质抑制指数升高，但使对照组的该指数降低。在基线时，前额叶功能连接也存在显著的组间差异，而利鲁唑使ASD组内的这种差异消失。我们的结果还表明，我们认为这是首次在ASD研究中发现，E-I通量可通过药物激发而“改变”，但其反应性与对照组显著不同。此外，我们的初步证据表明，即使在成年人中，通过靶向E-I也可使功能连接异常“正常化”。
