Defining the disturbance in cortical glutamate and GABA function in psychosis, its origins and consequences

精神分裂症是一种常见的疾病，通常开始于青少年晚期和二十多岁。通常有一段时间（前驱症状），在急性精神病症状发作之前，动机、兴趣和社交能力逐渐下降，如听到声音和有威胁性的偏执信念。精神病症状通常对抗精神病药物反应良好，但当精神病消失时，通常会有残留症状，患者会留下一定程度的冷漠，导致生活质量低下。我们没有药物可以逆转或预防这些残留的症状。找到更好的药物很困难，因为我们不知道潜在的大脑变化是什么；如果我们做到了，我们就可以开发针对这一过程的药物，逆转疾病或防止前驱症状发展为精神病。来自脑成像研究的越来越多的证据表明，大脑灰质的细微变化在前体症状中发生，并持续到急性期。灰质（神经递质）中的化学信使谷氨酸和氨基丁酸在某种程度上与精神错乱的过程和残留状态有关，这一观点引起了人们的极大热情。人们对苯环利定等药物的兴趣很大程度上来自于这种药物的效果，它可以诱发一种类似精神病的状态。然而，为了真正了解谷氨酸和GABA是否有问题，我们需要测量其在活人体内的释放和活动。使用一种叫做磁共振光谱（MRS）的技术来测量这些化学物质是可能的。在高磁场强度下，可以清楚地分离和测量不同的化合物。一项相关的技术可以让我们更进一步，测量谷氨酸神经元实际释放的量。这种方法从未应用于脑部疾病。我们将使用这些光谱方法对谷氨酸和GABA是否异常的问题给出决定性的“是”或“否”，无论是在疾病早期还是在患病超过10年的患者中。我们还想知道什么可能导致谷氨酸/GABA异常。有一个很好的例子表明，某种形式的炎症反应可能与急性精神病有关，急性精神病在死亡后留下了一些轻微的损害，这就是残余症状的原因。我们将使用国内最灵敏的正电子发射断层扫描（PET）相机进行检查。它可以检测到大脑中与炎症细胞结合的示踪剂，这在帕金森病等疾病中很明显。我们可能会发现，那些有PET炎症证据的人存在谷氨酸问题。或者它们可能是独立的风险因素。最后，我们想知道谷氨酸/氨基丁酸的变化是否真的会产生症状，以及它们是如何产生症状的。我们可以使用脑磁图（MEG）来检测脑细胞在头部外放电时产生的微小磁场。我们开始明白，灰质的不同部分通过同步放电产生活动波来相互交流。这表明不同的网络在大脑中做不同的工作，比如集中注意力或记忆。谷氨酸和伽马氨基丁酸使细胞彼此同步放电，因此这些神经递质的异常可能通过影响网络的运作方式产生症状。同时测量同一个人的MRS， PET和MEG是理想的，但要求很高。我们已经设计了一系列重叠的成对测试，这将使我们最终确定谷氨酸和GABA在精神分裂症中是否功能异常，炎症是否与此过程有关，以及症状是如何产生的。这一结果可能会改变游戏规则，并可能为新的药物治疗指明道路，并重新激发行业对开发精神分裂症新疗法的兴趣。

Schizophrenia is a common disorder which typically begins in the late teens and twenties. Often there is a period (the prodrome) of gradual decline in motivation, interest and sociability before the acute onset of psychotic symptoms such as hearing voices and having threatening paranoid beliefs. The psychotic symptoms usually respond quite well to antipspychotic drugs but there are often residual symptoms when the psychosis has died down and patients are left with a degree of apathy that leads to a poor quality of life. We do not have medications that reverse or prevent these residual symptoms. Finding better drugs is difficult because we do not know what the underlying brain changes are; if we did we could develop drugs targeted on the process and reverse the illness or prevent the prodrome progressing to psychosis. Increasing evidence from brain imaging studies suggest that subtle changes to the grey matter of the brain are occurring in the prodrome that continue into the acute phase. There is much enthusiasm for the idea that chemical messengers in the grey matter (neurotransmitters) called glutamate and GABA are somehow bound up with the process of becoming psychotic and with the residual state. Much of the interest comes from the effect of drugs like phencyclidine that can induce a state like a psychosis. However, to really know whether there is something wrong with glutamate and GABA we need to measure its release and activity in living people. It is possible to measure these chemicals using a technique called magnetic resonance spectroscopy (MRS). At high magnetic field strengths, the different compounds can be clearly separated and measured. A related technique allows us to go a step further and measure how much glutamate neurones are actually releasing. This method has never been applied to a brain condition. We will use these spectroscopic methods to give a decisive yes or no to the question of whether glutamate and GABA are abnormal, either early on the illnesses or in those with more than 10 years of illness. We also want to know what might cause glutamate/GABA abnormalities. There is a good case that some form of inflammatory response may be involved in acute psychosis that dies down having left some mild damage that accounts for the residual symptoms. We will check this using the most sensitive Positron Emission Tomography (PET) camera in the country. It detects tracers that bind to inflammatory cells in the brain and this is clearly seen in diseases such as Parkinson's disease. We might find that glutamate problems were present in those with PET evidence of inflammation. Or it might be that they are independent risk factors. Finally we want to know whether the glutamate/GABA changes actually produce symptoms and how they might do this. We can use magneto-encephalography (MEG) to detect tiny magnetic fields that brain cells induce outside the head when they fire. We are beginning to understand that different parts of the grey matter communicate with one another by firing in step to produce waves of activity. This has revealed that different networks do different jobs in the brain such as focussing attention or remembering things. Glutamate and GABA keep cells firing in step with each other and so abnormalities in these neurotransmitters may produce symptoms by affecting how networks operate. Measuring MRS, PET and MEG together in the same people would be ideal but very demanding. We have devised a series of overlapping pairs of tests that will enable us to finally settle whether glutamate and GABA are functioning abnormally in schizophrenia, whether inflammation is anything to do with the process and how symptoms might result. The results are potentially game-changing and could point the way to new drug treatments and re-invigorate the interest of industry in developing new treatments for schizophrenia.