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

定义精神病中皮质谷氨酸和 GABA 功能的紊乱、其起源和后果

• 批准号: MR/K020803/1
• 负责人: Bill Deakin
• 金额: $ 446.39万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK020803%2F1
• 关键词: Defining; disturbance; cortical; glutamate; GABA

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.

精神分裂症是一种常见疾病，通常从十几岁和二十多岁开始。通常，在精神病症状的急性发作之前，诸如听力声音和威胁偏执信仰的急性发作之前，动机，兴趣和社交能力的逐渐下降了一段时间。精神病症状通常对抗精神病药的反应良好，但是当精神病降低并且患者的冷漠程度时，通常会出现残留症状，导致生活质量差。我们没有逆转或防止这些残留症状的药物。找到更好的药物很困难，因为我们不知道大脑的基本变化是什么。如果我们这样做，我们可以开发针对该过程的药物，并扭转疾病或防止前途疾病发展为精神病。大脑成像研究的越来越多的证据表明，在急性阶段持续的前代中，大脑灰质的细微变化正在发生。人们对灰质（神经递质）中的化学信使（称为谷氨酸和GABA）的想法有很多热情，这与某种程度上束缚了成为精神病和残留状态的过程。大部分兴趣来自诸如苯基二酮等药物的作用，这些药物可以诱导像精神病这样的状态。但是，要真正知道谷氨酸和GABA是否有问题，我们需要衡量其在活人中的释放和活动。可以使用称为磁共振光谱（MRS）的技术测量这些化学物质。在高磁场强度下，可以清楚地分离和测量不同的化合物。一项相关的技术使我们能够进一步迈进，并测量多少谷氨酸神经元实际上正在释放。该方法从未应用于大脑状况。我们将使用这些光谱法对谷氨酸和GABA的疾病或患有超过10年疾病的患者的果态和GABA是异常的问题来确定性或否。我们还想知道什么可能导致谷氨酸/GABA异常。有一个很好的案例，某种形式的炎症反应可能涉及急性精神病，导致了一定的轻度损害，导致了残留症状。我们将使用该国最敏感的正弦发射断层扫描（PET）摄像头对此进行检查。它检测到与大脑中炎症细胞结合的示踪剂，这在帕金森氏病等疾病中很明显。我们可能会发现，在有炎症的宠物证据的人中存在谷氨酸问题。或者可能是它们是独立的风险因素。最后，我们想知道谷氨酸/GABA的变化是否实际上会产生症状以及如何做到这一点。我们可以使用磁脑线图（MEG）检测微细胞发射时脑细胞在头部外诱导的微小磁场。我们开始了解，灰质的不同部分通过逐步发射以产生活动浪潮来相互通信。这表明不同的网络在大脑中从事不同的工作，例如集中注意力或记住事物。谷氨酸和GABA使细胞相互发射，因此这些神经递质的异常可能会通过影响网络的运作方式产生症状。在同一人群中一起测量夫人，宠物和梅格是理想的，但苛刻。我们已经设计了一系列重叠的测试对，这将使我们能够最终解决谷氨酸和GABA在精神分裂症中是否异常起作用，是否与该过程以及症状如何导致炎症有关。结果可能会改变游戏规则，并可能指向新的药物治疗的道路，并重新激发行业对精神分裂症的新疗法的兴趣。

项目成果

Neuroinflammation as measured by positron emission tomography in patients with recent onset and established schizophrenia: implications for immune pathogenesis.

• DOI: 10.1038/s41380-020-0829-y
• 发表时间: 2021-09
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Conen S;Gregory CJ;Hinz R;Smallman R;Corsi-Zuelli F;Deakin B;Talbot PS
• 通讯作者: Talbot PS

Attenuated Post-Movement Beta Rebound Associated With Schizotypal Features in Healthy People.

• DOI: 10.1093/schbul/sby117
• 发表时间: 2019-06-18
• 期刊: Schizophrenia bulletin
• 影响因子: 6.6
• 作者: Hunt BAE;Liddle EB;Gascoyne LE;Magazzini L;Routley BC;Singh KD;Morris PG;Brookes MJ;Liddle PF
• 通讯作者: Liddle PF

Investigating the regional effect of the chemical shift displacement artefact on the J-modulated lactate signal at ultra high-field.

研究化学位移位移伪影对超高场 J 调制乳酸信号的区域影响。

• DOI: 10.1002/nbm.4440
• 发表时间: 2021
• 期刊: NMR in biomedicine
• 影响因子: 2.9
• 作者: Fernandes CC

A randomised clinical trial of methotrexate points to possible efficacy and adaptive immune dysfunction in psychosis.

• DOI: 10.1038/s41398-020-01095-8
• 发表时间: 2020-11-30
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Chaudhry IB;Husain MO;Khoso AB;Husain MI;Buch MH;Kiran T;Fu B;Bassett P;Qurashi I;Ur Rahman R;Baig S;Kazmi A;Corsi-Zuelli F;Haddad PM;Deakin B;Husain N
• 通讯作者: Husain N

T regulatory cells as a potential therapeutic target in psychosis? Current challenges and future perspectives.

• DOI: 10.1016/j.bbih.2021.100330
• 发表时间: 2021-11
• 期刊: Brain, behavior, & immunity - health
• 作者: Corsi-Zuelli F;Deakin B;de Lima MHF;Qureshi O;Barnes NM;Upthegrove R;Louzada-Junior P;Del-Ben CM
• 通讯作者: Del-Ben CM