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

基本信息

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

项目摘要

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的疾病，通常始于十几岁和二十几岁。在精神病症状（例如听到声音和具有威胁性偏执信念）急性发作之前，通常会经历一段时期（前驱症状），动机、兴趣和社交能力逐渐下降。精神病症状通常对抗精神病药物反应良好，但当精神病平息后，往往会出现残留症状，患者会出现一定程度的冷漠，导致生活质量下降。我们没有可以逆转或预防这些残留症状的药物。寻找更好的药物很困难，因为我们不知道潜在的大脑变化是什么；如果我们这样做了，我们就可以开发针对这一过程的药物并逆转疾病或防止前驱症状发展为精神病。越来越多的脑成像研究证据表明，前驱症状中大脑灰质发生了微妙的变化，并持续到急性期。人们对灰质（神经递质）中称为谷氨酸和 GABA 的化学信使在某种程度上与精神病的过程和残留状态有关的观点抱有极大的热情。人们的大部分兴趣来自于苯环己哌啶等药物的作用，它可以诱发精神病等状态。然而，要真正了解谷氨酸和 GABA 是否存在问题，我们需要测量其在活人体内的释放和活性。可以使用磁共振波谱 (MRS) 技术来测量这些化学物质。在高磁场强度下，可以清楚地分离和测量不同的化合物。相关技术使我们能够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大脑疾病。我们将使用这些光谱方法对谷氨酸和 GABA 是否异常（无论是在疾病早期还是在患病 10 年以上的患者）的问题给出决定性的是或否。我们还想知道什么可能导致谷氨酸/GABA 异常。有一个很好的例子，某种形式的炎症反应可能与急性精神病有关，这种炎症反应会消失，留下一些轻微的损害，从而导致残留症状。我们将使用国内最灵敏的正电子发射断层扫描 (PET) 相机对此进行检查。它可以检测与大脑中炎症细胞结合的示踪剂，这在帕金森病等疾病中可以清楚地看到。我们可能会发现那些有炎症 PET 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/GABA 的变化是否真的会产生症状以及它们是如何做到这一点的。我们可以使用脑磁图（MEG）来检测脑细胞放电时在头部外部感应出的微小磁场。我们开始了解到，灰质的不同部分通过同步发射来产生活动波来相互交流。这表明不同的网络在大脑中执行不同的工作，例如集中注意力或记住事物。谷氨酸和 GABA 使细胞彼此同步放电，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而产生症状。在同一个人身上同时测量 MRS、PET 和 MEG 是理想的选择，但要求很高。我们设计了一系列重叠的测试对，使我们能够最终确定谷氨酸和 GABA 在精神分裂症中是否功能异常、炎症是否与该过程有关以及症状如何产生。这些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，并重新激发业界开发精神分裂症新疗法的兴趣。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
通讯作者：
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
影响因子：
0
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