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的疾病，通常始于十几岁和二十多岁。通常会有一段时间(前驱症状)的动机、兴趣和社交能力逐渐下降，然后才会出现严重的精神病症状，如听到声音和有威胁的偏执信念。精神病症状通常对抗精神病药物反应良好，但当精神病消退，患者留下一定程度的冷漠，导致生活质量不佳时，往往会出现残留症状。我们没有逆转或预防这些残留症状的药物。很难找到更好的药物，因为我们不知道大脑潜在的变化是什么；如果我们知道了，我们就可以开发针对这一过程的药物，扭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，大脑灰质正在发生细微变化，一直持续到急性期。有很多人热衷于这样一种观点，即灰质中的化学信使(神经递质)谷氨酸和GABA以某种方式与变得精神病的过程和残留状态联系在一起。人们的兴趣很大程度上来自苯环利定等药物的效果，这些药物可能会导致精神错乱。然而，要真正知道谷氨酸和GABA是否有问题，我们需要测量它在活人身上的释放和活性。使用一种称为磁共振波谱(MRS)的技术来测量这些化学物质是可能的。在高磁场强度下，不同的化合物可以清楚地被分离和测量。一项相关的技术使我们能够更进一步地测量神经元实际上释放了多少谷氨酸。这种方法从未被应用于大脑疾病。我们将使用这些光谱方法来对谷氨酸和GABA是否异常的问题给出决定性的是或否，无论是在疾病的早期还是在那些疾病超过10年的人中。我们还想知道可能导致谷氨酸/GABA异常的原因。有一个很好的例子，某种形式的炎症反应可能参与了急性精神病的死亡，留下了一些轻微的损害，解释了残留的症状。我们将使用该国最灵敏的正电子发射断层扫描(PET)相机来检查这一点。它检测到与大脑中的炎性细胞结合的示踪剂，这在帕金森氏症等疾病中明显可见。我们可能会发现，在PET有炎症迹象的患者中存在谷氨酸问题。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，以及它们可能如何做到这一点。我们可以使用脑磁图(MEG)来检测脑细胞在发射时在头部外部感应的微小磁场。我们开始理解，灰质的不同部分通过同步激发来相互交流，从而产生一波又一波活动。这揭示了不同的网络在大脑中起着不同的作用，比如集中注意力或记忆事物。谷氨酸和GABA使细胞的活动保持同步，因此这些神经递质的异常可能会通过影响网络的运行而产生症状。在同一个人身上同时测量MRS、PET和MEG将是理想的，但要求非常高。我们已经设计了一系列重叠的测试对，这些测试将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，炎症是否与这一过程有关，以及症状可能会如何导致。这一结果可能会改变游戏规则，并可能为新药治疗指明方向，并重新激发工业界开发精神分裂症新疗法的兴趣。

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

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

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