Using computational modelling to characterise and plan treatments for schizophrenia

精神分裂症是一种精神障碍，其症状包括幻觉、妄想、认知和动机障碍。它影响了很多人——仅在英国就有50多万人——并可能导致终身残疾。我们目前只有一类药物可以治疗精神病症状（妄想和幻觉）。这些药物是在20世纪50年代发现的，它们阻断了大脑神经细胞中的一种受体：多巴胺2受体。它们帮助了三分之二的精神病患者，但其余的人仍有持续的症状。尽管进行了深入的研究，我们还没有发现任何治疗精神病的替代方法，而且根本没有治疗认知障碍的方法。大量证据表明，另一种受体的功能障碍也对精神病有重要影响：NMDA受体。NMDA受体存在于大脑各处，存在于各种细胞上——一些是兴奋性细胞（E细胞），一些是抑制性细胞（I细胞）。NMDA受体的不同亚型存在于这些不同的细胞上，存在于大脑的不同部位。来自精神病研究的不同证据表明，精神分裂症的主要问题可能是E细胞或I细胞上的NMDA受体功能障碍。例如，可能有不同组的患者有E细胞或I细胞功能障碍。或者I细胞可能会试图通过降低E细胞的活性来补偿NMDA受体的功能障碍。制药公司已经生产了许多可以作用于NMDA受体的药物，尽管有一些有希望的早期结果，但所有这些药物都没有通过大规模的临床试验。一个可能的原因是，并非所有诊断相同的患者都有相同的潜在病因。例如，导致呼吸困难的原因有很多（哮喘、肺炎、心力衰竭、肺纤维化等），它们都需要不同的治疗方法。精神病症状可能有许多潜在的原因：例如，一些人有E细胞问题，另一些人有I细胞问题。这些群体将需要分别针对E细胞或I细胞进行特异性治疗。这个项目的目的是找到识别这些具有“低E”或“低I”功能的子群体的方法，以及在哪个阶段他们可能是最好的目标。我将使用多种方法来做到这一点，但所有方法都是基于使用简单的任务（例如听音调），同时使用脑电图（EEG）记录大脑中的电信号。我将使用计算模型从这些记录的脑电图信号中估计E和I细胞的功能。我将研究处于不同疾病阶段的精神分裂症或精神病患者的数据集，以及有患精神病风险的年轻人的数据集。我还将研究老鼠，它们将接受同样的简单任务，并给予低剂量的药物，导致“低E”或“低I”状态。所有这些实验的目的都是为了确定1)现有的基于NMDA受体的药物最适合靶向哪些细胞（E或i），以及2)应该在什么时候（在什么疾病阶段）给药。在该项目的第二部分，我将在100名早期精神分裂症患者的样本中测试这些预测。我将使用他们大脑信号的计算模型来估计他们是否有“低E”和/或“低I”病理。然后，我将给他们服用一种增强E细胞功能的药物（例如）3个月，并测量其对症状和认知的影响。关键问题是：我的模型对E或I函数的估计能否预测药物的效果？如果是这样，这可能意味着我们可以使用这些模型来分配精神病的治疗方法，并在大规模的临床试验中测试这种方法。

Schizophrenia is a mental disorder that involves symptoms such as hallucinations, delusions, and cognitive and motivational impairments. It affects a large number of people - more than 500,000 in the UK alone - and can cause lifelong disability.We currently only have one family of drugs that can treat psychotic symptoms (delusions and hallucinations). These were discovered in the 1950s, and they block a receptor found in nerve cells in the brain: the dopamine 2 receptor. They help two thirds of people suffering from psychosis, but the remainder have ongoing symptoms. Despite intensive research, we have not found any alternative treatments for psychosis, and no treatment at all for cognitive impairment. Lots of evidence indicates that dysfunction in another receptor also makes a major contribution to psychosis: the NMDA receptor. The NMDA receptor exists all over the brain, on various kinds of cells - some excitatory (E cells), some inhibitory (I cells). Slightly different subtypes of the NMDA receptor exist on these different cells, and in different parts of the brain. Different strands of evidence from psychosis research indicate that the primary problem in schizophrenia might be NMDA receptor dysfunction on either E or I cells specifically. There might be different groups of patients with E or I cell dysfunction, for example. Or I cells might try to compensate for NMDA receptor dysfunction on E cells, by reducing their activity.Pharmaceutical companies have produced many drugs that can act at NMDA receptors, and despite some promising early results, all these drugs have failed large scale clinical trials. One likely reason is that not all patients with the same diagnosis have the same underlying causes of those symptoms. For example, there are many causes of breathlessness (asthma, pneumonia, heart failure, lung fibrosis, etc), and all require different treatments. There may well be numerous underlying causes of psychosis symptoms: for example, E cell problems in some, I cell problems in others. These groups would need treatments specifically targeted to E or I cells respectively.The aim of this project is to find ways of identifying these subgroups with 'low E' or 'low I' function, and at what stage they might best be targeted. I will do this using a variety of methods, but all are based around the use of simple tasks (e.g. listening to tones) whilst electrical signals in the brain are recorded using electroencephalography (EEG). I will use computational models to estimate E and I cell function from these recorded EEG signals.I will study datasets of participants with schizophrenia or psychosis at different stages of their illness and also a very large dataset of young people at risk of developing psychosis. I will also study mice who will undergo the same simple tasks, and who will be given low doses of drugs that cause either 'low E' or 'low I' states. The purpose of all these experiments is to establish i) which cells (E or I) would be the best to target with an existing NMDA receptor-based drug, and ii) when (at what illness stage) that drug should be given. In Part 2 of the project, I will test these predictions in a sample of 100 people with early schizophrenia. I will use computational models of their brain signals to estimate whether they have 'low E' and/or 'low I' pathology. I will then give them a drug boosting E cell function (for example) for 3 months, and measure its effects on symptoms and cognition. The key question is: can my model estimate of E or I function predict the effects of the drug? If so, this could mean we could use these models to assign treatments for psychosis, and test this approach in a large scale clinical trial.