Investigating the thermoregulatory role of neurovascular coupling and the anti-epileptogenic and neuroprotective effects of focal cerebral cooling

急性局灶性癫痫是一种已被证明难以治疗的疾病，对患有这种疾病的患者来说，往往会导致非常糟糕的结果。癫痫是一种大脑某些部位过度活跃的疾病，这可能会导致急性癫痫发作和永久性脑损伤；许多已经开发的药物在很长一段时间内都不起作用。在原发性脑损伤发生后，很少有治疗方法被证明对癫痫有效。一种很有前途的治疗癫痫的新方法被称为局灶降温(FC)。FC是一种将大脑中受影响的区域冷却到低于体温的方法。据认为，FC的工作原理是通过阻止大脑中的神经元激活。降温大脑显示的最合适的有益效果出现在那些掉进冰中并在数十分钟甚至几个小时后恢复的人身上，这些患者通过非常仔细的复温程序已经完全恢复，人们认为大脑损伤是可以防止的，因为冷水使大脑进入冬眠状态，使用的氧气非常少。FC采用了相同的降温策略，但重点放在大脑损伤的区域。在癫痫的情况下，它是停止大脑过度活跃的区域，并将其降低到正常水平，从而防止任何癫痫发作。虽然FC是一种非常有希望的治疗癫痫的方法，临床试验已经在计划中，但很少有研究开发FC治疗的优化方法，无论是根据大脑温度下降的持续时间和幅度，还是在了解FC工作的实际机制方面。对于这一应用，我们开发了一种在麻醉动物模型中进行FC治疗的方法，在该模型中，我们可以非常详细地测量大脑功能。作为这项应用的一部分产生的试点数据显示，FC的工作原理与预期不谋而合，它不仅减少了大脑中的基线神经元激活，而且还使大脑中的氧气更自由地可用，从而使大脑保持更长时间的健康，这第二种效应以前从未显示过。我们的初步实验还表明，局灶性皮质癫痫使大脑内温度显著升高超过20摄氏度，并导致可用氧气量急剧减少。这些可能是癫痫患者长期脑损伤的主要原因，并解释了FC提供治疗益处的原因。我们将利用我们的动物模型进行实验，以评估FC在正常动物中的最佳治疗条件，然后将这些结果应用于我们实验室的急性癫痫动物模型。该项目还将评估血液流动在大脑正常运作期间保持恒温的作用。在某些疾病或老年中，血液流动的变化实际上可能会导致大脑温度上升，并有可能再次导致大脑损伤(如癫痫)，这以前从未进行过系统的研究。

Acute focal epilepsy is a disease that has proved incredible difficult to treat and often results in very poor outcomes for the patients suffering from the condition. Epilepsy is a disease in which certain parts of the brain become over active this can lead to acute seizures and permanent brain damage; many of the drugs that have been developed don't work over a long time scale. There have been very few therapies that have been shown to work for epilepsy after the primary brain injury has occurred. A promising new treatment for epilepsy is called focal cooling (FC). FC is a method in which the effected region of the brain is cooled down below body temperature. It is thought that FC works by stopping neuronal activation in the brain. The most appropriate beneficial effects shown by cooling down the brain have been seen in people who have fallen through the ice and have been recovered after tens of minutes or even hours, these patients have been known to make a complete recovery with very careful re-warming procedures, it is thought brain damage is prevented as the cold water puts the brain into a hibernation state which uses very little oxygen. FC applies the same cooling strategy but focused on the area of brain damage. In the case of epilepsy it is to stop the over active region of the brain and bring it down to normal levels therefore preventing any seizures. Although FC is an incredibly promising method to treat epilepsy with clinical trials already being planned, there has been little research into developing an optimised method for FC treatment in terms of the duration and magnitude of temperature drop in the brain or even in understanding the actual mechanisms by which FC works. For this application we have developed a method for FC treatment in an anaesthetised animal model in which we can measure brain function in an extremely detailed way. The pilot data produced as part of this application shows that FC works as expected by reducing baseline neuronal activation in the brain but also that FC makes oxygen more freely available in the brain to keep it healthy for longer, this second effect has never been shown before. Our pilot experiments also show that focal cortical epilepsy dramatically increases the temperature within the brain by over 2oC and causes a dramatic reduction in the amount of available oxygen. These could be the main reasons for long term brain damage seen in epilepsy patients and explain why FC provides a therapeutic benefit. Using our animal model we will perform experiments to assess the best conditions for FC treatment in the normal animal and then apply these results to acute animal models of epilepsy in our laboratory. This project will also assess the role of blood flow in keeping the brain at a constant temperature during normal function. Alterations in blood flow in certain diseases or old age, may actually cause increases in brain temperature with the potential to cause brain damage (such as those seen in epilepsy) again this has never been systematically investigated before.