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

研究神经血管耦合的温度调节作用以及局灶性脑冷却的抗癫痫和神经保护作用

• 批准号: MR/M013553/1
• 负责人: Jason Berwick
• 金额: $ 56.49万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM013553%2F1
• 关键词: Investigating; thermoregulatory; role; neurovascular; coupling

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.

急性局灶性癫痫是一种难以治疗的疾病，通常会导致患者的预后非常差。癫痫是一种大脑某些部分过度活跃的疾病，这可能导致急性癫痫发作和永久性脑损伤;许多已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，很少有治疗癫痫的方法。一种有前途的癫痫新疗法被称为局灶性冷却（FC）。FC是一种将大脑受影响区域冷却到体温以下的方法。人们认为FC通过阻止大脑中的神经元激活来发挥作用。通过冷却大脑所表现出的最适当的有益效果已经在那些掉进冰中并在数十分钟甚至数小时后恢复的人身上看到，这些患者已经知道通过非常小心的重新加温程序完全恢复，人们认为，由于冷水使大脑进入休眠状态，大脑损伤得到了预防，其中使用很少的氧气。FC采用相同的冷却策略，但专注于脑损伤区域。在癫痫的情况下，它是停止大脑的过度活跃区域，并将其降低到正常水平，从而防止任何癫痫发作。虽然FC是一种非常有前途的治疗癫痫的方法，临床试验已经在计划中，但在大脑温度下降的持续时间和幅度方面，甚至在理解FC工作的实际机制方面，很少有研究开发FC治疗的优化方法。对于该应用，我们已经开发了一种在麻醉动物模型中进行FC治疗的方法，在该方法中，我们可以以非常详细的方式测量脑功能。作为该应用程序的一部分产生的试验数据表明，FC通过减少大脑中的基线神经元激活而发挥预期作用，而且FC使大脑中的氧气更自由地获得，以保持更长时间的健康，这第二种效果以前从未显示过。我们的初步实验还表明，局灶性皮质癫痫会使大脑内的温度急剧升高2摄氏度以上，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，并解释了为什么FC提供了治疗益处。使用我们的动物模型，我们将进行实验，以评估在正常动物中FC治疗的最佳条件，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保持大脑在正常功能期间的恒温中的作用。在某些疾病或老年血液流动的改变，实际上可能会导致大脑温度的增加，有可能导致脑损伤（如癫痫），这是以前从未系统研究过的。

项目成果

The Reversal Characteristics of GABAergic Neurons: A Neurovascular Model.

GABA 能神经元的逆转特征：神经血管模型。

• DOI: 10.1115/1.4056336
• 发表时间: 2023
• 期刊: Journal of biomechanical engineering
• 作者: David T

Physiological and Pathological Brain Activation in the Anesthetized Rat Produces Hemodynamic-Dependent Cortical Temperature Increases That Can Confound the BOLD fMRI Signal.

• DOI: 10.3389/fnins.2018.00550
• 发表时间: 2018
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Harris SS;Boorman LW;Das D;Kennerley AJ;Sharp PS;Martin C;Redgrave P;Schwartz TH;Berwick J
• 通讯作者: Berwick J

Small vessels, dementia and chronic diseases - molecular mechanisms and pathophysiology.

• DOI: 10.1042/cs20171620
• 发表时间: 2018-04-30
• 期刊: Clinical science (London, England : 1979)
• 作者: Horsburgh K;Wardlaw JM;van Agtmael T;Allan SM;Ashford MLJ;Bath PM;Brown R;Berwick J;Cader MZ;Carare RO;Davis JB;Duncombe J;Farr TD;Fowler JH;Goense J;Granata A;Hall CN;Hainsworth AH;Harvey A;Hawkes CA;Joutel A;Kalaria RN;Kehoe PG;Lawrence CB;Lockhart A;Love S;Macleod MR;Macrae IM;Markus HS;McCabe C;McColl BW;Meakin PJ;Miller A;Nedergaard M;O'Sullivan M;Quinn TJ;Rajani R;Saksida LM;Smith C;Smith KJ;Touyz RM;Trueman RC;Wang T;Williams A;Williams SCR;Work LM
• 通讯作者: Work LM

Seizure epicenter depth and translaminar field potential synchrony underlie complex variations in tissue oxygenation during ictal initiation.

• DOI: 10.1016/j.neuroimage.2017.12.088
• 发表时间: 2018-05-01
• 期刊: NeuroImage
• 影响因子: 5.7
• 作者: Harris SS;Boorman LW;Kennerley AJ;Sharp PS;Martin C;Redgrave P;Schwartz TH;Berwick J
• 通讯作者: Berwick J

Bidirectional alterations in brain temperature profoundly modulate spatiotemporal neurovascular responses in-vivo.

• DOI: 10.1038/s42003-023-04542-6
• 发表时间: 2023-02-17
• 期刊: Communications biology
• 影响因子: 5.9