Identification of excitability profiles following acquired brain injury: A biomarker of neuronal health

中风或创伤性脑损伤后预后的一个关键因素是继发性脑损伤的发展。这是一个对脑组织造成更多损害的过程，发生在最初事件发生后的几个小时和几天内。目前，我们几乎不能做什么来恢复大脑区域的正常工作，这些区域已经被最初的创伤或中风损坏，无法修复。然而，如果我们能够在继发性脑损伤发生的过程中检测到这一点，我们或许能够预防继发性脑损伤。在损伤之后，在损伤核心周围建立了一个脆弱但仍有潜在生存能力的脑组织区域。这是一个容易受到继发性脑损伤的区域，被称为“半影区”。我们现在知道，脑电波，称为“扩散去极化”(SD)，经常发生在受伤后的半影区。我们认为有一类特殊类型的十二烷基硫酸酯是非常有害的，并对继发性损伤过程有很大的贡献。然而，还有另一组十二烷基硫酸酯会带来额外的氧气和葡萄糖供应。这对半影区的神经元非常有益，可以帮助它们恢复。因此，虽然我们想要防止有害的SDS，但我们不想阻止那些可能是有利的。问题是，我们目前无法区分它们之间的区别。然而，我们可能能够区分的一种方法是检查它们对神经元健康的影响。在过去的几年里，我一直在努力开发一种方法来探测神经元健康并实时监测神经元活力的变化。现在，我想用这种方法来描述表明神经元活性下降的变化。这将使我们能够看到继发性脑损伤在患者的床边现场发生，让我们有更好的机会在为时已晚之前进行干预。我还想用这种方法来确定哪些十二烷基硫酸酯对神经元造成了伤害，哪些可能有助于它们的恢复。这将意味着我们可以为经历有害SD的患者提供个性化的治疗。此外，因为即使只有一个有害的SD也可能损害或杀死半影区的神经元，我们最好是完全防止它们的发生。这将意味着，我们将不得不确定使神经元只对有害的十二烷基硫酸钠敏感的变化。幸运的是，我们从临床前实验中了解到，组织环境中有一些非常具体的变化，使神经元容易患上有害的SD。重要的是，这些变化在可能有益的变化之前是看不到的。作为我在开发一种探索神经元健康的方法方面所做工作的一部分，我还建立了一种评估组织环境变化的方法，这些变化使神经元容易受到有害的SD的影响。我想用这个方法来看看我是否能预测哪些患者可能开始患上有害的抑郁症。这将意味着，在未来，我们可以对易感患者进行预防性治疗，而不是等待他们开始。最后，为了积极预防继发性脑损伤，我们需要知道神经元健康何时下降，以及哪些治疗方法可以有效地改善这一点。通过持续实时跟踪神经元健康状态，我的目标是为医生提供一个在线床边工具，既能识别健康下降的情况，又能就治疗干预的有效性提供即时反馈。将这种工具应用到临床实践中，有可能限制损伤后发生的继发性脑损伤的数量，从而显著改善患者的预后。

A key contributor to outcome following a stroke or a traumatic brain insult is the development of secondary brain injury. This is a process of more damage to brain tissue that occurs over a number of hours and days after the original event. Currently, there is little we can do to restore normal working in brain regions that have been damaged beyond repair by the initial trauma or stroke. However, we might be able to prevent secondary brain injury if we were able to detect this as it progresses.After an injury, a region of vulnerable but still potentially viable brain tissue is established around the injury core. This is the region that is susceptible to secondary brain injury and is called the 'penumbra'. We now know that electrical brain waves, called "spreading depolarisations" (SD), frequently occur in the penumbra after an injury. We believe a special class of these SDs to be very harmful and to contribute significantly to the process of secondary injury. However, there is another group of SDs that bring with them an extra supply of oxygen and glucose. This can be very beneficial to the neurons in the penumbra in helping them to recover. As such, whilst we would like to prevent SDs that are harmful, we do not want to prevent those that might be favourable. The problem is, we currently have no way of telling the difference between them. One way we might be able to tell the difference though is to examine the effect they have on the health of the neurons.Over the last few years I have worked to develop a method to probe neuronal health and to monitor changes in the viability of the neurons in real-time. Now I would like to use this method to characterise the changes that indicate declining neuronal viability. This would enable us to see secondary brain injury happening live at the patient's bedside, giving us a much better opportunity to intervene before it is too late. I would also like to use this method to identify which SDs are causing harm to the neurons and which ones are potentially helping them recover. This would mean that we could personalise treatments for patients experiencing harmful SDs.Furthermore, because even just one harmful SD will likely damage or kill neurons in the penumbra we would ideally like to prevent them from happening at all. This would mean though, that we would have to identify the changes that make neurons vulnerable only to harmful SDs. Luckily, we know from pre-clinical experiments that there are some very specific changes in the tissue environment that predispose neurons to harmful SD. Importantly, these changes are not seen before those that might be beneficial.As a part of the work I have done in developing a method to probe neuronal health, I have also established a way of assessing changes in the tissue environment that predispose neurons to harmful SDs. I would like to use this method to see if I can predict which patients are likely to begin having harmful SDs. This would mean that in the future, instead of waiting for them to start we could give pre-emptive treatments to susceptible patients.Finally, in order to actively prevent secondary brain injury, we need to know both when neuronal health is in decline and also what treatments are effective in improving this. By continuously tracking neuronal health status in real-time I aim to provide physicians with an online bedside tool that will both identify declining health and provide immediate feedback on the effectiveness of therapeutic interventions. The implementation of such a tool into clinical practice has the potential to limit the amount of secondary brain damage that occurs after an injury and thereby to significantly improve the outcome of the patients.