Blocking and modulation of Spreading Depolarisations in a gyrencephalic brain under high-definition multimodal monitoring including novel multispectral optical and photoacoustic tissue analysis

弥漫性去极化(SD)是一种新的机制，可导致神经危重患者的继发性损害和神经元死亡，包括蛛网膜下腔出血、缺血性中风和头部创伤。初步的临床和实验数据表明，SD在中脑和脑回均可被抑制，其损害可减轻50%，但在某些条件下，该疗法可能无效。不幸的是，到目前为止，缺乏足够的成像方法阻碍了神经保护研究。在小动物模型中成功的神经保护疗法和在人类中的有效疗法之间仍然缺乏联系。使用我们研究小组开发的成熟的脑回动物翻译模型，在一个新的拟议模型中，我们可以在3周内进行精细的临床评估，我们可以研究和表征目前用于人类其他目的的各种神经保护药物的有效性。该项目的目标是(1)建立一个新的多模式成像概念来描述SD的特征，(2)在翻译动物模型中比较评估SD抑制和衰减的疗法及其作为神经保护疗法的有效性。我们的研究方法基于使用皮层脑电成像(ECoG)和无线ECoG的多参数监测，并结合多光谱光学成像和光声成像。血流动力学反应及其后果的特征将通过多模式图像分析确定氧合、血容量、血流和速度、血管反应性、脑/梗死面积和脑连通性来实现。第一次，这些参数可以在组织的深处确定，从而使脑梗塞和抑郁的三维特征成为可能。基于这一新的成像概念，将使用一个轮脑动物模型来研究各种治疗方案。一个重要的目标是找到阻断SDS或减弱其最糟糕的血流动力学时相的最佳治疗组合，并在中风模型中量化最佳组合治疗所导致的梗塞面积缩小。该项目产生的知识将解决从动物模型到患者的缺失神经保护转换，而批准药物的使用将使未来成功的人类临床试验能够立即得到更好的规划和执行。

Spreading depolarisation (SD) is a novel identified mechanism that produces secondary damage and neuronal death in critically ill neurological patients, including subarachnoid haemorrhage, ischaemic stroke and head trauma. Preliminary clinical and experimental data indicates that SD can be inhibited in both lissencephalic and gyrencephalic brains and that the damage can be reduced by 50%, but under certain conditions the therapy could become ineffective. Unfortunately, the lack of adequate imaging methods hampers neuroprotective research to date. There is still a missing link between successful neuroprotective therapies in small animal models and effective therapies in humans. Using our well-established gyrencephalic animal translational models developed by our research group, and in a new proposed model that permits a fine clinical evaluation at 3 weeks, we can study and characterise the efficacy of various neuroprotective medications currently used in humans for other purposes.The goals of this project are (1) the establishment of a new multimodal imaging concept to characterise SDs and (2) the comparative evaluation of therapies for SD inhibition and attenuation and their efficacy as neuroprotective therapies in translational animal models.Our research methods are based on multiparametric monitoring using electrocorticography (ECoG) and wireless ECoG combined with multispectral optical imaging and photoacoustic imaging. Characterisation of the haemodynamic responses and their consequences will be achieved by determining oxygenation, blood volume, blood flow and velocities, vascular reactivity, brain/infarct size and brain connectivity via multimodal image analysis. For the first time, these parameters can be determined deep inside the tissue, thus enabling the three dimensional characterisation of brain infarction and SDs. Based on the novel imaging concept, a gyrencephalic animal model will be used to study various therapeutic regimens. An important goal is to find the best combination of therapies that either block SDs or attenuate their worst haemodynamic phases and to quantify the infarct size reduction resulting from the best combined treatment in a stroke model. The knowledge generated by this project will tackle the missing neuroprotective translation from animal models into patients, and the use of approved medications will enable an immediate, better planning and execution of a successful future clinical trial in humans.