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

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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.