Clinical Stimulation and Spreading Depolarization

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PROJECT SUMMARY/ ABSTRACT Clinical stimulation and physiologic fluctuations are a normal part of the early management of patients with severe strokes. It is possible, however, that episodic stimulation (inducing brain activation) or physiologic insults (such as hypotension) could in fact cause harm by triggering damaging spreading depolarization (SD) events in vulnerable brain. This is based on 1) a recent pre-clinical study in a mouse model of stroke, 2) our own preliminary data suggesting that such events are associated with subsequent SD, and 3) results of a major pivotal trial that showed worse outcomes in stroke patients who received early mobilization. It is therefore critically important to rigorously assess the effects of routine clinical interventions on SD in human subjects. The current study is part of our long-term goals, focused on understanding the mechanisms, consequences, and therapeutic approaches related to SD in acute neurological injury. With this application, we seek to determine whether normal interventions in the intensive care unit are associated with an increased risk of SD in the sensorimotor cortex in patients with large hemispheric strokes. We will assess this using subdural electrocorticography electrodes paired with tissue oxygen probes in the sensorimotor region adjacent to the infarct border in patients with large hemispheric stroke who require decompressive hemicraniectomy. We will then perform long term video EEG recordings to assess for stimulation events and collect continuous physiological measurements, all time locked with SD recordings. SD will also be scored with standard criteria. We will these assess whether more stimulation events or more transient physiologic insults are associated with SD using several statistical approaches. These analyses will provide fundamental insights into whether such events could trigger SD, which is expected to result in worsening stroke outcomes. Such findings would have important implications for patients, particularly with severe stroke, where early aggressive mobilization has been demonstrated to result in worse outcomes and larger strokes. If the mechanism of worse outcomes in these studies is confirmed to be related to SD triggering, then this would provide the foundation for future efforts to mitigate these effects or target SD to improve outcomes.