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Large-scale spatiotemporal neuronal activity dynamics predict cortical viability in a rodent model of ischemic stroke



Large-scale spatiotemporal neuronal activity dynamics predict cortical viability in a rodent model of ischemic stroke


Ellen G. Wann

Doctor of Philosophy in Biological Sciences

University of California, Irvine, 2017

Professor Ron Frostig, Chair

Stroke is the fifth leading cause of death in the United States and frequently results in long-term disability (Benjamin et al., 2017). Improved stroke treatments are necessary as current therapeutic strategies are only effective for a subset of stroke patients and only reduce damage or its functional consequences. Our previous research demonstrated a novel ischemic stroke treatment in rodents in which intermittent sensory (whisker) stimulation delivered within 2 h (early stimulation) after distal permanent Middle Cerebral Artery occlusion (pMCAo) evokes neuronal activity that induces retrograde reperfusion via collateral blood vessels and protects the ischemic cortex from infarct. However, the same intermittent sensory stimulation results in exacerbated damage if delivered 3 or more hours after pMCAo (late stimulation) (Davis et al., 2011; Lay et al. 2010; Lay et al. 2011). The function of evoked neuronal activity in this model highlights the relevance of neuronal activity in the outcome of ischemic stroke, a role that has not received much attention in pre-clinical and clinical stroke research. Characterizing acute ischemic neuronal activity dynamics is additionally important for understanding the temporal and spatial development of ischemic pathophysiology. The main hypothesis of the dissertation was that particular features of post-ischemic neuronal activity critically predict the fate of the ischemic cortex. Using a 32 microelectrode array spanning depths of primary somatosensory cortex (S1) and neighboring cortical regions, electrophysiological recordings generated for the first time a continuous spatiotemporal profile of local field potentials (synaptic potentials recorded as local field potentials, LFP) and multi-unit activity (action potentials, MUA) from the MCA territory before (baseline) and directly after (0-5 hours) distal MCA occlusion in early stimulation, late stimulation, pMCAo alone, and surgical sham animals. Although evoked activity persisted for hours after pMCAo, spatiotemporal analyses revealed that large-scale spontaneous neuronal activity was disrupted after ischemic onset. In infarcted (pMCAo alone and late stimulation) animals, abnormal temporal coordination (synchrony) of large-scale neuronal activity and its underlying oscillations continued throughout the acute ischemic period. Conversely, the effects of ischemia on spatiotemporal synchrony were reversed over the course of the protective early sensory stimulation treatment. If translatable to human EEG, insights gained from evaluating neuronal activity dynamics and identifying electrophysiological signatures of acute ischemia may be potentially useful for supplementing diagnostic strategies and facilitating stroke treatment administration.

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