Photothrombosis induced cortical stroke produces electrographic epileptic biomarkers in mice

Shaw, D. C.; Kondabolu, K.; Walsh, K. G.; Shi, W.; Rillosi, E.; Hsiung, M.; Eden, U.; Richardson, R. M.; Kramer, M. A.; Chu, C. J.; Han, X.

doi:10.1101/2024.03.01.582958

bioRxiv · 10.1101/2024.03.01.582958

Photothrombosis induced cortical stroke produces electrographic epileptic biomarkers in mice

Shaw, D. C.·Kondabolu, K.·Walsh, K. G.·Shi, W.·Rillosi, E.·Hsiung, M.·Eden, U.·Richardson, R. M.·Kramer, M. A.·Chu, C. J.·Han, X.

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Abstract

ObjectiveInterictal epileptiform spikes, high-frequency ripple oscillations, and their co-occurrence (spike ripples) in human scalp or intracranial voltage recordings are well-established epileptic biomarkers. While clinically significant, the neural mechanisms generating these electrographic biomarkers remain unclear. To reduce this knowledge gap, we introduce a novel photothrombotic stroke model in mice that reproduces focal interictal electrographic biomarkers observed in human epilepsy. MethodsWe induced a stroke in the motor cortex of C57BL/6 mice unilaterally (N=7) using a photothrombotic procedure previously established in rats. We then implanted intracranial electrodes (2 ipsilateral and 2 contralateral) and obtained intermittent local field potential (LFP) recordings over several weeks in awake, behaving mice. We evaluated the LFP for focal slowing and epileptic biomarkers - spikes, ripples, and spike ripples - using both automated and semi-automated procedures. ResultsDelta power (1-4 Hz) was higher in the stroke hemisphere than the non-stroke hemisphere in all mice (p<0.001). Automated detection procedures indicated that compared to the non-stroke hemisphere, the stroke hemisphere had an increased spike ripple (p=0.006) and spike rates (p=0.039), but no change in ripple rate (p=0.98). Expert validation confirmed the observation of elevated spike ripple rates (p=0.008) and a trend of elevated spike rate (p=0.055) in the stroke hemisphere. Interestingly, the validated ripple rate in the stroke hemisphere was higher than the non-stroke hemisphere (p=0.031), highlighting the difficulty of automatically detecting ripples. Finally, using optimal performance thresholds, automatically detected spike ripples classified the stroke hemisphere with the best accuracy (sensitivity 0.94, specificity 0.94). SignificanceCortical photothrombosis-induced stroke in commonly used C57BL/6 mice produces electrographic biomarkers as observed in human epilepsy. This model represents a new translational cortical epilepsy model with a defined irritative zone, which can be broadly applied in transgenic mice for cell type specific analysis of the cellular and circuit mechanisms of pathologic interictal activity. Key PointsO_LICortical photothrombosis in mice produces stroke with characteristic intermittent focal delta slowing. C_LIO_LICortical photothrombosis stroke in mice produces the epileptic biomarkers spikes, ripples, and spike ripples. C_LIO_LIAll biomarkers share morphological features with the corresponding human correlate. C_LIO_LISpike ripples better lateralize to the lesional cortex than spikes or ripples. C_LIO_LIThis cortical model can be applied in transgenic mice for mechanistic studies. C_LI

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Shaw, D. C., Kondabolu, K., Walsh, K. G., Shi, W., Rillosi, E., Hsiung, M., Eden, U., Richardson, R. M., Kramer, M. A., Chu, C. J., Han, X.. 2024-03-04. Photothrombosis induced cortical stroke produces electrographic epileptic biomarkers in mice. https://doi.org/10.1101/2024.03.01.582958

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