Shaw Dana C, Kondabolu Krishnakanth, Walsh Katherine G, Shi Wen, Rillosi Enrico, Hsiung Maxine, Eden Uri T, Richardson Robert M, Kramer Mark A, Chu Catherine J, Han Xue
bioRxiv. 2024 Mar 4:2024.03.01.582958. doi: 10.1101/2024.03.01.582958.
Interictal 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.
We 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.
Delta power (1-4 Hz) was higher in the stroke hemisphere than the non-stroke hemisphere in all mice ( <0.001). Automated detection procedures indicated that compared to the non-stroke hemisphere, the stroke hemisphere had an increased spike ripple ( =0.006) and spike rates ( =0.039), but no change in ripple rate ( =0.98). Expert validation confirmed the observation of elevated spike ripple rates ( =0.008) and a trend of elevated spike rate ( =0.055) in the stroke hemisphere. Interestingly, the validated ripple rate in the stroke hemisphere was higher than the non-stroke hemisphere ( =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).
Cortical 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.
Cortical photothrombosis in mice produces stroke with characteristic intermittent focal delta slowing.Cortical photothrombosis stroke in mice produces the epileptic biomarkers spikes, ripples, and spike ripples.All biomarkers share morphological features with the corresponding human correlate.Spike ripples better lateralize to the lesional cortex than spikes or ripples.This cortical model can be applied in transgenic mice for mechanistic studies.
在人类头皮或颅内电压记录中，发作间期癫痫样棘波、高频涟漪振荡及其共现（棘波-涟漪）是公认的癫痫生物标志物。尽管具有临床意义，但产生这些脑电图生物标志物的神经机制仍不清楚。为了缩小这一知识差距，我们在小鼠中引入了一种新型光血栓性中风模型，该模型可重现人类癫痫中观察到的局灶性发作间期脑电图生物标志物。
我们使用先前在大鼠中建立的光血栓形成程序，单侧诱导C57BL/6小鼠（N=7）运动皮层中风。然后植入颅内电极（同侧2个，对侧2个），并在数周内对清醒、活动的小鼠进行间歇性局部场电位（LFP）记录。我们使用自动和半自动程序评估LFP的局灶性减慢和癫痫生物标志物——棘波、涟漪和棘波-涟漪。
所有小鼠中风半球的δ功率（1-4Hz）均高于非中风半球（<0.001）。自动检测程序表明，与非中风半球相比，中风半球的棘波-涟漪（=0.006）和棘波率（=0.039）增加，但涟漪率无变化（=0.98）。专家验证证实了中风半球棘波-涟漪率升高（=0.008）和棘波率升高趋势（=0.055）的观察结果。有趣的是，中风半球经验证的涟漪率高于非中风半球（=0.031），突出了自动检测涟漪的难度。最后，使用最佳性能阈值，自动检测到的棘波-涟漪对中风半球的分类准确率最高（灵敏度0.94，特异性0.94）。
常用的C57BL/6小鼠中皮质光血栓形成诱导的中风产生了人类癫痫中观察到的脑电图生物标志物。该模型代表了一种新的转化性皮质癫痫模型，具有明确的刺激区，可广泛应用于转基因小鼠，用于对病理性发作间期活动的细胞和电路机制进行细胞类型特异性分析。
小鼠皮质光血栓形成导致中风，伴有特征性间歇性局灶性δ减慢。小鼠皮质光血栓形成性中风产生癫痫生物标志物棘波、涟漪和棘波-涟漪。所有生物标志物均与相应的人类对应物具有形态学特征。与棘波或涟漪相比，棘波-涟漪更好地定位于病变皮层。这种皮质模型可应用于转基因小鼠进行机制研究。
