Supplementary Material for: Distinct Biomarkers of ANT Stimulation and Seizure Freedom in an Epilepsy Patient with Ambulatory Hippocampal Electrocorticography

Background: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) and responsive neurostimulation (RNS) of the hippocampus are the predominant approaches to brain stimulation for treating mesial temporal lobe epilepsy (MTLE). Both are similarly effective at reducing seizures in drug resistant patients, but the underlying mechanisms are poorly understood. In rare cases where it becomes clinically indicated to use RNS and DBS simultaneously, ambulatory electrophysiology from RNS may provide the opportunity to measure the effects of ANT DBS in the putative seizure onset zone and identify biomarkers associated with clinical improvement. Here, one such patient became seizure free, allowing us to identify and compare the changes in hippocampal electrophysiology associated with ANT stimulation and with seizure freedom. Methods: Ambulatory electrocorticography and clinical history were retrospectively analyzed for a patient treated with RNS and DBS for MTLE. DBS artifacts were used to identify ANT stimulation periods on RNS recordings and measure peri-stimulus electrographic changes. Clinical history was used to determine the chronic electrographic changes associated with seizure freedom. Results: ANT stimulation acutely suppressed hippocampal gamma (25-90Hz) power, with minimal theta (4-8Hz) suppression and without clear effects on seizure frequency. Eventually, the patient became seizure free alongside the emergence of chronic gamma increase and theta suppression, which started at the same time as clobazam was introduced. Both seizure freedom and the associated electrophysiology persisted after inadvertent DBS discontinuation, further implicating the clobazam relationship. Unexpectedly, RNS detections and long episodes increased, although they were not considered to be electrographic seizures, and the patient remained clinically seizure-free. Conclusion: ANT stimulation and seizure freedom were associated with distinct, dissimilar spectral changes in RNS-derived electrophysiology. The time course of these changes supported a new medication as the most likely cause of clinical improvement. Broadly, this work showcases the use of RNS recordings to interpret the effects of multimodal therapy. Specifically, it lends additional credence to hippocampal theta suppression as a biomarker previously associated with seizure reduction in RNS patients.

背景：丘脑前核（anterior nucleus of the thalamus, ANT）脑深部电刺激（deep brain stimulation, DBS）与海马反应性神经刺激（responsive neurostimulation, RNS）是治疗内侧颞叶癫痫（mesial temporal lobe epilepsy, MTLE）的主流脑刺激手段。二者在耐药性癫痫患者的癫痫发作控制效果上相近，但背后的作用机制仍未明确。在极少数需同时启用RNS与DBS的临床场景中，RNS采集的动态电生理数据或可实现在疑似癫痫发作起始区监测ANT DBS的治疗效应，并筛选与临床症状改善相关的生物标志物。本研究纳入1例同时接受两种治疗且最终实现无癫痫发作的患者，借此识别并对比ANT刺激与癫痫发作缓解相关的海马脑电变化。方法：对1例因MTLE同时接受RNS与DBS治疗的患者的动态脑皮质电图（ambulatory electrocorticography）数据与临床病史进行回顾性分析。通过DBS伪迹定位RNS记录中的ANT刺激时段，并量化刺激前后的脑电变化；结合临床病史明确与癫痫发作缓解相关的慢性脑电改变。结果：ANT刺激可急性抑制海马γ频段（25~90Hz）功率，仅轻微抑制θ频段（4~8Hz）功率，且短期内未对发作频率产生明确影响。最终患者实现无癫痫发作，同时伴随慢性γ频段功率升高与θ频段功率抑制的出现，该变化与氯巴占（clobazam）的启用时间完全重合。在意外停用DBS后，患者仍维持无癫痫发作状态与上述脑电特征，进一步印证了其与氯巴占的关联。值得注意的是，RNS检测到的事件与长时程发作样事件均有所增加，但这些事件未被认定为脑电源性癫痫发作，患者临床状态仍保持无癫痫发作。结论：ANT刺激与癫痫发作缓解分别与RNS采集的脑电中两种截然不同的频谱变化相关。上述变化的时间进程提示，新型药物是患者临床症状改善的最可能诱因。本研究展示了利用RNS记录解读多模式治疗（multimodal therapy）效应的可行性，同时为「海马θ频段抑制可作为RNS患者癫痫发作缓解的生物标志物」这一既往结论提供了额外证据支持。