Brain-responsive neurostimulation (RNS) is firmly ensconced among treatment options for drug-resistant focal epilepsy, but over a quarter of patients treated with the RNS® System do not experience meaningful seizure reduction. Initial titration of RNS therapy is typically similar for all patients, raising the possibility that treatment response might be enhanced by consideration of patient-specific variables. Indeed, small, single-centre studies have yielded preliminary evidence that RNS System effectiveness depends on the brain state during which stimulation is applied. The generalizability of these findings remains unclear, however, and it is unknown whether state-dependent effects of responsive neurostimulation are also stratified by location of the seizure onset zone where stimulation is delivered. We aimed to determine whether state-dependent effects of the RNS System are evident in the large, diverse, multi-centre cohort of RNS System clinical trial participants and to test whether these effects differ between mesiotemporal and neocortical epilepsies. Eighty-one of 256 patients treated with the RNS System across 31 centres during clinical trials met the criteria for inclusion in this retrospective study. Risk states were defined in relation to phases of daily and multi-day cycles of interictal epileptiform activity that are thought to determine seizure likelihood. We found that the probabilities of risk state transitions depended on the stimulation parameter being changed, the starting seizure risk state and the stimulated brain region. Changes in two commonly adjusted stimulation parameters, charge density and stimulation frequency, produced opposite effects on risk state transitions depending on seizure localization. Greater variance in acute risk state transitions was explained by state-dependent responsive neurostimulation for bipolar stimulation in neocortical epilepsies and for monopolar stimulation in mesiotemporal epilepsies. Variability in the effectiveness of RNS System therapy across individuals may relate, at least partly, to the fact that current treatment paradigms do not account fully for fluctuations in brain states or locations of simulation sites. State-dependence of electrical brain stimulation may inform the development of next-generation closed-loop devices that can detect changes in brain state and deliver adaptive, localization-specific patterns of stimulation to maximize therapeutic effects.

中文翻译：

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反应性神经刺激的状态依赖性效应取决于癫痫发作定位


脑反应性神经刺激 （RNS） 在耐药性局灶性癫痫的治疗选择中占有重要地位，但超过四分之一接受 RNS® 系统治疗的患者没有经历有意义的癫痫发作减少。所有患者 RNS 治疗的初始滴度通常相似，这增加了通过考虑患者特异性变量来增强治疗反应的可能性。事实上，小型单中心研究已经产生了初步证据表明 RNS 系统的有效性取决于施加刺激的大脑状态。然而，这些发现的普遍性尚不清楚，并且尚不清楚反应性神经刺激的状态依赖性效应是否也按提供刺激的癫痫发作区的位置进行分层。我们旨在确定 RNS 系统的状态依赖性影响在 RNS 系统临床试验参与者的大型、多样化、多中心队列中是否明显，并测试这些影响在近颞叶和新皮质癫痫之间是否不同。在临床试验期间，在 31 个中心接受 RNS 系统的 256 名患者中，有 81 名符合本回顾性研究的纳入标准。根据发作间期癫痫样活动的每日和多日周期的阶段定义风险状态，这些活动被认为可以确定癫痫发作的可能性。我们发现风险状态转换的概率取决于被改变的刺激参数、开始癫痫发作的风险状态和受刺激的大脑区域。两个通常调整的刺激参数（电荷密度和刺激频率）的变化对风险状态转换产生了相反的影响，具体取决于癫痫发作的定位。 新皮质癫痫双极刺激和近颞叶癫痫单极刺激的状态依赖性反应性神经刺激解释了急性风险状态转换的更大差异。RNS 系统治疗效果在个体之间的差异可能至少部分地与当前治疗范式没有完全考虑大脑状态或模拟部位位置的波动有关。脑电刺激的状态依赖性可能为下一代闭环设备的开发提供信息，这些设备可以检测大脑状态的变化并提供适应性的、定位特异性的刺激模式，以最大限度地提高治疗效果。