Chiang Sharon, Khambhati Ankit N, Tcheng Thomas K, Loftman Audra Plenys, Hasulak Nicholas R, Mirro Emily A, Morrell Martha J, Rao Vikram R
Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
Department of Physiology and the Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, CA 94158, USA.
Brain. 2025 Feb 3;148(2):521-532. doi: 10.1093/brain/awae240.
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.
脑响应神经刺激（RNS）已稳固地成为耐药性局灶性癫痫治疗方案之一，但接受RNS®系统治疗的患者中，超过四分之一未经历有意义的癫痫发作减少。RNS治疗的初始滴定通常对所有患者都相似，这增加了通过考虑患者特定变量来提高治疗反应的可能性。事实上，小型单中心研究已产生初步证据表明，RNS系统的有效性取决于施加刺激时的脑状态。然而，这些发现的普遍性仍不清楚，并且尚不清楚响应性神经刺激的状态依赖性效应是否也按刺激部位的癫痫发作起始区位置分层。我们旨在确定RNS系统的状态依赖性效应在RNS系统临床试验参与者的大型、多样、多中心队列中是否明显，并测试这些效应在颞叶内侧癫痫和新皮质癫痫之间是否存在差异。在临床试验期间，31个中心接受RNS系统治疗的256名患者中有81名符合纳入这项回顾性研究的标准。风险状态是根据被认为决定癫痫发作可能性的发作间期癫痫样活动的每日和多日周期阶段来定义的。我们发现，风险状态转变的概率取决于正在改变的刺激参数、起始癫痫发作风险状态和受刺激的脑区。两个常用调整的刺激参数，即电荷密度和刺激频率的变化，根据癫痫发作定位对风险状态转变产生相反的影响。对于新皮质癫痫中的双极刺激和颞叶内侧癫痫中的单极刺激，急性风险状态转变的更大差异可通过状态依赖性响应性神经刺激来解释。RNS系统治疗效果在个体间的差异可能至少部分与当前治疗模式未充分考虑脑状态波动或模拟部位位置这一事实有关。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，这些设备可以检测脑状态变化并提供适应性、特定于定位的刺激模式，以最大化治疗效果。
