Ojeda David, Le Rolle Virginie, Romero-Ugalde Hector M, Gallet Clément, Bonnet Jean-Luc, Henry Christine, Bel Alain, Mabo Philippe, Carrault Guy, Hernández Alfredo I
INSERM, U1099, Rennes, France.
Université de Rennes 1, LTSI, Rennes, France.
PLoS One. 2016 Sep 30;11(9):e0163734. doi: 10.1371/journal.pone.0163734. eCollection 2016.
Although the therapeutic effects of Vagus Nerve Stimulation (VNS) have been recognized in pre-clinical and pilot clinical studies, the effect of different stimulation configurations on the cardiovascular response is still an open question, especially in the case of VNS delivered synchronously with cardiac activity. In this paper, we propose a formal mathematical methodology to analyze the acute cardiac response to different VNS configurations, jointly considering the chronotropic, dromotropic and inotropic cardiac effects. A latin hypercube sampling method was chosen to design a uniform experimental plan, composed of 75 different VNS configurations, with different values for the main parameters (current amplitude, number of delivered pulses, pulse width, interpulse period and the delay between the detected cardiac event and VNS onset). These VNS configurations were applied to 6 healthy, anesthetized sheep, while acquiring the associated cardiovascular response. Unobserved VNS configurations were estimated using a Gaussian process regression (GPR) model. In order to quantitatively analyze the effect of each parameter and their combinations on the cardiac response, the Sobol sensitivity method was applied to the obtained GPR model and inter-individual sensitivity markers were estimated using a bootstrap approach. Results highlight the dominant effect of pulse current, pulse width and number of pulses, which explain respectively 49.4%, 19.7% and 6.0% of the mean global cardiovascular variability provoked by VNS. More interestingly, results also quantify the effect of the interactions between VNS parameters. In particular, the interactions between current and pulse width provoke higher cardiac effects than the changes on the number of pulses alone (between 6 and 25% of the variability). Although the sensitivity of individual VNS parameters seems similar for chronotropic, dromotropic and inotropic responses, the interacting effects of VNS parameters provoke significantly different cardiac responses, showing the feasibility of a parameter-based functional selectivity. These results are of primary importance for the optimal, subject-specific definition of VNS parameters for a given therapy and may lead to new closed-loop methods allowing for the optimal adaptation of VNS therapy through time.
尽管迷走神经刺激(VNS)的治疗效果已在临床前和初步临床研究中得到认可,但不同刺激配置对心血管反应的影响仍是一个悬而未决的问题,尤其是在VNS与心脏活动同步进行时。在本文中,我们提出了一种形式化的数学方法,以联合考虑变时性、变传导性和变力性心脏效应,分析不同VNS配置下的急性心脏反应。选择拉丁超立方抽样方法来设计一个统一的实验方案,该方案由75种不同的VNS配置组成,主要参数(电流幅度、发放脉冲数、脉冲宽度、脉冲间期以及检测到的心脏事件与VNS开始之间的延迟)具有不同的值。将这些VNS配置应用于6只健康的麻醉绵羊,同时获取相关的心血管反应。使用高斯过程回归(GPR)模型估计未观察到的VNS配置。为了定量分析每个参数及其组合对心脏反应的影响,将索伯尔敏感性方法应用于获得的GPR模型,并使用自助法估计个体间敏感性标记。结果突出了脉冲电流、脉冲宽度和脉冲数的主导作用,它们分别解释了VNS引起的平均总体心血管变异性的49.4%、19.7%和6.0%。更有趣的是,结果还量化了VNS参数之间相互作用的影响。特别是,电流和脉冲宽度之间的相互作用引起的心脏效应比单独脉冲数的变化更大(变异性在6%至25%之间)。尽管单个VNS参数的敏感性对于变时性、变传导性和变力性反应似乎相似,但VNS参数的相互作用效应引起的心脏反应明显不同,这表明基于参数的功能选择性是可行的。这些结果对于给定治疗的VNS参数的最佳、个体特异性定义至关重要,并且可能导致新的闭环方法,允许VNS治疗随时间进行最佳调整。