Closed-Loop Vagus Nerve Stimulation Based on State Transition Models.

OBJECTIVE: Vagus nerve stimulation (VNS) is a potential therapeutic approach in a number of clinical applications. Although VNS is commonly delivered in an open-loop approach, it is now recognized that closed-loop stimulation may be necessary to optimize the therapy. In this paper, we propose an original generic closed-loop control system that can be readily integrated into an implantable device and allows for the adaptive modulation of multiple VNS parameters. METHODS: The proposed control method consists of a state transition model (STM), in which each state represents a set of VNS parameters, and a state transition algorithm that optimally selects the best STM state, minimizing the error between an observed physiological variable and a given target value. The proposed method has been integrated into a real-time adaptive VNS prototype system and has been applied here to the regulation of the instantaneous heart rate, working synchronously with cardiac cycles. A quantitative performance evaluation is performed on seven sheep by computing classical control performance indicators. A comparison with a proportional-integral (PI) controller is also performed. RESULTS: The STM controller presents a median mean square error, overshoot, and settling time, respectively, equal to 622.21 ms , 72.8%, and 7.5 beats. CONCLUSION: The proposed control method yields satisfactory accuracy and time response, while presenting a number of benefits over classical PI controllers. It represents a feasible approach for multiparametric VNS control on implantable devices. SIGNIFICANCE: Closed-loop multiparametric stimulation may improve response and minimize side effects on current pathologies treated by VNS.

A novel controller based on state-transition models for closed-loop vagus nerve stimulation: Application to heart rate regulation.

Vagus nerve stimulation (VNS) is an established adjunctive therapy for pharmacologically refractory epilepsy and depression and is currently in active clinical research for other applications. In current clinical studies, VNS is delivered in an open-loop approach, where VNS parameters are defined during a manual titration phase. However, the physiological response to a given VNS configuration shows significant inter and intra-patient variability and may significantly evolve through time. VNS closed-loop approaches, allowing for the optimization of the therapy in an adaptive manner, may be necessary to improve efficacy while reducing side effects. This paper proposes a generic, closed-loop control VNS system that is able to optimize a number of VNS parameters in an adaptive fashion, in order to keep a control variable within a specified range. Although the proposed control method is completely generic, an example application using the cardiac beat to beat interval (RR) as control variable will be developed in this paper. The proposed controller is based on a state transition model (STM) that can be configured using a partially or a fully-connected architecture, different model orders and different state-transition algorithms. The controller is applied to the adaptive regulation of heart rate and evaluated on 6 sheep, for 13 different targets, using partially-connected STM with 10 states. Also, partially and fully-connected STM defined by 30 states were applied to 7 other sheep for the same 10 targets. Results illustrate the interest of the proposed fully-connected STM and the feasibility of integrating this control system into an implantable neuromodulator.

An original piecewise model for computing energy expenditure from accelerometer and heart rate signals.

OBJECTIVE: Activity energy expenditure (EE) plays an important role in healthcare, therefore, accurate EE measures are required. Currently available reference EE acquisition methods, such as doubly labeled water and indirect calorimetry, are complex, expensive, uncomfortable, and/or difficult to apply on real time. To overcome these drawbacks, the goal of this paper is to propose a model for computing EE in real time (minute-by-minute) from heart rate and accelerometer signals. APPROACH: The proposed model, which consists of an original branched model, uses heart rate signals for computing EE on moderate to vigorous physical activities and a linear combination of heart rate and counts per minute for computing EE on light to moderate physical activities. Model parameters were estimated from a given data set composed of 53 subjects performing 25 different physical activities (light-, moderate- and vigorous-intensity), and validated using leave-one-subject-out. A different database (semi-controlled in-city circuit), was used in order to validate the versatility of the proposed model. Comparisons are done versus linear and nonlinear models, which are also used for computing EE from accelerometer and/or HR signals. MAIN RESULTS: The proposed piecewise model leads to more accurate EE estimations ([Formula: see text], [Formula: see text] and [Formula: see text] J kg-1 min-1 and [Formula: see text], [Formula: see text], and [Formula: see text] J kg-1 min-1 on each validation database). SIGNIFICANCE: This original approach, which is more conformable and less expensive than the reference methods, allows accurate EE estimations, in real time (minute-by-minute), during a large variety of physical activities. Therefore, this model may be used on applications such as computing the time that a given subject spent on light-intensity physical activities and on moderate to vigorous physical activities (binary classification accuracy of 0.8155).

Sensitivity Analysis of Vagus Nerve Stimulation Parameters on Acute Cardiac Autonomic Responses: Chronotropic, Inotropic and Dromotropic Effects.

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.