Nonlinear Closed-Loop Predictive Control of Heart Rate and Blood Pressure Using Vagus Nerve Stimulation: An In Silico Study.

We propose a nonlinear model-based control technique for regulating the heart rate and blood pressure using vagus nerve neuromodulation. The closed-loop framework is based on an in silico model of the rat cardiovascular system for the simulation of the hemodynamic response to multi-location vagal nerve stimulation. The in silico model is derived by compartmentalizing the various physiological components involved in the closed-loop cardiovascular system with intrinsic baroreflex regulation to virtually generate nominal and hypertension-related heart dynamics of rats in rest and exercise states. The controller, using a reduced cycle-averaged model, monitors the outputs from the in silico model, estimates the current state of the reduced model, and computes the optimum stimulation locations and the corresponding parameters using a nonlinear model predictive control algorithm. The results demonstrate that the proposed control strategy is robust with respect to its ability to handle setpoint tracking and disturbance rejection in different simulation scenarios.

Controlling neocortical epileptic seizures using forced temporal spike-time stimulation: an in silico computational study.

Epileptic seizure is typically characterized by highly synchronized episodes of neural activity. Existing stimulation therapies focus purely on suppressing the pathologically synchronized neuronal firing patterns during the ictal (seizure) period. While these strategies are effective in suppressing seizures when they occur, they fail to prevent the re-emergence of seizures once the stimulation is turned off. Previously, we developed a novel neurostimulation motif, which we refer to as "Forced Temporal Spike-Time Stimulation" (FTSTS) that has shown remarkable promise in long-lasting desynchronization of excessively synchronized neuronal firing patterns by harnessing synaptic plasticity. In this paper, we build upon this prior work by optimizing the parameters of the FTSTS protocol in order to efficiently desynchronize the pathologically synchronous neuronal firing patterns that occur during epileptic seizures using a recently published computational model of neocortical-onset seizures. We show that the FTSTS protocol applied during the ictal period can modify the excitatory-to-inhibitory synaptic weight in order to effectively desynchronize the pathological neuronal firing patterns even after the ictal period. Our investigation opens the door to a possible new neurostimulation therapy for epilepsy.

CONTROL-CORE: A Framework for Simulation and Design of Closed-Loop Peripheral Neuromodulation Control Systems.

Closed-loop Vagus Nerve Stimulation (VNS) based on physiological feedback signals is a promising approach to regulate organ functions and develop therapeutic devices. Designing closed-loop neurostimulation systems requires simulation environments and computing infrastructures that support i) modeling the physiological responses of organs under neuromodulation, also known as physiological models, and ii) the interaction between the physiological models and the neuromodulation control algorithms. However, existing simulation platforms do not support closed-loop VNS control systems modeling without extensive rewriting of computer code and manual deployment and configuration of programs. The CONTROL-CORE project aims to develop a flexible software platform for designing and implementing closed-loop VNS systems. This paper proposes the software architecture and the elements of the CONTROL-CORE platform that allow the interaction between a controller and a physiological model in feedback. CONTROL-CORE facilitates modular simulation and deployment of closed-loop peripheral neuromodulation control systems, spanning multiple organizations securely and concurrently. CONTROL-CORE allows simulations to run on different operating systems, be developed in various programming languages (such as Matlab, Python, C++, and Verilog), and be run locally, in containers, and in a distributed fashion. The CONTROL-CORE platform allows users to create tools and testbenches to facilitate sophisticated simulation experiments. We tested the CONTROL-CORE platform in the context of closed-loop control of cardiac physiological models, including pulsatile and nonpulsatile rat models. These were tested using various controllers such as Model Predictive Control and Long-Short-Term Memory based controllers. Our wide range of use cases and evaluations show the performance, flexibility, and usability of the CONTROL-CORE platform.

Data Driven Control of Vagus Nerve Stimulation for the Cardiovascular System: An in Silico Computational Study.

Vagus nerve stimulation is an emerging therapy that seeks to offset pathological conditions by electrically stimulating the vagus nerve through cuff electrodes, where an electrical pulse is defined by several parameters such as pulse amplitude, pulse width, and pulse frequency. Currently, vagus nerve stimulation is under investigation for the treatment of heart failure, cardiac arrhythmia and hypertension. Through several clinical trials that sought to assess vagus nerve stimulation for the treatment of heart failure, stimulation parameters were determined heuristically and the results were inconclusive, which has led to the suggestion of using a closed-loop approach to optimize the stimulation parameters. A recent investigation has demonstrated highly specific control of cardiovascular physiology by selectively activating different fibers in the vagus nerve. When multiple locations and multiple stimulation parameters are considered for optimization, the design of closed-loop control becomes considerably more challenging. To address this challenge, we investigated a data-driven control scheme for both modeling and controlling the rat cardiovascular system. Using an existing in silico physiological model of a rat heart to generate synthetic input-output data, we trained a long short-term memory network (LSTM) to map the effect of stimulation on the heart rate and blood pressure. The trained LSTM was utilized in a model predictive control framework to optimize the vagus nerve stimulation parameters for set point tracking of the heart rate and the blood pressure in closed-loop simulations. Additionally, we altered the underlying in silico physiological model to consider intra-patient variability, and diseased dynamics from increased sympathetic tone in designing closed-loop VNS strategies. Throughout the different simulation scenarios, we leveraged the design of the controller to demonstrate alternative clinical objectives. Our results show that the controller can optimize stimulation parameters to achieve set-point tracking with nominal offset while remaining computationally efficient. Furthermore, we show a controller formulation that compensates for mismatch due to intra-patient variabilty, and diseased dynamics. This study demonstrates the first application and a proof-of-concept for using a purely data-driven approach for the optimization of vagus nerve stimulation parameters in closed-loop control of the cardiovascular system.

Mapping Vagus Nerve Stimulation Parameters to Cardiac Physiology using Long Short-term Memory Network.

Vagus nerve stimulation (VNS) is an emerging therapeutic strategy for pathological conditions in a variety of diseases; however, several challenges arise for applying this stimulation paradigm in automated closed-loop control. In this work, we propose a data driven approach for predicting the impact of VNS on physiological variables. We apply this approach on a synthetic dataset created with a physiological model of a rat heart. Through training several neural network models, we found that a long short term memory (LSTM) architecture gave the best performance on a test set. Further, we found the neural network model was capable of mapping a set of VNS parameters to the correct response in the heart rate and the mean arterial blood pressure. In closed-loop control of biological systems, a model of the physiological system is often required and we demonstrate using a data driven approach to meet this requirement in the cardiac system.

Experimental design of a "Snap-on" and standalone single-bed oxygen concentrator for medical applications.

A novel single-bed, "Snap-on" and standalone, medical oxygen concentrator design based on a rapid pressure swing adsorption process was investigated for continuous oxygen supply. The Snap-on concentrator design is easy to hook up to an existing compressed air source, and the unit can then be readily used to produce oxygen for medical applications. It is easily transportable and compared to a traditional oxygen concentrator with its dedicated compressor, the Snap-on concentrator is particularly relevant for the oxygen therapy needs of a larger number of patients in situations such as COVID-19. A commercially available LiLSX zeolite was used for the separation of oxygen from compressed ambient air. The experiments were performed at different feed air pressures using a constant supply of house air in the lab. Further, the device performance was also analyzed using a standalone medium size air compressor. The minimum bed size factor obtained with compressed house air was 100 lb/tons per day contained (TPDc) O2 at a cycle time of 7 s, whereas the minimum bed size factor obtained with a medium size air compressor weighing about 12 lbs was 210 lb/TPDc O2 at a cycle time of 14.5 s under the same feed pressures of 3.1 bar at an oxygen product purity of 90%. The product oxygen flow rate was nearly double for the same amount of adsorbent when using house air for the Snap-on design. The primary reason for this significantly higher oxygen production was the substantially higher and stable air throughput capacity of a typical house air compressor that enabled rapid cycling of the process at near-constant feed pressure compared to a medium size compressor used in a medical oxygen concentrator. The oxygen recovery was approximately 34% for both cases. Thus, the Snap-on oxygen concentrator was found to be easier to build and it delivered more oxygen for medical use compared to standalone units in locations where a constant supply of compressed feed air is available. This is typically the case in facilities such as hospitals, military medical camps and cruise ships. Further, the Snap-on design offers other benefits such as ease of transportation, higher reliability and lower weight.

Effects of Exercise on EEG Activity and Standard Tools Used to Assess Concussion.

A variety of cognitive assessment tools are used to determine the functional status of the brain before and after injury in athletes. Questionnaires, neuropsychological tests, and electroencephalographic (EEG) measures have been recently used to directly assess brain function on and near the playing field. However, exercise can affect cognitive performance and EEG measures of cortical activity. To date, little empirical evidence exists on the effects of acute exercise on these measures of neurological function. We therefore quantified athlete performance on a standardized battery of concussion assessment tools and EEG measurements immediately before and after acute exercise to simulate conditions of athletic competition. Heart rate and arterial oxygen levels were collected before and after the exercise challenge consisting of a 1-mile run. Together these data, from a gender-balanced cohort of collegiate athletes, demonstrated that moderate to hard levels of acute exercise improved performance on the King-Devick test (K-D test) and Standardized Assessment of Concussion (SAC) component of the Sport Concussion Assessment Tool (SCAT3). Gender played an important role in these effects, and performance was most affected by exercise in female athletes. EEG activity in the theta band (4-8 Hz) was decreased during periods of quiet resting with eyes open or eyes closed. Additionally, exercise produced a slowing of the EEG during the K-D test and a shift to higher frequencies during the balance assessment of the SCAT3. Together, these data indicate that exercise alone can influence outcome measures of cognitive assessment tools used to assess brain function in athletes. Finally, care must be taken to acquire postinjury measurements during a comparable physiologic state to that in which baseline assessment data were measured, and further research is needed into the factors influencing outcome measures of these tests.

On the continuous differentiability of inter-spike intervals of synaptically connected cortical spiking neurons in a neuronal network.

We derive conditions for continuous differentiability of inter-spike intervals (ISIs) of spiking neurons with respect to parameters (decision variables) of an external stimulating input current that drives a recurrent network of synaptically connected neurons. The dynamical behavior of individual neurons is represented by a class of discontinuous single-neuron models. We report here that ISIs of neurons in the network are continuously differentiable with respect to decision variables if (1) a continuously differentiable trajectory of the membrane potential exists between consecutive action potentials with respect to time and decision variables and (2) the partial derivative of the membrane potential of spiking neurons with respect to time is not equal to the partial derivative of their firing threshold with respect to time at the time of action potentials. Our theoretical results are supported by showing fulfillment of these conditions for a class of known bidimensional spiking neuron models.

Gene regulatory network modeling using literature curated and high throughput data.

Building on the linear matrix inequality (LMI) formulation developed recently by Zavlanos et al. (Automatica: Special Issue Syst Biol 47(6):1113-1122, 2011), we present a theoretical framework and algorithms to derive a class of ordinary differential equation (ODE) models of gene regulatory networks using literature curated data and microarray data. The solution proposed by Zavlanos et al. (Automatica: Special Issue Syst Biol 47(6):1113-1122, 2011) requires that the microarray data be obtained as the outcome of a series of controlled experiments in which the network is perturbed by over-expressing one gene at a time. We note that this constraint may be relaxed for some applications and, in addition, demonstrate how the conservatism in these algorithms may be reduced by using the Perron-Frobenius diagonal dominance conditions as the stability constraints. Due to the LMI formulation, it follows that the bounded real lemma may easily be used to make use of additional information. We present case studies that illustrate how these algorithms can be used on datasets to derive ODE models of the underlying regulatory networks.

Algorithms for sleep-wake identification using actigraphy: a comparative study and new results.

The aim of this study was to investigate two new scoring algorithms employing artificial neural networks and decision trees for distinguishing sleep and wake states in infants using actigraphy and to validate and compare the performance of the proposed algorithms with known actigraphy scoring algorithms. The study employed previously recorded longitudinal physiological infant data set from the Collaborative Home Infant Monitoring Evaluation (CHIME) study conducted between 1994 and 1998 [http://dccwww.bumc.bu.edu/ChimeNisp/Main_Chime.asp; Sleep26 (1997) 553] at five clinical sites around the USA. The original CHIME data set contains recordings of 1079 infants <1 year old. In our study, we used the overnight polysomnography scored data and ankle actimeter (Alice 3) raw data for 354 infants from this data set. The participants were heterogeneous and grouped into four categories: healthy term, preterm, siblings of SIDS and infants with apparent life-threatening events (apnea of infancy). The selection of the most discriminant actigraphy features was carried out using Fisher's discriminant analysis. Approximately 80% of all the epochs were used to train the artificial neural network and decision tree models. The models were then validated on the remaining 20% of the epochs. The use of artificial neural networks and decision trees was able to capture potentially nonlinear classification characteristics, when compared to the previously reported linear combination methods and hence showed improved performance. The quality of sleep-wake scoring was further improved by including more wake epochs in the training phase and by employing rescoring rules to remove artifacts. The large size of the database (approximately 337,000 epochs for 354 patients) provided a solid basis for determining the efficacy of actigraphy in sleep scoring. The study also suggested that artificial neural networks and decision trees could be much more routinely utilized in the context of clinical sleep search.