An Alternative Approach to Estimate Solute Concentration: Exploiting the Information Embedded in the Solid Phase.

The solute concentration in crystallization processes is generally estimated by observing properties of the liquid phase. Here, a novel method for online estimation of the change in the solute concentration caused by seeded batch crystallization or dissolution of a population of crystals in suspension is presented. The method is based on multiprojection imaging to track variations in the total solid volume of the population, thus enabling inference of the solute concentration through the mass conservation constraint. The solute concentration estimates obtained in this way are validated by using them to measure the solubilities of ß l-glutamic acid and vanillin in water within certain temperature ranges and comparing them to literature data. The presented method shows promise in estimating the solute concentration reliably under circumstances where employing conventional techniques is challenging.

Neural correlates of visuomotor adjustments during scaling of human finger movements.

Visually guided finger movements include online feedback of current effector position to guide target approach. This visual feedback may be scaled or otherwise distorted by unpredictable perturbations. Although adjustments to visual feedback scaling have been studied before, the underlying brain activation differences between upscaling (visual feedback larger than real movement) and downscaling (feedback smaller than real movement) are currently unknown. Brain activation differences between upscaling and downscaling might be expected because within-trial adjustments during upscaling require corrective backwards accelerations, whereas correcting for downscaling requires forward accelerations. In this behavioural and fMRI study we investigated adjustments during up- and downscaling in a target-directed finger flexion-extension task with real-time visual feedback. We found that subjects made longer and more complete within-trial corrections for downscaling perturbations than for upscaling perturbations. The finger task activated primary motor (M1) and somatosensory (S1) areas, premotor and parietal regions, basal ganglia, and cerebellum. General scaling effects were seen in the right pre-supplementary motor area, dorsal anterior cingulate cortex, inferior parietal lobule, and dorsolateral prefrontal cortex. Stronger activations for down- than for upscaling were observed in M1, supplementary motor area (SMA), S1 and anterior cingulate cortex. We argue that these activation differences may reflect differing online correction for upscaling vs. downscaling during finger flexion-extension.

Correction: Virtual Hand Feedback Reduces Reaction Time in an Interactive Finger Reaching Task.

[This corrects the article DOI: 10.1371/journal.pone.0154807.].

Virtual Hand Feedback Reduces Reaction Time in an Interactive Finger Reaching Task.

Computer interaction via visually guided hand or finger movements is a ubiquitous part of daily computer usage in work or gaming. Surprisingly, however, little is known about the performance effects of using virtual limb representations versus simpler cursors. In this study 26 healthy right-handed adults performed cued index finger flexion-extension movements towards an on-screen target while wearing a data glove. They received each of four different types of real-time visual feedback: a simple circular cursor, a point light pattern indicating finger joint positions, a cartoon hand and a fully shaded virtual hand. We found that participants initiated the movements faster when receiving feedback in the form of a hand than when receiving circular cursor or point light feedback. This overall difference was robust for three out of four hand versus circle pairwise comparisons. The faster movement initiation for hand feedback was accompanied by a larger movement amplitude and a larger movement error. We suggest that the observed effect may be related to priming of hand information during action perception and execution affecting motor planning and execution. The results may have applications in the use of body representations in virtual reality applications.

Closed-loop neuromodulation of spinal sensorimotor circuits controls refined locomotion after complete spinal cord injury.

Neuromodulation of spinal sensorimotor circuits improves motor control in animal models and humans with spinal cord injury. With common neuromodulation devices, electrical stimulation parameters are tuned manually and remain constant during movement. We developed a mechanistic framework to optimize neuromodulation in real time to achieve high-fidelity control of leg kinematics during locomotion in rats. We first uncovered relationships between neuromodulation parameters and recruitment of distinct sensorimotor circuits, resulting in predictive adjustments of leg kinematics. Second, we established a technological platform with embedded control policies that integrated robust movement feedback and feed-forward control loops in real time. These developments allowed us to conceive a neuroprosthetic system that controlled a broad range of foot trajectories during continuous locomotion in paralyzed rats. Animals with complete spinal cord injury performed more than 1000 successive steps without failure, and were able to climb staircases of various heights and lengths with precision and fluidity. Beyond therapeutic potential, these findings provide a conceptual and technical framework to personalize neuromodulation treatments for other neurological disorders.

Spatially distributed sequential stimulation reduces fatigue in paralyzed triceps surae muscles: a case study.

Functional electrical stimulation (FES) is limited by the rapid onset of muscle fatigue caused by localized nerve excitation repeatedly activating only a subset of motor units. The purpose of this study was to investigate reducing fatigue by sequentially changing, pulse by pulse, the area of stimulation using multiple surface electrodes that cover the same area as one electrode during conventional stimulation. Paralyzed triceps surae muscles of an individual with complete spinal cord injury were stimulated, via the tibial nerve, through four active electrodes using spatially distributed sequential stimulation (SDSS) that was delivered by sending a stimulation pulse to each electrode one after another with 90° phase shift between successive electrodes. For comparison, single electrode stimulation was delivered through one active electrode. For both modes of stimulation, the resultant frequency to the muscle as a whole was 40 Hz. Isometric ankle torque was measured during fatiguing stimulations lasting 2 min. Each mode of stimulation was delivered a total of six times over 12 separate days. Three fatigue measures were used for comparison: fatigue index (final torque normalized to maximum torque), fatigue time (time for torque to drop by 3 dB), and torque-time integral (over the entire trial). The measures were all higher during SDSS (P < 0.001), by 234, 280, and 171%, respectively. The results are an encouraging first step toward addressing muscle fatigue, which is one of the greatest problems for FES.

Wearable neural prostheses. Restoration of sensory-motor function by transcutaneous electrical stimulation.

In this article, we focus on the least invasive interface: transcutaneous ES (TES), i.e., the use of surface electrodes as an interface between the stimulator and sensory-motor systems. TES is delivered by a burst of short electrical charge pulses applied between pairs of electrodes positioned on the skin. Monophasic or charge-balanced biphasic (symmetric or asymmetric) stimulation pulses can be delivered. The latter ones have the advantage to provide contraction force while minimizing tissue damage.

Charge and energy minimization in electrical/magnetic stimulation of nervous tissue.

In this work we address the problem of stimulating nervous tissue with the minimal necessary energy at reduced/minimal charge. Charge minimization is related to a valid safety concern (avoidance and reduction of stimulation-induced tissue and electrode damage). Energy minimization plays a role in battery-driven electrical or magnetic stimulation systems (increased lifetime, repetition rates, reduction of power requirements, thermal management). Extensive new theoretical results are derived by employing an optimal control theory framework. These results include derivation of the optimal electrical stimulation waveform for a mixed energy/charge minimization problem, derivation of the charge-balanced energy-minimal electrical stimulation waveform, solutions of a pure charge minimization problem with and without a constraint on the stimulation amplitude, and derivation of the energy-minimal magnetic stimulation waveform. Depending on the set stimulus pulse duration, energy and charge reductions of up to 80% are deemed possible. Results are verified in simulations with an active, mammalian-like nerve fiber model.

Experimental implementation of automatic 'cycle to cycle' control to a nonlinear chiral simulated moving bed separation.

In order to better exploit the economic potential of the simulated moving bed chromatography a 'cycle to cycle' controller which only requires the information about the linear adsorption behavior and the overall average porosity of the columns has been proposed. Recently, an automated on-line HPLC monitoring system which determines the concentrations in the two product streams averaged over one cycle, and returns them as feedback information to the controller was implemented. The new system allows for an accurate determination of the average concentration of the product streams even if the plant is operated at high concentrations. This paper presents the experimental implementation of the 'cycle to cycle' control concept to the separation of guaifenesin enantiomers under nonlinear chromatographic conditions, i.e. at high feed concentrations. Different case studies have been carried out to challenge the controller under realistic operation conditions, e.g. introducing pump disturbances and changing the feed concentration during the operation. The experimental results clearly demonstrate that the controller can indeed deliver the specified purities and improve the process performance.

The influence of electrode size on selectivity and comfort in transcutaneous electrical stimulation of the forearm.

Transcutaneous electrical stimulation (TES) is a technique to artificially activate motor nerves and muscles. It can be used for rehabilitation or the restoration of lost motor functions, e.g., in subjects with brain or spinal cord lesions. Apart from selectively activating motor nerves and muscles, TES activates sensory fibers and pain receptors, producing discomfort and pain. Clinicians try to minimize discomfort by optimizing stimulation parameters, electrode location, and electrode size. There are some studies that found optimal electrode sizes for certain stimulation sites (e.g., gastrocnemius), however the underlying effects why certain electrode sizes are preferred by patients is not well understood. We used a TES model consisting of a finite element (FE) model and a nerve model to assess the influence of different electrode sizes on the selectivity and the perceived comfort for various anatomies. Motor thresholds calculated using the TES model were compared with motor thresholds that were obtained from measurements performed on the forearm of ten human volunteers. Results of the TES model indicate that small electrodes (0.8 x 0.8 cm(2)) are more comfortable for thin fat layers (0.25 cm) and superficial nerves (0.1 cm) and larger electrodes (4.1 x 4.1 cm(2)) are more comfortable for thicker fat layers (2 cm) and deeper nerves (1.1 cm) at a constant recruitment.

Array electrode design for transcutaneous electrical stimulation: a simulation study.

Array electrodes are a promising technology that is likely to bring transcutaneous electrical stimulation (TES) a step forward. The dynamic adaptation of electrode size and position helps to simplify the use of electrical stimulation systems and to increase their clinical efficacy. However, up to now array electrodes were built by trial and error and it is unclear how, for example, the gaps between the array elements or the resistivity of the electrode-skin interface material influence the current distribution. A TES model that comprises a finite element model and a nerve model has been used to analyze the influence of array electrode gaps and gel resistivities on nerve activation. Simulation results indicate that the resistivity of the electrode-skin interface layer should be adapted depending on the size of the gaps between the array elements. Furthermore, the gap sizes should be smaller than 3mm in order to keep losses small.

Implementation of an automated on-line high-performance liquid chromatography monitoring system for 'cycle to cycle' control of simulated moving beds.

In continuous chromatography simulated moving bed (SMB) is a firmly established powerful technique for the separation of fine chemicals and enantiomers. The use of a controller could improve the operation conditions and increase the productivity of an SMB unit. However, the performance of any controller is greatly affected by the reliability and the quality of the feedback information from the plant. Therefore, to overcome the limitations of optical detectors, such as UV and polarimeter, an automated on-line HPLC monitoring system was developed and installed to monitor the product streams. The performance of the system is tested experimentally separating a mixture of guaifenesin enantiomers on Chiralcel OD columns with ethanol as mobile phase in our laboratory SMB unit under both linear and nonlinear chromatographic conditions. The results show that the new monitoring system provides precise and accurate data about the concentration of the components in the two product streams. Moreover, they prove that despite disturbances a combination of the controller and the new on-line monitoring system allows to fulfill the product specifications and to improve the performance of the process in terms of feed throughput and solvent consumption.

A model for transcutaneous current stimulation: simulations and experiments.

Complex nerve models have been developed for describing the generation of action potentials in humans. Such nerve models have primarily been used to model implantable electrical stimulation systems, where the stimulation electrodes are close to the nerve (near-field). To address if these nerve models can also be used to model transcutaneous electrical stimulation (TES) (far-field), we have developed a TES model that comprises a volume conductor and different previously published non-linear nerve models. The volume conductor models the resistive and capacitive properties of electrodes, electrode-skin interface, skin, fat, muscle, and bone. The non-linear nerve models were used to conclude from the potential field within the volume conductor on nerve activation. A comparison of simulated and experimentally measured chronaxie values (a measure for the excitability of nerves) and muscle twitch forces on human volunteers allowed us to conclude that some of the published nerve models can be used in TES models. The presented TES model provides a first step to more extensive model implementations for TES in which e.g., multi-array electrode configurations can be tested.

Assessment of finger forces and wrist torques for functional grasp using new multichannel textile neuroprostheses.

New multichannel textile neuroprotheses were developed, which comprise multiple sets of transcutaneous electrode arrays and connecting wires embroidered into a fabric layer. The electrode arrays were placed on the forearm above the extrinsic finger flexors and extensors. Activation regions for selective finger flexion and wrist extension were configured by switching a subset of the array elements between cathode, anode, and off states. We present a new isometric measurement system for the assessment of finger forces and wrist torques generated using the new neuroprostheses. Finger forces (from the middle phalanxes) were recorded using five load cells mounted on a "grasp handle" that can be arbitrarily positioned in space. The hand and the grasp handle were rigidly mounted to a 6-degree of freedom load cell, and the forces and torques about the wrist were recorded. A vacuum cushion was used to comfortably fixate the forearm. The position and orientation of the forearm, wrist, fingers, and handle were recorded using a new three-dimensional position measurement system (accuracy <+/-1 mm). The measurement system was integrated into the real-time multichannel transcutaneous electrode environment, which is able to control the spatiotemporal position of multiple activation regions. Using the combined system and textile neuroprosthesis, we were able to optimize the activation regions to produce selective finger and wrist articulation, enabling improved functional grasp.

On the modeling of drug induced respiratory depression in the non-steady-state.

The ability of anesthetic agents to provide adequate analgesia and sedation is limited by the ventilatory depression associated with overdosing in spontaneously breathing patients. Therefore, quantitation of drug induced ventilatory depression is a pharmacokinetic-pharmacodynamic problem relevant to the practice of anesthesia. Although several studies describe the effect of respiratory depressant drugs on isolated endpoints, an integrated description of drug induced respiratory depression with parameters identifiable from clinically available data is not available. This study proposes a physiological model of CO2 disposition, ventilatory regulation, and the effects of anesthetic agents on the control of breathing. The predictive performance of the model is evaluated through simulations aimed at reproducing experimental observations of drug induced hypercarbia and hypoventilation associated with intravenous administration of a fast-onset, highly potent anesthetic mu agonist (including previously unpublished experimental data determined after administration of 1 mg alfentanil bolus). The proposed model structure has substantial descriptive capability and can provide clinically relevant predictions of respiratory inhibition in the non-steady-state to enhance safety of drug delivery in the anesthetic practice.

Drug-induced respiratory depression: an integrated model of drug effects on the hypercapnic and hypoxic drive.

Drug-induced respiratory depression is a common side effect of the agents used in anesthesia practice to provide analgesia and sedation. Depression of the ventilatory drive in the spontaneously breathing patient can lead to severe cardiorespiratory events and it is considered a primary cause of morbidity. Reliable predictions of respiratory inhibition in the clinical setting would therefore provide a valuable means to improve the safety of drug delivery. Although multiple studies investigated the regulation of breathing in man both in the presence and absence of ventilatory depressant drugs, a unified description of respiratory pharmacodynamics is not available. This study proposes a mathematical model of human metabolism and cardiorespiratory regulation integrating several isolated physiological and pharmacological aspects of acute drug-induced ventilatory depression into a single theoretical framework. The description of respiratory regulation has a parsimonious yet comprehensive structure with substantial predictive capability. Simulations relative to the synergistic interaction of the hypercarbic and hypoxic respiratory drive and the global effect of drugs on the control of breathing are in good agreement with published experimental data. Besides providing clinically relevant predictions of respiratory depression, the model can also serve as a test bed to investigate issues of drug tolerability and dose finding/control under non-steady-state conditions.

Experimental implementation of automatic 'cycle to cycle' control of a chiral simulated moving bed separation.

In the absence of a suitable controller, currently simulated moving beds (SMBs) are operated suboptimally to cope with system uncertainties and to guarantee robustness of operation. Recently, we have developed a 'cycle to cycle' optimizing controller that not only makes use of minimal system information, i.e. only the Henry constants and average bed voidage, but also optimizes the process performance and taps the full economic potential of the SMB technology. The experimental implementation of the 'cycle to cycle' optimizing controller had been carried out for achiral separation. For chiral separation however, application of any online controller has not been possible because an appropriate online monitoring system has not been available. This work reports and discusses the first experimental implementation of the 'cycle to cycle' optimizing control for chiral separations. A mixture of guaifenesin enantiomers is separated on Chiralcel OD columns with ethanol as mobile phase in a eight-column four sections laboratory SMB unit. The results show that the controller, although using minimal information about the retention of the two enantiomers, is able to meet product and process specifications, can optimize the process performance, and is capable of rejecting disturbances that may occur during the operation of the SMB plant.

The well-being model: a new drug interaction model for positive and negative effects.

BACKGROUND: Drugs are routinely combined in anesthesia and pain management to obtain an enhancement of the desired effects. However, a parallel enhancement of the undesired effects might take place as well, resulting in a limited therapeutic usefulness. Therefore, when addressing the question of optimal drug combinations, side effects must be taken into account. METHODS: By extension of a previously published interaction model, the authors propose a method to study drug interactions considering also their side effects. A general outcome parameter identified as patient's well-being is defined by superposition of positive and negative effects. Well-being response surfaces are computed and analyzed for varying drugs pharmacodynamics and interaction types. In particular, the existence of multiple maxima and of optimal drug combinations is investigated for the combination of two drugs. RESULTS: Both drug pharmacodynamics and interaction type affect the well-being surface and the deriving optimal combinations. The effect of the interaction parameters can be explained in terms of synergy and antagonism and remains unchanged for varying pharmacodynamics. For all simulations performed for the combination of two drugs, the presence of more than one maximum was never observed. CONCLUSIONS: The model is consistent with clinical knowledge and supports previously published experimental results on optimal drug combinations. This new framework improves understanding of the characteristics of drug combinations used in clinical practice and can be used in clinical research to identify optimal drug dosing.

Pharmacodynamic modelling of drug-induced ventilatory depression and automatic drug dosing in conscious sedation.

In conscious sedation (CS) procedures, the patient is sedated but retains the ability to breathe spontaneously. Drug-induced ventilatory depression represents a dangerous side effect of CS, possibly leading to hypoventilation and subsequent hypoxia. In this work, we propose a new pharmacodynamic model for drug-induced ventilatory depression. The model presents a parsimonious structure and shows good agreement with experimental data for different drugs. In addition, we explore the innovative idea of regulating drug infusion during CS by means of a feedback control system based on measurements of transcutaneous partial pressure of CO(2). In simulations, the controller proves able to maintain a predefined target of CO(2) despite pain, external disturbances and inter-patient variability in the sensibility to the drug. The implementation of the controller during CS procedures would improve clinical practice minimizing the occurrence of drug-induced ventilatory depression by tailoring drug infusion to patient's needs.

New multi-channel transcutaneous electrical stimulation technology for rehabilitation.

Transcutaneous (surface) electrical stimulation (TES) is a widely applied technique for muscle atrophy treatment, muscle force training, endurance training, pain treatment, functional movement therapy, and the restoration of motor functions. We present a new TES technology based on a multi-channel stimulation approach, which allows us to perform real-time spatial and temporal variations of the electrical current density on the skin surface and in deeper tissue layers. This new approach can generate a better muscle selectivity and improved muscle activation patterns compared to state of art TES systems, which operate with predetermined electrode positions. In simulations using a finite element model (FEM) of the distal arm we could show that the nerve activation in the muscle layer is not significantly influenced by the structure of the multi-channel electrode, if the gap between elements is less than 2 mm. Experiments in healthy volunteers allowed us to measure the selectivity of single finger activations. We could also show in stroke subjects that this novel multi-channel approach was able to generate selective finger and wrist extension movements that were strong enough to overcome flexion hyperactivity. For future applications in rehabilitation a full integration of the stimulation hardware into a garment sleeve would be helpful. Once fully integrated, this new technology has a high potential to increase the ease of use, stimulation and wear comfort. It is able to improve muscle selectivity compared to state of the art TES systems, and allows the implementation of a variety of new applications for the medical and consumer market.