The Effects of Different Motor Teaching Strategies on Learning a Complex Motor Task.

During the learning of a new sensorimotor task, individuals are usually provided with instructional stimuli and relevant information about the target task. The inclusion of haptic devices in the study of this kind of learning has greatly helped in the understanding of how an individual can improve or acquire new skills. However, the way in which the information and stimuli are delivered has not been extensively explored. We have designed a challenging task with nonintuitive visuomotor perturbation that allows us to apply and compare different motor strategies to study the teaching process and to avoid the interference of previous knowledge present in the naïve subjects. Three subject groups participated in our experiment, where the learning by repetition without assistance, learning by repetition with assistance, and task Segmentation Learning techniques were performed with a haptic robot. Our results show that all the groups were able to successfully complete the task and that the subjects' performance during training and evaluation was not affected by modifying the teaching strategy. Nevertheless, our results indicate that the presented task design is useful for the study of sensorimotor teaching and that the presented metrics are suitable for exploring the evolution of the accuracy and precision during learning.

Does enforcing glenohumeral joint stability matter? A new rapid muscle redundancy solver highlights the importance of non-superficial shoulder muscles.

The complexity of the human shoulder girdle enables the large mobility of the upper extremity, but also introduces instability of the glenohumeral (GH) joint. Shoulder movements are generated by coordinating large superficial and deeper stabilizing muscles spanning numerous degrees-of-freedom. How shoulder muscles are coordinated to stabilize the movement of the GH joint remains widely unknown. Musculoskeletal simulations are powerful tools to gain insights into the actions of individual muscles and particularly of those that are difficult to measure. In this study, we analyze how enforcement of GH joint stability in a musculoskeletal model affects the estimates of individual muscle activity during shoulder movements. To estimate both muscle activity and GH stability from recorded shoulder movements, we developed a Rapid Muscle Redundancy (RMR) solver to include constraints on joint reaction forces (JRFs) from a musculoskeletal model. The RMR solver yields muscle activations and joint forces by minimizing the weighted sum of squared-activations, while matching experimental motion. We implemented three new features: first, computed muscle forces include active and passive fiber contributions; second, muscle activation rates are enforced to be physiological, and third, JRFs are efficiently formulated as linear functions of activations. Muscle activity from the RMR solver without GH stability was not different from the computed muscle control (CMC) algorithm and electromyography of superficial muscles. The efficiency of the solver enabled us to test over 3600 trials sampled within the uncertainty of the experimental movements to test the differences in muscle activity with and without GH joint stability enforced. We found that enforcing GH stability significantly increases the estimated activity of the rotator cuff muscles but not of most superficial muscles. Therefore, a comparison of shoulder model muscle activity to EMG measurements of superficial muscles alone is insufficient to validate the activity of rotator cuff muscles estimated from musculoskeletal models.

Challenges and solutions for application and wider adoption of wearable robots.

The science and technology of wearable robots are steadily advancing, and the use of such robots in our everyday life appears to be within reach. Nevertheless, widespread adoption of wearable robots should not be taken for granted, especially since many recent attempts to bring them to real-life applications resulted in mixed outcomes. The aim of this article is to address the current challenges that are limiting the application and wider adoption of wearable robots that are typically worn over the human body. We categorized the challenges into mechanical layout, actuation, sensing, body interface, control, human-robot interfacing and coadaptation, and benchmarking. For each category, we discuss specific challenges and the rationale for why solving them is important, followed by an overview of relevant recent works. We conclude with an opinion that summarizes possible solutions that could contribute to the wider adoption of wearable robots.

Binary and Hybrid Work-Condition Maps for Interactive Exploration of Ergonomic Human Arm Postures.

Ergonomics of human workers is one of the key elements in design and evaluation of production processes. Human ergonomics have a major impact on productivity as well as chronic health risks incurred by inappropriate working postures and conditions. In this paper we propose a novel method for estimating and communicating the ergonomic work condition called Binary Work-Condition Map, which provides a visualized feedback about work conditions of different configurations of an arm. The map is of binary nature and is derived by imposing the desired thresholds on considered ergonomic and safety related criteria. Therefore, the suggested arm postures in the map guarantee that all considered criteria are satisfied. This eliminates the ambiguity compared to state-of-the-art maps that uses continuous scales derived from weighted sum of multiple ergonomics criteria. In addition, to combine the advantages of both the binary map and the continuous map, we additionally propose a Hybrid Work-Condition Map that rules out unsuitable workspace with the binary map approach and renders the suitable workspace with the continuous map approach. The proposed approach was tested in simulation for various tasks and conditions. In addition, we conducted subjective evaluation experiments to compare the proposed methods with the state-of-the art method regarding the usability. The results indicated that the binary map is simpler to use, while the hybrid map is a good tradeoff between the binary and the continuous map. In selecting the map, strong points of each map should be considered with respect to the requirements of a specific application and task.

Target of initial sub-movement in multi-component arm-reaching strategy.

Goal-directed human reaching often involves multi-component strategy with sub-movements. In general, the initial sub-movement is fast and less precise to bring the limb's endpoint in the vicinity of the target as soon as possible. The final sub-movement then corrects the error accumulated during the previous sub-movement in order to reach the target. We investigate properties of a temporary target of the initial sub-movement. We hypothesise that the peak spatial dispersion of movement trajectories in the axis perpendicular to the movement is in front of the final reaching target, and that it indicates the temporary target of the initial sub-movement. The reasoning is that the dispersion accumulates, due to signal-dependent noise during the initial sub-movement, until the final corrective sub-movement is initiated, which then reduces the dispersion to successfully reach the actual target. We also hypothesise that the reaching movement distance and size of the actual target affect the properties of the temporary target of the initial sub-movement. The increased reaching movement distance increases the magnitude of peak dispersion and moves its location away from the actual target. On the other hand, the increased target size increases the magnitude of peak dispersion and moves its location closer to the actual target.

Assistive Arm-Exoskeleton Control Based on Human Muscular Manipulability.

This paper introduces a novel control framework for an arm exoskeleton that takes into account force of the human arm. In contrast to the conventional exoskeleton controllers where the assistance is provided without considering the human arm biomechanical force manipulability properties, we propose a control approach based on the arm muscular manipulability. The proposed control framework essentially reshapes the anisotropic force manipulability into the endpoint force manipulability that is invariant with respect to the direction in the entire workspace of the arm. This allows users of the exoskeleton to perform tasks effectively in the whole range of the workspace, even in areas that are normally unsuitable due to the low force manipulability of the human arm. We evaluated the proposed control framework with real robot experiments where subjects wearing an arm exoskeleton were asked to move a weight between several locations. The results show that the proposed control framework does not affect the normal movement behavior of the users while effectively reduces user effort in the area of low manipulability. Particularly, the proposed approach augments the human arm force manipulability to execute tasks equally well in the entire workspace of the arm.

Elucidating molecular properties of kappa-carrageenan as critical material attributes contributing to drug dissolution from pellets with a multivariate approach.

Multivariate data analysis (MVDA) and artificial neural networks (ANN) are supporting statistical methodologies required for successful development and manufacturing of drug products. To address this purpose, a complex dataset from 49 industrially produced capsules filled with pellets was first analyzed through the development of a multiple linear regression model focused on determining raw material attributes or process parameters with a significant impact on drug dissolution. Based on the model, the following molecular and micrometrics properties of κ-carrageenan have been identified as critical material attributes with the highest contribution to drug dissolution: molecular weight and polydispersity index, viscosity, content of potassium ions, wettability, particle size, and density. The process parameters identified to control the drug dissolution behavior of pellets were amount of granulation liquid, torque of dry blend, spheronization parameters, and yields after screening. To further scrutinize the dataset, an ANN model was subsequently built, incorporating 29 batches addressing drug particle size and process parameters such as torque during granulation and spheronization time as critical factors. Finally, this study demonstrates the ability of MVDA and ANN to allow prediction of the key performance drivers influencing the drug dissolution of industrially developed capsules filled with pellets and it highlights their complementary relationship.

Staying on your feet: the effectiveness of posture and handles in counteracting balance perturbation.

Stairways, public transport and inclined walkways are often considered as sites with higher likelihood of falls due to a sudden loss of balance. Such sites are usually marked with warning signs, equipped with non-slip surfaces and handles or handrails to avert or decrease this likelihood. Especially, handles are supposed to provide additional support in cases of a sudden loss of balance. However, the mechanisms of using handles for balance at different heights are not yet fully disclosed. We simulated full body perturbations by applying an anterior force to the waist and investigated effectiveness and mechanisms of balance recovery in five different postures: step stance and normal stance with or without holding handles at different heights. Results indicate that both step stance and holding handles at different vertical positions sufficiently assist balance recovery, compared to normal stance. While there was no significant effect of handle in CoM displacement, the shoulder height handle required the lowest handle force, indicating a difference in using the handle. Practitioner summary: To investigate handle use for balance recovery, we perturbed healthy young adults in different standing positions. Even though the use of different handles had a similar effect, the lowest forces were exerted on the shoulder height handle indicating a preferred handle position for balance recovery. Abbreviation: AP: antero-posterior; CNS: Central nervous system; CoM: Center of Mass; CoMmax: Maximal displacement of the center of mass; CoP: Center of pressure; FHmax: Maximal resultant force exerted on the handle; hFHmax: Maximal horizontal force exerted on the handle; vFHmax; Maximal vertical force exerted on the handle; M1-M8: Perturbation force magnitude.

Corrigendum: Unifying Speed-Accuracy Trade-Off and Cost-Benefit Trade-Off in Human Reaching Movements.

[This corrects the article on p. 615 in vol. 11, PMID: 29379424.].

Corrigendum: Unifying Speed-Accuracy Trade-Off and Cost-Benefit Trade-Off in Human Reaching Movements.

[This corrects the article on p. 615 in vol. 11, PMID: 29379424.].

A Human-Robot Co-Manipulation Approach Based on Human Sensorimotor Information.

This paper aims to improve the interaction and coordination between the human and the robot in cooperative execution of complex, powerful, and dynamic tasks. We propose a novel approach that integrates online information about the human motor function and manipulability properties into the hybrid controller of the assistive robot. Through this human-in-the-loop framework, the robot can adapt to the human motor behavior and provide the appropriate assistive response in different phases of the cooperative task. We experimentally evaluate the proposed approach in two human-robot co-manipulation tasks that require specific complementary behavior from the two agents. Results suggest that the proposed technique, which relies on a minimum degree of task-level pre-programming, can achieve an enhanced physical human-robot interaction performance and deliver appropriate level of assistance to the human operator.

Unifying Speed-Accuracy Trade-Off and Cost-Benefit Trade-Off in Human Reaching Movements.

Two basic trade-offs interact while our brain decides how to move our body. First, with the cost-benefit trade-off, the brain trades between the importance of moving faster toward a target that is more rewarding and the increased muscular cost resulting from a faster movement. Second, with the speed-accuracy trade-off, the brain trades between how accurate the movement needs to be and the time it takes to achieve such accuracy. So far, these two trade-offs have been well studied in isolation, despite their obvious interdependence. To overcome this limitation, we propose a new model that is able to simultaneously account for both trade-offs. The model assumes that the central nervous system maximizes the expected utility resulting from the potential reward and the cost over the repetition of many movements, taking into account the probability to miss the target. The resulting model is able to account for both the speed-accuracy and the cost-benefit trade-offs. To validate the proposed hypothesis, we confront the properties of the computational model to data from an experimental study where subjects have to reach for targets by performing arm movements in a horizontal plane. The results qualitatively show that the proposed model successfully accounts for both cost-benefit and speed-accuracy trade-offs.

Holding a Handle for Balance during Continuous Postural Perturbations-Immediate and Transitionary Effects on Whole Body Posture.

When balance is exposed to perturbations, hand contacts are often used to assist postural control. We investigated the immediate and the transitionary effects of supportive hand contacts during continuous anteroposterior perturbations of stance by automated waist-pulls. Ten young adults were perturbed for 5 min and required to maintain balance by holding to a stationary, shoulder-high handle and following its removal. Center of pressure (COP) displacement, hip, knee and ankle angles, leg and trunk muscle activity and handle contact forces were acquired. The analysis of results show that COP excursions are significantly smaller when the subjects utilize supportive hand contact and that the displacement of COP is strongly correlated to the perturbation force and significantly larger in the anterior than posterior direction. Regression analysis of hand forces revealed that subjects utilized the hand support significantly more during the posterior than anterior perturbations. Moreover, kinematical analysis showed that utilization of supportive hand contacts alter posture of the whole body and that postural readjustments after the release of the handle, occur at different time scales in the hip, knee and ankle joints. Overall, our findings show that supportive hand contacts are efficiently used for balance control during continuous postural perturbations and that utilization of a handle has significant immediate and transitionary effects on whole body posture.

Adaptive Control of Exoskeleton Robots for Periodic Assistive Behaviours Based on EMG Feedback Minimisation.

In this paper we propose an exoskeleton control method for adaptive learning of assistive joint torque profiles in periodic tasks. We use human muscle activity as feedback to adapt the assistive joint torque behaviour in a way that the muscle activity is minimised. The user can then relax while the exoskeleton takes over the task execution. If the task is altered and the existing assistive behaviour becomes inadequate, the exoskeleton gradually adapts to the new task execution so that the increased muscle activity caused by the new desired task can be reduced. The advantage of the proposed method is that it does not require biomechanical or dynamical models. Our proposed learning system uses Dynamical Movement Primitives (DMPs) as a trajectory generator and parameters of DMPs are modulated using Locally Weighted Regression. Then, the learning system is combined with adaptive oscillators that determine the phase and frequency of motion according to measured Electromyography (EMG) signals. We tested the method with real robot experiments where subjects wearing an elbow exoskeleton had to move an object of an unknown mass according to a predefined reference motion. We further evaluated the proposed approach on a whole-arm exoskeleton to show that it is able to adaptively derive assistive torques even for multiple-joint motion.

High-throughput automated dissolution method applicable for a wide dose range of controlled release pellets.

The aim of the present study was to demonstrate the application of an automated high-throughput (HT) dissolution method as a useful screening tool for characterization of controlled release pellets in the formulation development phase. Five controlled release pellet formulations with drug substances exhibiting high or low solubility were chosen to investigate the correlation of the automated HT dissolution method with the conventional dissolution testing. Overall, excellent correlations (R(2 )>( )0.96) between the HT and the conventional dissolution method were obtained. In one case the initial unsatisfactory correlation (R(2 )=( )0.84) and poor method agreement (SD = 12.5) was improved by optimizing the HT dissolution method with design of experiment approach. Here in comparison to initial experimental HT dissolution settings, increased amount of pellets (25% of the capsule filling mass), lower temperature (22 °C) and no shaking resulted in significantly better correlation (R(2 )=( )0.97) and method agreement (SD = 5.3). These results show that such optimization is valuable for the development of HT dissolution methods. In conclusion, the high correlation of dissolution profiles obtained from the conventional and the automated HT dissolution method combined with low within-sample and measurement system variability, justifies the utilization of the automated HT dissolution method during development phase of controlled release pellets.

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Levetiracetam.

Literature and experimental data relevant for the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing levetiracetam are reviewed. Data on solubility and permeability suggest that levetiracetam belongs to class I of the biopharmaceutical classification system (BCS). Levetiracetam's therapeutic use, its wide therapeutic index, and its favorable pharmacokinetic properties make levetiracetam a valid candidate for the BCS-based biowaiver approach. Further, no BE studies with levetiracetam IR formulations in which the test formulation failed to show BE with the comparator have been reported in the open literature. On the basis of the overall evidence, it appears unlikely that a BCS-based biowaiver approach for levetiracetam IR solid oral dosage forms formulated with established excipients would expose patients to undue risks. Thus, the BCS-based biowaiver approach procedure is recommended for IR solid oral dosage form containing levetiracetam, provided the excipients in the formulation are also present in products that have been approved in countries belonging to or associated with the International Committee on Harmonization and are used in their usual quantities, and provided the dissolution profiles of the test and reference product comply with the current requirements for BCS-based biowaivers.

The characterization of the human cell line Calu-3 under different culture conditions and its use as an optimized in vitro model to investigate bronchial epithelial function.

In this study we have investigated the effects of different cell culture conditions on the Calu-3 epithelial cell model. Calu-3 cells were cultured in media A-MEM at the air-liquid (A-L) or liquid-liquid (L-L) interface for one or three wks (weeks). Different cryomethods were tested and the cell line was characterized using histochemistry, immunofluorescence, transmission and scanning electron microscopy, transepithelial resistance (TEER) measurements, permeability studies, and gene profiling of 84 drug transporters. Cell culture was successful in A-MEM with only 2.5% FBS. Cell proliferation and viability depended on the cryopreservation method. All Calu-3 models expressed CK7, occludin, and E-cadherin. The A-L interface resulted in a more biomimetic native bronchial epithelium displaying pseudostratified columnar epithelium with more microvilli and secretory vesicles than at the L-L interface, where the epithelium was cuboidal, but exhibited higher TEER values and lower dextran permeabilities. Longer time in culture significantly decreased dextran permeability and increased the expression of specific drug transporters. Drug transporter expression was also notably influenced by the culture interface, where the A-L interface yielded a higher expression of drug transporter genes than the L-L interface. Since cell culture interface and time in culture affect Calu-3 cell differentiation, barrier integrity, permeability properties, and drug transporter expression, culture conditions need to be considered and standardized when using the Calu-3 cell line as an in vitro model for aerosol drug delivery and screening of bronchial drug candidates.

The characterization of the human nasal epithelial cell line RPMI 2650 under different culture conditions and their optimization for an appropriate in vitro nasal model.

PURPOSE: The further characterization of the cell line RPMI 2650 and the evaluation of different culture conditions for an in vitro model for nasal mucosa. METHODS: Cells were cultured in media MEM or A-MEM at air-liquid (A-L) or liquid-liquid (L-L) interfaces for 1 or 3 weeks. Different cryopreservation methods and cell culture techniques were evaluated with immunolabelling of junctional proteins, ultrastructural analysis using electron microscopy, transepithelial electrical resistance (TEER) measurements, permeation studies with dextran and jacalin, and gene expression profiling of 84 drug transporters. RESULTS: Cell proliferation and differentiation depended on the used medium. The established epithelia expressed occludin, claudin-1, and E-cadherin under all conditions. Cells grown at the A-L interface formed more layers and exhibited a higher TEER and lower dextran and jacalin permeability than at the L-L interface, where cells morphologically exhibited a more differentiated phenotype. The expression of ABC and SLC transporters depended on culture duration and interface. CONCLUSIONS: The RPMI 2650 cells form a polarized epithelium resembling nasal mucosa. However, different culture conditions have a significant effect on cell ultrastructure, barrier integrity, and gene expression, and should be considered when using this cell line as an in vitro model for drug permeability studies and screening of nasal drug candidates.

Effects of supportive hand contact on reactive postural control during support perturbations.

There are many everyday situations in which a supportive hand contact is required for an individual to counteract various postural perturbations. By emulating situations when balance of an individual is challenged, we examined functional role of supportive hand contact at different locations where balance of an individual was perturbed by translational perturbations of the support surface. We examined the effects of handle location, perturbation direction and perturbation intensity on the postural control and the forces generated in the handle. There were significantly larger centre-of-pressure (CoP) displacements for perturbations in posterior direction than for perturbations in anterior direction. Besides, the perturbation intensity significantly affected the peak CoP displacement in both perturbation directions. However, the position of the handle had no effects on the peak CoP displacement. On the contrary, there were significant effects of perturbation direction, perturbation intensity and handle position on the maximal force in the handle. The effect of the handle position was significant for the perturbations in posterior direction where the lowest maximal forces were recorded in the handle located at the shoulder height. They were comparable to the forces in the handle at eye height and significantly lower than the forces in the handle located either lower or further away from the shoulder. In summary, our results indicate that although the location of a supportive hand contact has no effect on the peak CoP displacement of healthy individuals, it affects the forces that an individual needs to exert on the handle in order to counteract support perturbations.

Evaluation of the light scattering and the turbidity microtiter plate-based methods for the detection of the excipient-mediated drug precipitation inhibition.

The excipient-mediated precipitation inhibition is classically determined by the quantification of the dissolved compound in the solution. In this study, two alternative approaches were evaluated, one is the light scattering (nephelometer) and other is the turbidity (plate reader) microtiter plate-based methods which are based on the quantification of the compound precipitate. Following the optimization of the nephelometer settings (beam focus, laser gain) and the experimental conditions, the screening of 23 excipients on the precipitation inhibition of poorly soluble fenofibrate and dipyridamole was performed. The light scattering method resulted in excellent correlation (r>0.91) between the calculated precipitation inhibitor parameters (PIPs) and the precipitation inhibition index (PI(classical)) obtained by the classical approach for fenofibrate and dipyridamole. Among the evaluated PIPs AUC100 (nephelometer) resulted in only four false positives and lack of false negatives. In the case of the turbidity-based method a good correlation of the PI(classical) was obtained for the PIP maximal optical density (OD(max), r=0.91), however, only for fenofibrate. In the case of the OD(max) (plate reader) five false positives and two false negatives were identified. In conclusion, the light scattering-based method outperformed the turbidity-based one and could be reliably used for identification of novel precipitation inhibitors.