Effect of engineered anisotropy on the susceptibility of human pluripotent stem cell-derived ventricular cardiomyocytes to arrhythmias

Human (h) pluripotent stem cells (PSC) such as embryonic stem cells (ESC) can be directed into cardiomyocytes (CMs), representing a potential unlimited cell source for disease modeling, cardiotoxicity screening and myocardial repair. Although the electrophysiology of single hESC-CMs is now better defined, their multi-cellular arrhythmogenicity has not been thoroughly assessed due to the lack of a suitable experimental platform. Indeed, the generation of ventricular (V) fibrillation requires single-cell triggers as well as sustained multi-cellular reentrant events. Although native VCMs are aligned in a highly organized fashion such that electrical conduction is anisotropic for coordinated contractions, hESC-derived CM (hESC-CM) clusters are heterogenous and randomly organized, and therefore not representative of native conditions. Here, we reported that engineered alignment of hESC-VCMs on biomimetic grooves uniquely led to physiologically relevant responses. Aligned but not isotropic control preparations showed distinct longitudinal (L) and transverse (T) conduction velocities (CV), resembling the native human V anisotropic ratio (AR = LCV/TCV = 1.8–2.0). Importantly, the total incidence of spontaneous and inducible arrhythmias significantly reduced from 57% in controls to 17–23% of aligned preparations, thereby providing a physiological baseline for assessing arrhythmogenicity. As such, promotion of pro-arrhythmic effect (e.g., spatial dispersion by β adrenergic stimulation) could be better predicted. Mechanistically, such anisotropy-induced electrical stability was not due to maturation of the cellular properties of hESC-VCMs but their physical arrangement. In conclusion, not only do functional anisotropic hESC-VCMs engineered by multi-scale topography represent a more accurate model for efficacious drug discovery and development as well as arrhythmogenicity screening (of pharmacological and genetic factors), but our approach may also lead to future transplantable prototypes with improved efficacy and safety against arrhythmias.     

Age-related differences in sensorimotor representation of space in drawing by hand

Objective

To address the question of the space sensorimotor representation during hand-writing and its modifications with aging. We have chosen to study the drawing ellipses without visual guidance. We hypothesized that the decreased manual dexterity associated with aging could be attributed, in part, to the modification of space representation for action.

Methods

Young and elderly subjects drew ellipses with the tip of the index in the three anatomical planes: sagittal, frontal and horizontal. The 3D movements were recorded by a portable Video Recorder (3DVR) adapted to a clinical examination room with a natural light source.

Results

All subjects showed large disparities in errors in the various planes. Errors were maximal in the horizontal plane. These findings confirm the assumption of an anisotropic action-related representation of space when the movement is performed in a peripersonal frame of reference. Compared with young subjects, the results demonstrate that aging is associated with an important decreased ability to draw precisely ellipses in the three body-defined reference frames.

Conclusion

Space representation is altered with aging. This finding supports the idea that the central nervous system is apparently able to maintain hand-drawing performance at a good level independently of the anisotropic character of the egocentric space.

Significance

These findings may contribute to introducing new functional clinical tests and open new perspectives for future investigations on the age-related changes in hand function.     

Challenges for emerging neurostimulation-based therapies for real-time seizure control

In step with the worthwhile aim of this special issue, two junior investigators impart their insights on the therapeutic challenges imposed by pharmacoresistant epilepsies and offer viable approaches to improvement of treatment outcomes. Sunderam's comprehensive perspective addresses issues of critical importance for the design of efficacious therapies. Talathi delves into the thorny roles of so-called “interictal” spikes in ictio- and epileptogenesis, roles that are central to understanding the dynamics of these phenomena and implicitly of how to prevent them or abort them. First, however, Osorio and co-workers illustrate the complex behavior of the epileptogenic network and point to the importance of real-time intraindividual adaptation and optimization of therapies for seizures originating from the same epileptogenic network.     

Estimation of Cardiac Bidomain Parameters from Extracellular Measurement: Two Dimensional Study

Cardiac tissue conductivity measurements can be used to assess the electrical substrate underlying normal and abnormal wavefront propagation. We describe a method of solving the inverse cardiac bidomain model to estimate average longitudinal and transverse intra and extra-cellular conductivities and fiber angle relative to an electrode array placed arbitrarily on the epi- or endocardial surface. A Newton–Raphson reconstruction method and two Tikhonov-type regularizations were able to stably identify conductivities and fiber angles in tissue models having anisotropies similar to those in real cardiac tissue. The reconstruction methods were tested with data from increasingly realistic two dimensional cardiac bidomain models and performed well both when measurement noise was added, and when simulated experimental and forward model matching was diminished. This approach may be a suitable basis for continuous monitoring of myocardial condition in-vivo via a catheter based electrode array.     

Reduced Parameter Formulation for Incorporating Fiber Level Viscoelasticity into Tissue Level Biomechanical Models

Collagen is known to be a viscoelastic material and therefore is an important source of time dependent behavior in soft tissue. Though there are material models for soft tissue that rely on properties and structure of constituent collagen fibers, such models generally utilize only the elastic properties of collagen, and thus the resulting tissue level response does not possess any viscoelastic features. Here, the time dependent properties of collagen are directly incorporated into a fiber based hyperelastic model using the one dimensional theory of quasi-linear viscoelasticity within the context of a locally defined, anisotropic representation of extracellular matrix structure. The resulting model possesses seven material parameters and, using numerical and computational analysis, is shown to successfully predict many key features of soft tissue response including anisotropy, strain hardening, preconditioning, and rate independent hysteresis. A formulation is also introduced for incorporating fiber level viscoelasticity into structural models derived from a continuous representation of fiber structure.     

Developmental dyslexia and spatial relationship perception

According to wide literature, a global impairment in the temporal and spatial domains as well as an increased crowding effect is common of dyslexics. The aim of the study was to evaluate if such subjects suffer from a more general impairment of spatial relationship perception (SRP) and in particular from anomalous spatial relationship anisotropy (SRA) thus accounting both for their global perceptual distortions and abnormal crowding. SRP of 39 young disabled readers and 23 normal subjects were measured by a specifically designed psychophysical technique based on circular and elliptical target recognitions. A general impairment of SRP characterized by increased horizontal/vertical anisotropy was found in the dyslexic sample compared to the controls. In the second part of the experiment, reading efficiency and reading time were measured by MNREAD^© reading cards in standard conditions and after increasing horizontal spatial extension of the sentence by different values. We suppose this modification could well compensate the abnormal anisotropy found in dyslexics. Data obtained in the two groups were compared. A strong correlation between reading efficiency (a parameter we have specifically devised) and horizontal spatial text relationship values were present in the patients (r = .87, p < .01), but not in the controls. The same was found taking into consideration mean reading time (r = ?.82, p < .01). We therefore gather that an alteration of SRP, characterized by an increased anisotropy may be involved in developmental dyslexia.     

Computer aided diagnosis system for Alzheimer disease using brain diffusion tensor imaging features selected by Pearson's correlation

The aim of this paper is to obtain discriminant features from two scalar measures of Diffusion Tensor Imaging (DTI) data, Fractional Anisotropy (FA) and Mean Diffusivity (MD), and to train and test classifiers able to discriminate Alzheimer's Disease (AD) patients from controls on the basis of features extracted from the FA or MD volumes. In this study, support vector machine (SVM) classifier was trained and tested on FA and MD data. Feature selection is done computing the Pearson's correlation between FA or MD values at voxel site across subjects and the indicative variable specifying the subject class. Voxel sites with high absolute correlation are selected for feature extraction. Results are obtained over an on-going study in Hospital de Santiago Apostol collecting anatomical T1-weighted MRI volumes and DTI data from healthy control subjects and AD patients. FA features and a linear SVM classifier achieve perfect accuracy, sensitivity and specificity in several cross-validation studies, supporting the usefulness of DTI-derived features as an image-marker for AD and to the feasibility of building Computer Aided Diagnosis systems for AD based on them.     

Stiffening by fiber reinforcement in soft materials: a hyperelastic theory at large strains and its application

This work defines an incompressible, hyperelastic theory of anisotropic soft materials at finite strains, which is tested by application to the experimental response of fiber-reinforced rubber materials. The experimental characterization is performed using a uniaxial testing device with optical measures of the deformation, using two different reinforcing materials on a ground rubber matrix. In order to avoid non-physical responses of the underlying structural components of the material, the kinematics of the deformation are described using a novel deformation tensor, which ensures physical consistency at large strains. A constitutive relation for incompressible fiber-reinforced materials is presented, while issues of stability and ellipticity for the hyperelastic solution are considered to impose necessary restrictions on the constitutive parameters. The theoretical predictions of the proposed model are compared with the anisotropic experimental responses, showing high fitting accuracy in determining the mechanical parameters of the model. The constitutive theory is suitable to account for the anisotropic response at large compressive strains, opening perspectives for many applications in tissue engineering and biomechanics.