Secondary flow in bifurcations - Important effects of curvature, bifurcation angle and stents.

Coronary bifurcations have complex flow patterns including secondary flow zones and helical flow, which directly affect pathophysiological mechanisms such as the development of atherosclerosis. The objective of this study was to generate insights into the effects of curvature, bifurcation angle and the presence of stents on flow patterns and resulting haemodynamics in coronary left main bifurcations. The blood flow and associated metrics were modelled in both idealised and patient-specific bifurcations with varying curvature and bifurcation angles with and without stents, resulting in a total of 128 geometries considered. The results showed that larger curvature of bifurcating vessels has a significant influence on secondary flow, especially with distance to the bifurcation region, causing a skew, spin and asymmetry of Dean vortices, an increase in helical flow intensity with symmetry loss, and a decrease in adversely low time-average wall shear stress (TAWSS). Generally, asymmetric flow patterns coincided with adversely low TAWSS regions. In identical stented geometries, the presence of the stents induced local recirculation immediately adjacent to the stent struts, thus generating adversely low TAWSS in these areas, with some effect on the overall secondary flow. Overall, the effect of stents outweighed the effect of curvature and BA. This new knowledge contributes to a better understanding of the joint effects of curvature, bifurcation angle, and stents on flow patterns and haemodynamics in coronary bifurcations.

A systematic review and computational modelling analysis of unilateral montages in electroconvulsive therapy.

OBJECTIVE: To examine the clinical outcomes of ECT unilateral placements compared in prior studies and apply insights from computational modelling to understand differences between placements. METHODS: PubMed, Embase, Scopus and PsycINFO and reference lists were systematically searched for studies of depressed patients where two unilateral placements were compared and clinical outcomes were reported. Computational modelling was done to generate electric field maps for each unilateral placement identified in the systematic review. RESULTS: A total of 29 studies met criteria for inclusion. Eight studies reported efficacy outcomes and 23 studies reported cognitive outcomes. Most studies found no significant difference in efficacy between right unilateral (RUL) and left unilateral (LUL) ECT, and no difference was found between temporo-parietal and fronto-temporal ECT. For the majority of studies, RUL placements had better verbal anterograde memory outcomes compared with the LUL placements. There was some evidence suggestive of cognitive advantages for fronto-frontal and fronto-parietal placements relative to temporo-parietal ECT. CONCLUSIONS: For efficacy, studies mainly focused on the comparison of right vs. left hemispheric stimulation, with the available evidence suggesting no substantive difference. RUL placements tended to have better verbal anterograde memory outcomes relative to LUL placements, though limited differences were found between the RUL placements.

Computational models of Bitemporal, Bifrontal and Right Unilateral ECT predict differential stimulation of brain regions associated with efficacy and cognitive side effects.

BACKGROUND: Extensive clinical research has shown that the efficacy and cognitive outcomes of electroconvulsive therapy (ECT) are determined, in part, by the type of electrode placement used. Bitemporal ECT (BT, stimulating electrodes placed bilaterally in the frontotemporal region) is the form of ECT with relatively potent clinical and cognitive side effects. However, the reasons for this are poorly understood. OBJECTIVE: This study used computational modelling to examine regional differences in brain excitation between BT, Bifrontal (BF) and Right Unilateral (RUL) ECT, currently the most clinically-used ECT placements. Specifically, by comparing similarities and differences in current distribution patterns between BT ECT and the other two placements, the study aimed to create an explanatory model of critical brain sites that mediate antidepressant efficacy and sites associated with cognitive, particularly memory, adverse effects. METHODS: High resolution finite element human head models were generated from MRI scans of three subjects. The models were used to compare differences in activation between the three ECT placements, using subtraction maps. RESULTS AND CONCLUSION: In this exploratory study on three realistic head models, Bitemporal ECT resulted in greater direct stimulation of deep midline structures and also left temporal and inferior frontal regions. Interpreted in light of existing knowledge on depressive pathophysiology and cognitive neuroanatomy, it is suggested that the former sites are related to efficacy and the latter to cognitive deficits. We hereby propose an approach using binarised subtraction models that can be used to optimise, and even individualise, ECT therapies.

Current steering for high resolution retinal implants.

To significantly increase the resolution achievable by a retinal prosthesis without requiring additional electrodes, a current steering technique could be utilized. In this study, a finite element model was constructed to analyze the local concentrations of charge carrying ions within a saline bath due to concurrent stimulation from two electrodes surrounded by a hexagonal arrangement of return electrodes. By altering the return pathways, tissue activation and identification of unique stimulation patterns is possible. Ag/Ag-Cl electrodes and a voltage controlled current source were developed to validate the finite element model, with the model accurately predicting saline bath measurements. The average error in the returned currents between the finite element model and experimental results was 2% relative to the stimulus current.

Simulation of left ventricle flow dynamics with dilated cardiomyopathy during the filling phase.

Dilated cardiomyopathy (DCM) is a common cardiac disease which leads to the deterioration in cardiac performance. A computational fluid dynamics (CFD) approach can be used to enhance our understanding of the disease, by providing us with a detailed map of the intraventricular flow and pressure distributions. In the present work, effect of ventricular size on the intraventricular flow dynamics and intraventricular pressure gradients (IVPGs) was studied using two different implementation methods, i.e. the geometry-prescribed and the fluid structure interaction (FSI) methods. Results showed that vortex strength and IVPGs are significantly reduced in a dilated heart, leading to an increased risk of thrombus formation and impaired ventricular filling. We suggest FSI method as the ultimate method in studying ventricular dysfunction as it provides additional cardiac disease prognostic factors and more realistic model implementation.

Fluid structure interaction simulation of left ventricular flow dynamics under left ventricular assist device support.

For patient's receiving mechanical circulatory support, malfunction of the left ventricular assist device (LVADs) as well as mal-positioning of the cannula imposes serious threats to their life. It is therefore important to characterize the flow pattern and pressure distribution within the ventricle in the presence of an LVAD. In this paper, we present a 2D axisymmetric fluid structure interaction model of the passive left ventricle (LV) incorporating an LVAD cannula to simulate the effect of the LVAD cannula placement on the vortex dynamics. Results showed that larger recirculation area was formed at the cannula tip with increasing cannula insertion depth, and this is believed to reduce the risk of thrombus formation. Furthermore, we also simulated suction events (collapse of the LV) by closing the inlet. Vortex patterns were significantly altered under this condition, and the greatest LV wall displacement was observed at the part of the myocardium closest to the cannula tip.

Electric crosstalk impairs spatial resolution of multi-electrode arrays in retinal implants.

Active multi-electrode arrays are used in vision prostheses, including optic nerve cuffs and cortical and retinal implants for stimulation of neural tissue. For retinal implants, arrays with up to 1500 electrodes are used in clinical trials. The ability to convey information with high spatial resolution is critical for these applications. To assess the extent to which spatial resolution is impaired by electric crosstalk, finite-element simulation of electric field distribution in a simplified passive tissue model of the retina is performed. The effects of electrode size, electrode spacing, distance to target cells, and electrode return configuration (monopolar, tripolar, hexagonal) on spatial resolution is investigated in the form of a mathematical model of electric field distribution. Results show that spatial resolution is impaired with increased distance from the electrode array to the target cells. This effect can be partly compensated by non-monopolar electrode configurations and larger electrode diameters, albeit at the expense of lower pixel densities due to larger covering areas by each stimulation electrode. In applications where multi-electrode arrays can be brought into close proximity to target cells, as presumably with epiretinal implants, smaller electrodes in monopolar configuration can provide the highest spatial resolution. However, if the implantation site is further from the target cells, as is the case in suprachoroidal approaches, hexagonally guarded electrode return configurations can convey higher spatial resolution.

Experimental validation of a polyvinylidene fluoride sensing element in a tactile sensor.

A tactile sensor for robotic applications is described, inspired by the mechanoreceptors in the glabrous skin of the human hand, in order to replicate the sensory function of both slow adapting and fast adapting mechanoreceptors. Strain gauges were used for the slow adapting receptors, and polyvinylidene fluoride (PVDF) film was used to replicate the fast adapting receptors. A finite element analysis (FEA) model was used to predict the output response of the PVDF film, and verified experimentally. The PVDF film was observed to respond linearly to mechanical stress and exhibited increased gain at higher frequencies. "Ramp and hold" stimuli were applied to the tactile unit sensor, and the PVDF film only responded at contact onset and offset, similar to the response of fast adapting receptors. The PVDF acted as a dynamic sensing element for the proposed tactile sensor unit.

Experimental validation of a tactile sensor model for a robotic hand.

We describe a tactile sensor for a robotic hand, based on the mechanoreceptors in the glabrous skin of the human hand to replicate the sensory function of both slow adapting and fast adapting receptors. Strain gauges are used for the slow adapting receptors, and polyvinylidene fluoride (PVDF) film was used to replicate the function of the fast adapting receptors. One unit sensor consisted of four strain gauges and a single PVDF film, embedded beneath a square protrusion. The protrusion helped localize the applied force onto the region or 'receptive field' of the sensing unit. Strain gauges were orientated to enable the unit sensor to identify the tri-axial force components. Multiple linear regression was used to predict the components of force. The regression model with interaction terms gave good prediction with mean percentage errors of less than 15% for each force component.

Charge recovery during concurrent stimulation for a vision prosthesis.

Parallel or concurrent stimulation in an epiretinal neuroprosthesis is likely necessary in order to deliver sufficient phosphenes for effective vision. Important issues with concurrent stimulation are the effect of current distribution which introduces current leakage or 'cross talk' between adjacent electrodes and charge recovery which determines balanced charge being delivered/recovered at each electrode from the previous phase. In this paper, we present the effect of concurrent stimulation of two hexagonally arranged platinum electrode arrays on charge recovery. Balanced and imbalanced (unequal) currents were delivered to the hexagonal arrays when they were immersed in physiological saline. Both simulation and experimental results revealed that charge was not recovered at individual electrodes, particularly when imbalanced currents were delivered. However, total charge injected to both hexagonal arrays was recovered.

Current distribution during parallel stimulation: implications for an epiretinal neuroprosthesis.

A simplified mathematical model has been developed in order to better understand local current spread when multiple simultaneous current sources are used in an epiretinal neuroprosthesis. To test the model, pairs of platinum electrodes of 430 μm diameter and an intra-pair spacing of 1 mm between centers, were arranged either in-line or in parallel, in a bath of physiological saline. Each pair was separated by distances from 1 mm to 6 mm. The currents in each electrode in the bath were measured and compared with the computational model of the same arrangement. This approach allowed us to quantify return current interaction between parallel sources. As predicted, with parallel electrodes and matching currents in each electrode pair, there is no current cross-talk. However with imbalanced current sources, significant cross-talk is evident. The cross-talk decreases as a function of electrode pair separation. The implication of this work in the design of an epiretinal neuroprosthesis is discussed.

An FPGA-Based Vision Prosthesis Prototype: Implementing an Efficient Multiplexing Method for Addressing Electrodes.

A prototype of an epi-retinal vision prosthesis based upon an efficient electrode addressing schema has been developed. This system has the ability to stimulate multiple electrode regions simultaneously, hence greatly improving the maximum rate of stimulation compared to many currently available neural stimulation devices based on serial stimulation protocols. To minimize the problem of cross talk between stimulating electrodes, a hexagon layout of electrodes was implemented. Basic tests were completed using a field programmable gate array logic system driving analogue circuitry to inject current into physiological saline via electrodes in hexagon arrangements and in a simple paired arrangement. The hexagon layout of electrodes was shown to clearly reduce the interaction between multiple current sources and hence cross talk.

Inhomogeneity of action potential waveshape assists frequency entrainment of cardiac pacemaker cells.

In this paper, we have employed ionic models of sinoatrial node cells to investigate the synchronization of a pair of coupled cardiac pacemaker cells from central and peripheral regions of the sinoatrial node. The free-running cycle length of the cell models was perturbed using two independent techniques and the minimum coupling conductance required to achieve frequency entrainment was used to assess the relative ease with which various cell pairs achieve entrainment. The factors effecting entrainment were further investigated using single-cell models paced with an artificial biphasic coupling current. Our simulation results suggest that dissimilar cell types, those with largely different upstroke velocities entrain more easily, that is, they require less coupling conductance to achieve 1:1 frequency entrainment. We, therefore, propose that regional variation in action-potential waveshape within the sinoatrial node assists frequency synchronization in vivo.

Vagal entrainment of heart rate is simulated by an integrator with feedback.

Paradoxical stable entrainment of heart rate to inhibitory vagal impulses can be simulated with two distinct mathematical models; a complex ionic current model of sinoatrial node pacemaker activity, as well as a simple integrator with non-linear feedback. We show that both models exhibit similar entrainment characteristics to repetitive vagal stimuli. By applying a sharp disturbance to each model whilst entrained, the subsequent path of cycle length recovery can be described by dynamic phase response curves and phase-phase plots, the properties of which dictate whether stable entrainment is possible.

Regional heterogeneity of function in nonischemic dilated cardiomyopathy.

OBJECTIVE: To quantify regional three-dimensional (3D) motion and myocardial strain using magnetic resonance (MR) tissue tagging in patients with non-ischemic dilated cardiomyopathy (DCM). METHODS: MR grid tagged images were obtained in multiple short- and long-axis planes in thirteen DCM patients. Regional 3D displacements and strains were calculated with the aid of a finite element model. Five of the patients were also imaged after LV volume reduction by partial left ventriculectomy (PLV), combined with mitral and tricuspid valve repair. RESULTS: DCM patients showed consistent, marked regional heterogeneity. Systolic lengthening occurred in the septum in both circumferential (%S(C) -5+/-7%) and longitudinal (%S(L) -2+/-5%) shortening components (negative values indicating lengthening). In contrast, the lateral wall showed relatively normal systolic shortening (%S(C) 12+/-6% and %S(L) 6+/-5%, P<0.001 lateral vs. septal walls). A geometric estimate of regional stress was correlated with shortening on a regional basis, but could not account for the differences in shortening between regions. In the five patients imaged post-PLV, septal function recovered (%S(C) 9+/-5%,%S(L) 6+/-5%, P<0.02 pre vs. post) with normalization of wall stress, whereas lateral wall shortening was reduced (%S(C) 7+/-6%,%S(L) 3+/-3%, P<0.02 pre vs. post) around the site of surgical resection. CONCLUSIONS: A consistent pattern of regional heterogeneity of myocardial strain was seen in all patients. Reduced function may be related to increased wall stress, since recovery of septal function is possible after PLV. However, simple geometric stress determinants are not sufficient to explain the functional heterogeneity observed.

A triaxial-measurement shear-test device for soft biological tissues.

A novel shear-test device for soft biological tissue, capable of applying simple shear deformations simultaneously in two orthogonal directions while measuring the resulting forces generated in three axes, is described. We validated the device using a synthetic gel, the properties of which were ascertained from independent tensile and rotational shear tests. Material parameters for the gel were fitted using neo-Hookean analytical solutions to the independent test data, and these matched the results from the device. Preliminary results obtained with rat septal myocardium are also presented to demonstrate the feasibility of the apparatus in determining the shear characteristics of living tissue.

Review of ionic models of vagal-cardiac pacemaker control.

Mathematical models of ion currents in pacemaker cells of the heart and their associated modulation by vagal stimulation have provided numerous insights into the ionic mechanisms underlying parasympathetic control of heart rate. In this article, ionic models described in the literature are reviewed and compared, with a view to examining their effectiveness in reproducing known chronotropic responses to vagal stimulation.

Simulations of postvagal tachycardia at the single cell pacemaker level: a new hypothesis.

Simulations performed on a single cell model of rabbit sinoatrial node activity after prolonged vagal stimulation have been able to reproduce the known characteristics of cycle length recovery, including the presence of rapid and slow recovery phases and the transient undershoot phenomenon known as postvagal tachycardia (PVT). In the model, the PVT component has been hypothesized to result from the recovery of background levels of the muscarinic K+ current iK,ACh from desensitization due to prolonged exposure to acetylcholine (ACh) neurotransmitter. Other components of the recovery were found to be due to the inactivation of iK,ACh after the hydrolysis of ACh (rapid phase) and the recovery of the hyperpolarizing-activated current i(f) from its ACh-induced inhibition (slow phase). The magnitudes of both the rapid component and the PVT were found to increase linearly with preceding vagally mediated increase in cycle length, whereas the gain of the slow component was found to saturate, reflecting the limited contribution of i(f) inhibition to cycle prolongation.

Vagal control of sinoatrial rhythm: a mathematical model.

The ionic mechanisms underlying vagal control of the cardiac pacemaker were investigated using a new single cell mathematical model of sinoatrial node electrical activity. The model was formulated from a wide range of electrophysiological data available in the literature, with particular reference to whole cell recordings from enzymatically isolated sinoatrial node cells. Development of the model was prompted by the lack of an existing physiologically accurate formulation of sinoatrial node activity that could reproduce the known complex chronotropic response of the pacemaker to brief-burst vagal stimulation, as observed in whole animal and isolated sinus node preparations. Features of the model include the dynamic modulation of the hyperpolarisation-activated current (i(f)) and the L-type calcium current (iCa,L) by acetylcholine, the improved characterisation of the muscarinic potassium current (iK,ACh), assigning the entire background potassium current (ib,K) to spontaneous openings of its channels, and the utilisation of second order kinetics for acetylcholine within the neuroeffector junction. Simulations performed using brief vagal stimuli elicited a strong hyperpolarisation of the membrane which prolonged the cycle in which it was delivered in a phase-dependent manner. This phase-dependency was presented in the form of a standard phase response curve which was characterised by a positive linear slope region, a breakpoint characteristic and a "no effect" zone in which the vagal pulse could no longer prolong the cycle. The breakpoint was manifested as a discontinuity in the curve which was examined by bracketing this point at the limit of the double precision arithmetic employed. At these boundary points on either side of the breakpoint, the vagal stimulus was able to activate outward iK,ACh in such a manner as to finely balance the increasing inward iCa,L trying to generate phase 0 upstroke. On decay of iK,ACh, the membrane either subsequently repolarised or fired to produce an action potential depending on the precise phase of the stimulus. The positive linear slope portion of the PRC was characterised by a strong resetting type behaviour in which the membrane hyperpolarised to approximately the same value, irrespective of the phase of stimulus delivery. For vagal stimulus bursts applied throughout the "no effect" zone, outward iK,ACh was not sufficiently activated in order to overcome the strong inward drive of iCa,L and could not prevent upstroke occurring. For these vagal stimuli, the subsequent cycle was hyperpolarised and prolonged. The size of the "no effect" zone was directly related to the inherent latency incorporated in the activation characteristic of iK,ACh. In contrast to previous models of vagal pacemaker control, our new model was able to reproduce the classical triphasic chronotropic response to brief vagal stimulation characterised by a primary inhibition response, a postinhibitory rebound and a secondary inhibition response. In particular, the postinhibitory rebound was due to activation of the inward hyperpolarisation-activated current by the vagally-induced membrane hyperpolarisation, whilst the secondary inhibition phase resulted from the inhibition of the hyperpolarisation-activated current by acetylcholine. The model suggests that the complex chronotropic responses of the cardiac pacemaker to brief vagal stimulation arises from inherent ionic mechanisms operating within the sinoatrial node.