Emerging trends in the development of flexible optrode arrays for electrophysiology.

Optical-electrode (optrode) arrays use light to modulate excitable biological tissues and/or transduce bioelectrical signals into the optical domain. Light offers several advantages over electrical wiring, including the ability to encode multiple data channels within a single beam. This approach is at the forefront of innovation aimed at increasing spatial resolution and channel count in multichannel electrophysiology systems. This review presents an overview of devices and material systems that utilize light for electrophysiology recording and stimulation. The work focuses on the current and emerging methods and their applications, and provides a detailed discussion of the design and fabrication of flexible arrayed devices. Optrode arrays feature components non-existent in conventional multi-electrode arrays, such as waveguides, optical circuitry, light-emitting diodes, and optoelectronic and light-sensitive functional materials, packaged in planar, penetrating, or endoscopic forms. Often these are combined with dielectric and conductive structures and, less frequently, with multi-functional sensors. While creating flexible optrode arrays is feasible and necessary to minimize tissue-device mechanical mismatch, key factors must be considered for regulatory approval and clinical use. These include the biocompatibility of optical and photonic components. Additionally, material selection should match the operating wavelength of the specific electrophysiology application, minimizing light scattering and optical losses under physiologically induced stresses and strains. Flexible and soft variants of traditionally rigid photonic circuitry for passive optical multiplexing should be developed to advance the field. We evaluate fabrication techniques against these requirements. We foresee a future whereby established telecommunications techniques are engineered into flexible optrode arrays to enable unprecedented large-scale high-resolution electrophysiology systems.

Modulating individual axons and axonal populations in the peripheral nerve using transverse intrafascicular multichannel electrodes.

Objective.A transverse intrafascicular multichannel electrode (TIME) may offer advantages over more conventional cuff electrodes including higher spatial selectivity and reduced stimulation charge requirements. However, the performance of TIME, especially in the context of non-conventional stimulation waveforms, remains relatively unexplored. As part of our overarching goal of investigating stimulation efficacy of TIME, we developed a computational toolkit that automates the creation and usage ofin siliconerve models with TIME setup, which solves nerve responses using cable equations and computes extracellular potentials using finite element method.Approach.We began by implementing a flexible and scalable Python/MATLAB-based toolkit for automatically creating models of nerve stimulation in the hybrid NEURON/COMSOL ecosystems. We then developed a sciatic nerve model containing 14 fascicles with 1,170 myelinated (A-type, 30%) and unmyelinated (C-type, 70%) fibers to study fiber responses over a variety of TIME arrangements (monopolar and hexapolar) and stimulation waveforms (kilohertz stimulation and cathodic ramp modulation).Main results.Our toolkit obviates the conventional need to re-create the same nerve in two disparate modeling environments and automates bi-directional transfer of results. Our population-based simulations suggested that kilohertz stimuli provide selective activation of targeted C fibers near the stimulating electrodes but also tended to activate non-targeted A fibers further away. However, C fiber selectivity can be enhanced by hexapolar TIME arrangements that confined the spatial extent of electrical stimuli. Improved upon prior findings, we devised a high-frequency waveform that incorporates cathodic DC ramp to completely remove undesirable onset responses.Conclusion.Our toolkit allows agile, iterative design cycles involving the nerve and TIME, while minimizing the potential operator errors during complex simulation. The nerve model created by our toolkit allowed us to study and optimize the design of next-generation intrafascicular implants for improved spatial and fiber-type selectivity.

Liquid crystal electro-optical transducers for electrophysiology sensing applications.

Objective.Biomedical instrumentation and clinical systems for electrophysiology rely on electrodes and wires for sensing and transmission of bioelectric signals. However, this electronic approach constrains bandwidth, signal conditioning circuit designs, and the number of channels in invasive or miniature devices. This paper demonstrates an alternative approach using light to sense and transmit the electrophysiological signals.Approach.We develop a sensing, passive, fluorophore-free optrode based on the birefringence property of liquid crystals (LCs) operating at the microscale.Main results.We show that these optrodes can have the appropriate linearity (µ± s.d.: 99.4 ± 0.5%,n = 11 devices), relative responsivity (µ± s.d.: 57 ± 12%V-1,n = 5 devices), and bandwidth (µ± s.d.: 11.1 ± 0.7 kHz,n = 7 devices) for transducing electrophysiology signals into the optical domain. We report capture of rabbit cardiac sinoatrial electrograms and stimulus-evoked compound action potentials from the rabbit sciatic nerve. We also demonstrate miniaturisation potential by fabricating multi-optrode arrays, by developing a process that automatically matches each transducer element area with that of its corresponding biological interface.Significance.Our method of employing LCs to convert bioelectric signals into the optical domain will pave the way for the deployment of high-bandwidth optical telecommunications techniques in ultra-miniature clinical diagnostic and research laboratory neural and cardiac interfaces.

Fluid structure computational model of simulating mitral valve motion in a contracting left ventricle.

BACKGROUND: Fluid structure interaction simulations h hold promise in studying normal and abnormal cardiac function, including the effect of fluid dynamics on mitral valve (MV) leaflet motion. The goal of this study was to develop a 3D fluid structure interaction computational model to simulate bileaflet MV when interacting with blood motion in left ventricle (LV). METHODS: The model consists of ideal geometric-shaped MV leaflets and the LV, with MV dimensions based on human anatomical measurements. An experimentally-based hyperelastic isotropic material was used to model the mechanical behaviour of the MV leaflets, with chordae tendineae and papillary muscle tips also incorporated. LV myocardial tissue was prescribed using a transverse isotropic hyperelastic formulation. Incompressible Navier-Stokes fluid formulations were used to govern the blood motion, and the Arbitrary Lagrangian Eulerian (ALE) method was employed to determine the mesh deformation of the fluid and solid domains due to trans-valvular pressure on MV boundaries and the resulting leaflet movement. RESULTS: The LV-MV generic model was able to reproduce physiological MV leaflet opening and closing profiles resulting from the time-varying atrial and ventricular pressures, as well as simulating normal and prolapsed MV states. Additionally, the model was able to simulate blood flow patterns after insertion of a prosthetic MV with and without left ventricular outflow tract flow obstruction. In the MV-LV normal model, the regurgitant blood flow fraction was 10.1 %, with no abnormality in cardiac function according to the mitral regurgitation severity grades reported by the American Society of Echocardiography. CONCLUSION: Our simulation approach provides insights into intraventricular fluid dynamics in a contracting LV with normal and prolapsed MV function, as well as aiding in the understanding of possible complications after transcatheter MV implantation prior to clinical trials.

Multiphysics Computational Modelling of the Cardiac Ventricles.

Development of cardiac multiphysics models has progressed significantly over the decades and simulations combining multiple physics interactions have become increasingly common. In this review, we summarise the progress in this field focusing on various approaches of integrating ventricular structures. electrophysiological properties, myocardial mechanics, as well as incorporating blood hemodynamics and the circulatory system. Common coupling approaches are discussed and compared, including the advantages and shortcomings of each. Currently used strategies for patient-specific implementations are highlighted and potential future improvements considered.

The role of regional myocardial topography post-myocardial infarction on infarct extension.

Infarct extension involves necrosis of healthy myocardium in the border zone (BZ), progressively enlarging the infarct zone (IZ) and recruiting the remote zone (RZ) into the BZ, eventually leading to heart failure. The mechanisms underlying infarct extension remain unclear, but myocyte stretching has been suggested as the most likely cause. Using human patient-specific left-ventricular (LV) numerical simulations established from cardiac magnetic resonance imaging (MRI) of myocardial infarction (MI) patients, the correlation between infarct extension and regional mechanics abnormality was investigated by analysing the fibre stress-strain loops (FSSLs). FSSL abnormality was characterised using the directional regional external work (DREW) index, which measures FSSL area and loop direction. Sensitivity studies were also performed to investigate the effect of infarct stiffness on regional myocardial mechanics and potential for infarct extension. We found that infarct extension was correlated to severely abnormal FSSL in the form of counter-clockwise loop at the RZ close to the infarct, as indicated by negative DREW values. In regions demonstrating negative DREW values, we observed substantial fibre stretching in the isovolumic relaxation (IVR) phase accompanied by a reduced rate of systolic shortening. Such stretching in IVR phase in part of the RZ was due to its inability to withstand the high LV pressure that was still present and possibly caused by regional myocardial stiffness inhomogeneity. Further analysis revealed that the occurrence of severely abnormal FSSL due to IVR fibre stretching near the RZ-BZ boundary was due to a large amount of surrounding infarcted tissue, or an excessively stiff IZ.

Predicting the outcome of transcatheter mitral valve implantation using image-based computational models.

BACKGROUND: The appropriate placement and size selection of mitral prostheses in transcatheter mitral valve implantation (TMVI) is critical, as encroachment on the left ventricular outflow tract (LVOT) may lead to flow obstruction. Recent advances in computed tomography (CT) can be employed for pre-procedural planning of mitral prosthetic valve placement. This study aims to develop patient-specific computational fluid dynamics models of the left ventricle (LV) in the presence of a mitral valve prosthesis to investigate blood flow and LVOT pressure gradient during systole. METHODS: Patient-specific computational fluid dynamics simulations of TMVI with varied cardiac anatomy and insertion angles were performed (n = 30). Wide-volume full cycle cardiovascular CT images prior to TMVI were used as source anatomical data (n = 6 patients). Blood movement was governed by Navier-Stokes equations and the LV endocardial wall deformation was derived from each patient's CT images. RESULTS: The computed pressure gradients in the presence of the mitral prosthesis compared well with clinically measured gradients. Analysis of the effects of prosthetic valve angulation, aorto-mitral annular angle, ejection fraction, LV size and new LVOT area (neo-LVOT) after TMVI in silico revealed that the neo-LVOT area (p < 0.001) was the most significant factor affecting LVOT pressure gradient. Angulation of the mitral valve can substantially mitigate LVOT gradient. CONCLUSIONS: Computational fluid dynamics simulation is a promising method to aid in pre-TMVI planning and understanding the factors underlying LVOT obstruction.

Computational Simulation Expands Understanding of Electrotransfer-Based Gene Augmentation for Enhancement of Neural Interfaces.

The neural interface is a critical factor in governing efficient and safe charge transfer between a stimulating electrode and biological tissue. The interface plays a crucial role in the efficacy of electric stimulation in chronic implants and both electromechanical properties and biological properties shape this. In the case of cochlear implants, it has long been recognized that neurotrophins can stimulate growth of the target auditory nerve fibers into a favorable apposition with the electrode array, and recently such arrays have been re-purposed to enable electrotransfer (electroporation)-based neurotrophin gene augmentation to improve the "bionic ear." For both this acute bionic array-directed electroporation and for chronic conventional cochlear implant arrays, the electric fields generated in target tissue during pulse delivery are central to efficacy, but are challenging to map. We present a computational model for predicting electric fields generated by array-driven DNA electrotransfer in the cochlea. The anatomically realistic model geometry was reconstructed from magnetic resonance images of the guinea pig cochlea and an eight-channel electrode array embedded within this geometry. The model incorporates a description of both Faradaic and non-Faradaic mechanisms occurring at the electrode-electrolyte interface with frequency dependency optimized to match experimental impedance spectrometry measurements. Our simulations predict that a tandem electrode configuration with four ganged cathodes and four ganged anodes produces three to fourfold larger area in target tissue where the electric field is within the range for successful gene transfer compared to an alternate paired anode-cathode electrode configuration. These findings matched in vivo transfection efficacy of a green fluorescent protein (GFP) reporter following array-driven electrotransfer of the reporter-encoding plasmid DNA. This confirms utility of the developed model as a tool to optimize the safety and efficacy of electrotransfer protocols for delivery of neurotrophin growth factors, with the ultimate aim of using gene augmentation approaches to improve the characteristics of the electrode-neural interfaces in chronically implanted neurostimulation devices.

Neurotrophin gene augmentation by electrotransfer to improve cochlear implant hearing outcomes.

This Review outlines the development of DNA-based therapeutics for treatment of hearing loss, and in particular, considers the potential to utilize the properties of recombinant neurotrophins to improve cochlear auditory (spiral ganglion) neuron survival and repair. This potential to reduce spiral ganglion neuron death and indeed re-grow the auditory nerve fibres has been the subject of considerable pre-clinical evaluation over decades with the view of improving the neural interface with cochlear implants. This provides the context for discussion about the development of a novel means of using cochlear implant electrode arrays for gene electrotransfer. Mesenchymal cells which line the cochlear perilymphatic compartment can be selectively transfected with (naked) plasmid DNA using array - based gene electrotransfer, termed 'close-field electroporation'. This technology is able to drive expression of brain derived neurotrophic factor (BDNF) in the deafened guinea pig model, causing re-growth of the spiral ganglion peripheral neurites towards the mesenchymla cells, and hence into close proximity with cochlear implant electrodes within scala tympani. This was associated with functional enhancement of the cochlear implant neural interface (lower neural recruitment thresholds and expanded dynamic range, measured using electrically - evoked auditory brainstem responses). The basis for the efficiency of close-field electroporation arises from the compression of the electric field in proximity to the ganged cochlear implant electrodes. The regions close to the array with highest field strength corresponded closely to the distribution of bioreporter cells (adherent human embryonic kidney (HEK293)) expressing green fluorescent reporter protein (GFP) following gene electrotransfer. The optimization of the gene electrotransfer parameters using this cell-based model correlated closely with in vitro and in vivo cochlear gene delivery outcomes. The migration of the cochlear implant electrode array-based gene electrotransfer platform towards a clinical trial for neurotrophin-based enhancement of cochlear implants is supported by availability of a novel regulatory compliant mini-plasmid DNA backbone (pFAR4; plasmid Free of Antibiotic Resistance v.4) which could be used to package a 'humanized' neurotrophin expression cassette. A reporter cassette packaged into pFAR4 produced prominent GFP expression in the guinea pig basal turn perilymphatic scalae. More broadly, close-field gene electrotransfer may lend itself to a spectrum of potential DNA therapeutics applications benefitting from titratable, localised, delivery of naked DNA, for gene augmentation, targeted gene regulation, or gene substitution strategies.

Mediating Retinal Ganglion Cell Spike Rates Using High-Frequency Electrical Stimulation.

Recent retinal studies have directed more attention to sophisticated stimulation strategies based on high-frequency (>1.0 kHz) electrical stimulation (HFS). In these studies, each retinal ganglion cell (RGC) type demonstrated a characteristic stimulus-strength-dependent response to HFS, offering the intriguing possibility of focally targeting retinal neurons to provide useful visual information by retinal prosthetics. Ionic mechanisms are known to affect the responses of electrogenic cells during electrical stimulation. However, how these mechanisms affect RGC responses is not well understood at present, particularly when applying HFS. Here, we investigate this issue via an in silico model of the RGC. We calibrate and validate the model using an in vitro retinal preparation. An RGC model based on accurate biophysics and realistic representation of cell morphology, was used to investigate how RGCs respond to HFS. The model was able to closely replicate the stimulus-strength-dependent suppression of RGC action potentials observed experimentally. Our results suggest that spike inhibition during HFS is due to local membrane hyperpolarization caused by outward membrane currents near the stimulus electrode. In addition, the extent of HFS-induced inhibition can be largely altered by the intrinsic properties of the inward sodium current. Finally, stimulus-strength-dependent suppression can be modulated by a wide range of stimulation frequencies, under generalized electrode placement conditions. In vitro experiments verified the computational modeling data. This modeling and experimental approach can be extended to further our understanding on the effects of novel stimulus strategies by simulating RGC stimulus-response profiles over a wider range of stimulation frequencies and electrode locations than have previously been explored.

Impact of myocardial infarction on intraventricular vortex and flow energetics assessed using computational simulations.

Flow energetics have been proposed as early indicators of progressive left ventricular (LV) functional impairment in patients with myocardial infarction (MI), but its correlation with individual MI parameters has not been fully explored. Using electro-fluid-structure interaction LV models, this study investigated the correlation between four MI parameters: infarct size, infarct multiplicity, regional enhancement of contractility at the viable myocardium area (RECVM), and LV mechanical dyssynchrony (LVMD) with intraventricular vortex and flow energetics. In LV with small infarcts, our results showed that infarct appearance amplified the energy dissipation index (DI), where substantial viscous energy loss was observed in areas with high flow velocity and near the infarct-vortex interface. The LV with small multiple infarcts and RECVM showed remarkable DI increment during systole and diastole. In correlation analysis, the systolic kinetic energy fluctuation index (E') was positively related to ejection fraction (EF) (R2  = 0.982) but negatively correlated with diastolic E' (R2  = 0.970). Diastolic E' was inversely correlated with vortex kinetic energy (R2  = 0.960) and vortex depth (R2  = 0.876). We showed an excessive systolic DI could differentiate infarcted LV with normal EF from healthy LV. Strong flow acceleration, LVMD, and vortex-infarct interactions were predominant factors that induced excessive DI in infarcted LVs. Instead of causing undesired flow turbulence, high systolic E' suggested the existence of energetic flow acceleration, while high diastolic E' implied an inefficient diastolic filling. Thus, systolic E' is not a suitable early indicator for progressive LV dysfunction in MI patients, while diastolic E' may be a useful index to indicate diastolic impairment in these patients.

Optimizing Stimulation Strategies for Retinal Electrical Stimulation: a Modelling Study.

In this research, a continuum multi-compartmental model of retinal electrical stimulation was utilized to find the best strategy for activating retinal ganglion cells (RGCs). Two types of return electrodes configuration placed suprachoroidally were used: monopolar and hexapolar. The current was delivered either simultaneously or sequentially with two kinds of waveforms: biphasic symmetric charge-balanced cathodic and anodic first pulses. Our results revealed there is no significant difference in current threshold between single monopolar and hexapolar stimulation regardless of the applied current stimulus waveform. Moreover, sequential stimulation for both monopolar or hexapolar was more effective in reducing current threshold than simultaneous stimulation when biphasic cathodic first pulses were used. Concurrent monopolar stimulation was significant in reducing the current threshold compared to single monopolar whereas concurrent hexapolar did not alter the current threshold. Overall, concurrent monopolar stimulation was efficacious in reducing current threshold regardless of the stimulus waveforms and sequential stimulation was more useful only with biphasic cathodic first pulses.

A Multiphysics Biventricular Cardiac Model: Simulations With a Left-Ventricular Assist Device.

Computational models have become essential in predicting medical device efficacy prior to clinical studies. To investigate the performance of a left-ventricular assist device (LVAD), a fully-coupled cardiac fluid-electromechanics finite element model was developed, incorporating electrical activation, passive and active myocardial mechanics, as well as blood hemodynamics solved simultaneously in an idealized biventricular geometry. Electrical activation was initiated using a simplified Purkinje network with one-way coupling to the surrounding myocardium. Phenomenological action potential and excitation-contraction equations were adapted to trigger myocardial contraction. Action potential propagation was formulated within a material frame to emulate gap junction-controlled propagation, such that the activation sequence was independent of myocardial deformation. Passive cardiac mechanics were governed by a transverse isotropic hyperelastic constitutive formulation. Blood velocity and pressure were determined by the incompressible Navier-Stokes formulations with a closed-loop Windkessel circuit governing the circulatory load. To investigate heart-LVAD interaction, we reduced the left ventricular (LV) contraction stress to mimic a failing heart, and inserted a LVAD cannula at the LV apex with continuous flow governing the outflow rate. A proportional controller was implemented to determine the pump motor voltage whilst maintaining pump motor speed. Following LVAD insertion, the model revealed a change in the LV pressure-volume loop shape from rectangular to triangular. At higher pump speeds, aortic ejection ceased and the LV decompressed to smaller end diastolic volumes. After multiple cycles, the LV cavity gradually collapsed along with a drop in pump motor current. The model was therefore able to predict ventricular collapse, indicating its utility for future development of control algorithms and pre-clinical testing of LVADs to avoid LV collapse in recipients.

A biopotential optrode array: operation principles and simulations.

We propose an optical electrode 'optrode' sensor array for biopotential measurements. The transduction mechanism is based on deformed helix ferroelectric liquid crystals which realign, altering the optrode's light reflectance properties, relative to applied potential fields of biological cells and tissue. A computational model of extracellular potential recording by the optrode including the electro-optical transduction mechanism is presented, using a combination of time-domain and frequency-domain finite element analysis. Simulations indicate that the device has appropriate temporal response to faithfully transduce neuronal spikes, and spatial resolution to capture impulse propagation along a single neuron. These simulations contribute to the development of multi-channel optrode arrays for spatio-temporal mapping of electric events in excitable biological tissue.

Quantitative analysis of intraventricular flow-energetics and vortex in ischaemic hearts.

OBJECTIVE: This study investigated the intraventricular flow dynamics in ischaemic heart disease patients. PATIENTS AND METHODS: Fourteen patients with normal ejection fraction and 16 patients with reduced ejection fraction were compared with 20 healthy individuals. Phase-contrast MRI was used to assess intraventricular flow variables and speckle-tracking echocardiography to assess myocardial strain and left ventricular (LV) dyssynchrony. Infarct size was acquired using delayed-enhancement MRI. RESULTS: The results obtained showed no significant differences in intraventricular flow variables between the healthy group and the patients with normal ejection fraction group, whereas considerable reductions in kinetic energy (KE) fluctuation index, E' (P<0.001) and vortex KE (P=0.003) were found in the patients with reduced ejection fraction group. In multivariate analysis, only vortex KE and infarct size were significantly related to LV ejection fraction (P<0.001); furthermore, vortex KE was correlated negatively with energy dissipation, energy dissipation index (r=-0.44, P=0.021). CONCLUSION: This study highlights that flow energetic indices have limited applicability as early predictors of LV progressive dysfunction, whereas vortex KE could be an alternative to LV performance.

A continuum model of electrical stimulation of multi-compartmental retinal ganglion cells.

A continuum multi-domain model of electrical stimulation of the retina is presented. Each point in the retinal ganglion cell layer could be thought of as representing a single cell, whose biophysics is described using a four-compartment formulation incorporating varying ion channel expressions in the soma, axon initial segment, dendrites and axon. Our continuum model was validated against a discrete morphologically-realistic OFF RGC model, using intra- and extra-cellular electrical stimulation scenarios. Simulations from the continuum model reproduced the same results as that of the discrete model. Our continuum model is the first multi-domain model to represent all main RGC compartments, not just the soma. Moreover, we demonstrated that this model allows the investigation of axonal activation which has been observed to influence the perception of phosphenes.

A generic cardiac biventricular fluid-electromechanics model.

We present a fully-coupled fluid-electromechanics model of the heart using a generic biventricular structure to provide a tool for future multiphysics interaction studies. A simplified Purkinje fibre structure was embedded within the myocardium along with transmural variation of action potential duration to obtain realistic activation and relaxation sequences. To ease computational requirements, phenomenological action potential and excitation-contraction formulations were chosen, and coupled to transverse isotropic hyperelastic myocardial material physics. The action potential propagation was discretised within the material frame to achieve electromechanical coupling with gap junction-controlled propagation. Blood haemodynamics was represented by incompressible Navier-Stokes equations, whereby, the endocardial displacement deforms the blood domain, whilst blood pressure and viscous stress exert load on the myocardium. Realistic electrical activation and relaxation sequences were achieved along with basic cardiac mechanical properties such as torsion and apex displacement. The pressure-volume loops for both ventricles matched known values, and vortex formation was noted during the filling phase. The model could facilitate a better understanding of multiphysics and biventricular interactions under pathologic conditions and help formulate better treatments.

Image-based fluid dynamics analysis of left ventricle outflow tract pressure gradient after deployment transcatheter mitral valve.

The goal of this study was to develop an image-based model to computational investigate blood flow and pressure gradients resulting from left ventricular (LV) wall motion after the implantation of a mitral valve (MV) prosthesis. Two image-based 3D models were reconstructed from multi-slice computed tomography images obtained from patients undergoing transcatheter MV replacement. Navier-Stokes equations were then used to compute the fluid motion. Outflow tract obstruction of the models with MV prosthesis were identified by calculating the difference between LV systolic and aortic pressures. It was found that computed outflow track obstruction compared well with actual obstruction data obtained from two patients. Our study indicates computational modeling can be a valuable tool to investigate the optimal placement of prosthetic valves guided by individualized anatomical data.

Differential effect of brief electrical stimulation on voltage-gated potassium channels.

Electrical stimulation of neuronal tissue is a promising strategy to treat a variety of neurological disorders. The mechanism of neuronal activation by external electrical stimulation is governed by voltage-gated ion channels. This stimulus, typically brief in nature, leads to membrane potential depolarization, which increases ion flow across the membrane by increasing the open probability of these voltage-gated channels. In spiking neurons, it is activation of voltage-gated sodium channels (NaV channels) that leads to action potential generation. However, several other types of voltage-gated channels are expressed that also respond to electrical stimulation. In this study, we examine the response of voltage-gated potassium channels (KV channels) to brief electrical stimulation by whole cell patch-clamp electrophysiology and computational modeling. We show that nonspiking amacrine neurons of the retina exhibit a large variety of responses to stimulation, driven by different KV-channel subtypes. Computational modeling reveals substantial differences in the response of specific KV-channel subtypes that is dependent on channel kinetics. This suggests that the expression levels of different KV-channel subtypes in retinal neurons are a crucial predictor of the response that can be obtained. These data expand our knowledge of the mechanisms of neuronal activation and suggest that KV-channel expression is an important determinant of the sensitivity of neurons to electrical stimulation.NEW & NOTEWORTHY This paper describes the response of various voltage-gated potassium channels (KV channels) to brief electrical stimulation, such as is applied during prosthetic electrical stimulation. We show that the pattern of response greatly varies between KV channel subtypes depending on activation and inactivation kinetics of each channel. Our data suggest that problems encountered when artificially stimulating neurons such as cessation in firing at high frequencies, or "fading," may be attributed to KV-channel activation.

The role of infarct transmural extent in infarct extension: A computational study.

Infarct extension, a process involving progressive extension of the infarct zone (IZ) into the normally perfused border zone (BZ), leads to continuous degradation of the myocardial function and adverse remodelling. Despite carrying a high risk of mortality, detailed understanding of the mechanisms leading to BZ hypoxia and infarct extension remains unexplored. In the present study, we developed a 3D truncated ellipsoidal left ventricular model incorporating realistic electromechanical properties and fibre orientation to examine the mechanical interaction among the remote, infarct and BZs in the presence of varying infarct transmural extent (TME). Localized highly abnormal systolic fibre stress was observed at the BZ, owing to the simultaneous presence of moderately increased stiffness and fibre strain at this region, caused by the mechanical tethering effect imposed by the overstretched IZ. Our simulations also demonstrated the greatest tethering effect and stress in BZ regions with fibre direction tangential to the BZ-remote zone boundary. This can be explained by the lower stiffness in the cross-fibre direction, which gave rise to a greater stretching of the IZ in this direction. The average fibre strain of the IZ, as well as the maximum stress in the sub-endocardial layer, increased steeply from 10% to 50% infarct TME, and slower thereafter. Based on our stress-strain loop analysis, we found impairment in the myocardial energy efficiency and elevated energy expenditure with increasing infarct TME, which we believe to place the BZ at further risk of hypoxia. Copyright © 2016 John Wiley & Sons, Ltd.