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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. [ABSTRACT FROM AUTHOR]

Atrial Electrical Restitution Heterogeneity Introduction This study aims to characterize the regional variability in rate-adaptation in the atria. Methods and Results Action potential (AP) responses to pulses with uniform as well as pseudo-random non-uniform pacing intervals were recorded from rabbit sino-atrial node, right and left atrial pectinate as well as pulmonary vein antrum tissue preparations using conventional intracellular glass microelectrodes. Steady-state restitution curves were reconstructed for various AP waveform metrics. We observed significant variability between the four regions under basal pacing representing the rabbit resting heart rate as well as regional variability in rate-adaptation to increased pacing frequencies. Right-left atrial restitution differences were further confirmed using the non-uniform pacing protocol, with significant differences in AP amplitude, duration (APD) as well as maximum phase 0 depolarization rate restitution curves in response to an identical sequence of non-uniform pacing intervals. In addition, we report regional differences in alternans of AP waveform metrics, over a wide range of pacing frequencies and not simply prior to 1:1 entrainment being lost. We also observed an increase in APD90 along the conduction pathway from the left atrium to pulmonary vein junction. Conclusions Our results identified significant regional differences in electrical restitution in the rabbit atria and suggest their dependency on both baseline AP morphology and local intrinsic differences in rate-adaptation. We propose that the atrial heterogeneity in rate-adaptation could contribute to arrhythmogenesis and the greater susceptibility of pulmonary vein myocardial sleeves to ectopic foci and reentrant activity. [ABSTRACT FROM AUTHOR]

A generic cardiomyocyte ionic model, whose complexity lies between a simple phenomenological formulation and a biophysically detailed ionic membrane current description, is presented.Themodel provides a user-defined number of ionic currents, employing two-gate Hodgkin-Huxley type kinetics. Its generic nature allows accurate reconstruction of action potential waveforms recorded experimentally from a range of cardiac myocytes. Using a multiobjective optimisation approach, the generic ionic model was optimised to accurately reproduce multiple action potential waveforms recorded from central and peripheral sinoatrial nodes and right atrial and left atrial myocytes from rabbit cardiac tissue preparations, under different electrical stimulus protocols and pharmacological conditions. When fitted simultaneously to multiple datasets, the time course of several physiologically realistic ionic currents could be reconstructed. Model behaviours tend to be well identified when extra experimental information is incorporated into the optimisation. [ABSTRACT FROM AUTHOR]

In rat tail artery, activation of postjunctional α2-adrenoceptors by noradrenaline (NA) released from sympathetic axons produces a slow depolarization (NAD) of the smooth muscle through a decrease in K+ conductance. In this study we used intracellular recording to investigate whether the K+ channel involved is the ATP-sensitive K+ (KATP) channel. Changes in membrane resistance were monitored by measuring the time constant of decay of excitatory junction potentials. The KATP channel blockers, glibenclamide (10 μm) and PNU 37883A (5 μm), depolarized the smooth muscle and increased membrane resistance. Conversely, the KATP channel openers, pinacidil (0.1 and 0.5 μm) and levcromakalim (0.1 μm), hyperpolarized the smooth muscle and decreased membrane resistance. Activation of KATP channels with calcitonin gene-related peptide (CGRP; 10 nm) also hyperpolarized the smooth muscle and decreased membrane resistance. The NAD was abolished by both glibenclamide and PNU 37883A but was potentiated by CGRP. However, unlike CGRP, the directly acting KATP channel openers, pinacidil and levcromakalim, inhibited the NAD. The effects of other K+ channel blockers were also determined. A high concentration of Ba2+(1 mm), which would be expected to block KATP channels, abolished the NAD, whereas teteraethylammonium (1 mm) and 4-aminopyridine (1 mm) increased its amplitude. Apamin (0.5 μm) and a lower concentration of Ba2+ (0.1 mm) did not affect the NAD. These findings indicate that activation of α2-adrenoceptors by neurally released NA depolarizes the membrane of vascular smooth muscle by inhibiting KATP channels open in the resting membrane. [ABSTRACT FROM AUTHOR]

Liquid crystals (LCs) are recognised as an emerging type of responsive and functional materials that exhibit diverse technological applications. The spatial arrangement or alignment of LC molecules creates an optical anisotropy, which influences the propagation of light. This study presents an automated image processing algorithm designed to quantitatively assess LC alignment. The algorithm calculates the image structure tensor and computes a score ranging from 0 to 1 to represent the uniformity of LC alignment. The tool was verified on both artificially generated images of lines with pre-defined orientations and then tested on microscope images of LCs. For the latter, test samples of deformed helix ferroelectric LCs were constructed using three different alignment methods. Analysis of microscopic images of samples prepared utilising photoalignment, polymer rubbing, and oblique evaporation alignment techniques, determined average alignment scores (mean ± standard error of the mean) of 0.44 ± 0.03, 0.26 ± 0.1, and 0.17 ± 0.04, respectively, in comparison to commercially sourced control samples with a score of 0.64 ± 0.03 (n = 5 each). This study paves the way for automated objective assessment of LC alignment, a critical aspect to ensure the optimal performance, reliability, and efficiency of various devices and sensors relying on LC technology. • The structural arrangement or alignment of liquid crystal molecules underpins their functionality in a variety of devices. • This study presents an automated image processing algorithm designed to quantitatively assess liquid crystal alignment. • The algorithm was verified on artificially generated images of pre-defined lines and then tested on microscope images of LCs. • The algorithm was able to identify differences in liquid crystal samples prepared using a variety of alignment methods. [ABSTRACT FROM AUTHOR]

An in vitro preparation of the guinea-pig cornea was used to study the effects of the K+ channel blockers 4-aminopyridine (4-AP), tetraethylammonium (TEA) and Ba2+ on nerve terminal impulses (NTIs) recorded extracellularly from cold sensory receptors. These receptors have an ongoing discharge of NTIs that is increased by cooling and decreased by heating. The K+ channel blocker 4-AP reduced the negative amplitude of the diphasic (positive–negative) NTIs, whereas TEA and Ba2+ prolonged the duration of the negative component. As the shape of the NTI is determined by the first derivative (d V/d t) of the membrane voltage change, these changes in the negative component are consistent with the blockade of K+ channels that contribute to action potential repolarization. Only TEA changed the basal activity of the receptors, increasing the likelihood of burst discharges. Ba2+ selectively reduced the response of the receptors to heating, whereas neither 4-AP nor TEA modified the response to heating or to cooling. The findings indicate that K+ channels blocked by 4-AP, TEA and Ba2+ contribute to action potential repolarization in corneal cold receptors, and that ionic mechanisms that underlie the reduction in NTI frequency in response to heating differ from those that increase activity in response to cooling. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. • Cochlear mesenchymal cells can be targeted for gene electrotransfer via electric field compression using cochlear implants. • Regeneration of cochlear peripheral neurites after neurotrophin gene augmentation via bionic array-based electrotransfer. • Local recombinant neurotrophin expression enhances neural recruitment and electrically evoked auditory brainstem responses. • Bionic array directed gene electrotransfer requires low voltages albeit higher than existing cochlear implant capabilities. • Regulatory-permissive mini-plasmids free of antibiotic resistance genes achieve efficient gene expression in the cochlea. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]