Ionic Current Flow Research Articles

Repair of traumatic plasmalemmal damage to neurons and other eukaryotic cells.

The repair (sealing) of plasmalemmal damage, consisting of small holes to complete transections, is critical for cell survival, especially for neurons that rarely regenerate cell bodies. We first describe and evaluate different measures of cell sealing. Some measures, including morphological/ultra-structural observations, membrane potential, and input resistance, provide very ambiguous assessments of plasmalemmal sealing. In contrast, measures of ionic current flow and dye barriers can, if appropriately used, provide more accurate assessments. We describe the effects of various substances (calcium, calpains, cytoskeletal proteins, ESCRT proteins, mUNC-13, NSF, PEG) and biochemical pathways (PKA, PKC, PLC, Epac, cytosolic oxidation) on plasmalemmal sealing probability, and suggest that substances, pathways, and cellular events associated with plasmalemmal sealing have undergone a very conservative evolution. During sealing, calcium ion influx mobilizes vesicles and other membranous structures (lysosomes, mitochondria, etc.) in a continuous fashion to form a vesicular plug that gradually restricts diffusion of increasingly smaller molecules and ions over a period of seconds to minutes. Furthermore, we find no direct evidence that sealing occurs through the collapse and fusion of severed plasmalemmal leaflets, or in a single step involving the fusion of one large wound vesicle with the nearby, undamaged plasmalemma. We describe how increases in perikaryal calcium levels following axonal transection account for observations that cell body survival decreases the closer an axon is transected to the perikaryon. Finally, we speculate on relationships between plasmalemmal sealing, Wallerian degeneration, and the ability of polyethylene glycol (PEG) to seal cell membranes and rejoin severed axonal ends – an important consideration for the future treatment of trauma to peripheral nerves. A better knowledge of biochemical pathways and cytoplasmic structures involved in plasmalemmal sealing might provide insights to develop treatments for traumatic nerve injuries, stroke, muscular dystrophy, and other pathologies.

Study on non-linear bistable dynamics model based EEG signal discrimination analysis method

Electroencephalogram (EEG) is the recording of electrical activity along the scalp. EEG measures voltage fluctuations generating from ionic current flows within the neurons of the brain. EEG signal is looked as one of the most important factors that will be focused in the next 20 years. In this paper, EEG signal discrimination based on non-linear bistable dynamical model was proposed. EEG signals were processed by non-linear bistable dynamical model, and features of EEG signals were characterized by coherence index. Experimental results showed that the proposed method could properly extract the features of different EEG signals.

Ivabradine: A Unique and Intriguing Medication for Treating Cardiovascular Disease.

There has been much research linking elevated resting heart rate to cardiovascular morbidity and mortality. Based on these findings, a lower resting heart rate would be of theoretical benefit in patients with cardiovascular disease. From a pathophysiologic perspective, a lower resting heart rate would be of particular benefit in patients with ischemic heart disease and/or heart failure. Although β-blockers and nondihydropyridine calcium channel blockers are effective at lowering heart rate, they have many other pharmacologic effects that may not be desirable in some patients, such as negative inotropy. Ivabradine is a drug designed to lower heart rate without any other demonstrable pharmacologic effects; in other words, a pure heart rate-lowering drug. It functions by blocking the hyperpolarization-activated cyclic nucleotide gated channels (f-channels) specific for the sinoatrial node and disrupting If ion current flow. This effectively prolongs diastolic depolarization and slows firing in the sinoatrial node, which lowers heart rate. The effects of ivabradine are most pronounced at higher heart rates (use-dependence), which is important in minimizing the development of symptomatic bradycardia. Clinical trials have demonstrated ivabradine to be an effective antianginal drug both alone and in combination with β-blocker therapy, although it has not been shown to produce a demonstrable effect on reducing major adverse cardiovascular events. In patients with heart failure, ivabradine has demonstrated many hemodynamic benefits, but its effect on clinical outcomes have been mixed and dependent on baseline heart rate, ie, the drug may be of benefit with higher baseline heart rates, but detrimental with low baseline heart rates. The adverse effects of ivabradine are not uncommon, but are rarely severe and include visual disturbances, bradycardia, and atrial fibrillation. Although ivabradine is a very interesting new agent, its variable benefits in large-scale clinical trials leave its exact place in therapy still somewhat nebulous. Unanswered questions include which patient populations would benefit most from this drug, and which concomitant medications would produce the best clinical outcomes when used with ivabradine.

Some fundamental properties for regular element of electroencephalography signals semigroup during epileptic seizure

Electroencephalography (EEG) is a record of electrical activity along the scalp. It is measures voltage fluctuations resulting from ionic current flows within the neurons of the brain. EEG is most often used to diagnose epilepsy, which causes understandable abnormalities in EEG readings. The mathematical analysis of EEG signals assists medical specialists by providing a clarification of the brain activity being observed, so increasing the information about the structure and function of the human brain. EEG signals during epileptic seizure can be viewed as a semigroup of square matrices under matrix multiplication, and every element in that semigroup is shown to be regular. In this paper, we will present some main properties of regular element of EEG signals during epileptic seizure.

Multistep current signal in protein translocation through graphene nanopores.

In nanopore sensing experiments, the properties of molecules are probed by the variation of ionic currents flowing through the nanopore. In this context, the electronic properties and the single-layer thickness of graphene constitute a major advantage for molecule characterization. Here we analyze the translocation pathway of the thioredoxin protein across a graphene nanopore, and the related ionic currents, by integrating two nonequilibrium molecular dynamics methods with a bioinformatic structural analysis. To obtain a qualitative picture of the translocation process and to identify salient features we performed unsupervised structural clustering on translocation conformations. This allowed us to identify some specific and robust translocation intermediates, characterized by significantly different ionic current flows. We found that the ion current strictly anticorrelates with the amount of pore occupancy by thioredoxin residues, providing a putative explanation of the multilevel current scenario observed in recently published translocation experiments.

Modeling of charge-mass transport in solid electrolyte-based electrochemical nanomanufacturing process

A numerical model was developed to capture the charge-mass transport in electrochemical nanomanufacturing processes based on mixed-conducting solid electrolyte material systems. This model was verified by the matching of numerical predictions and experimental measurements of process parameters. The model was also used to predict parameters affecting ionic current flow, and to study the temporal and spatial transport properties of solid electrolyte silver sulfide during an electrode dissolution process. Conditions in which phase separation could occur in silver sulfide were found. Enhanced transport properties due to confinement in lateral dimensions were also observed through the developed model.

Free-standing graphene membranes on glass nanopores for ionic current measurements

A method is established to reliably suspend graphene monolayers across glass nanopores as a simple, low cost platform to study ionic transport through graphene membranes. We systematically show that the graphene seals glass nanopore openings with areas ranging from 180 nm2 to 20 μm2, allowing detailed measurements of ionic current and transport through graphene. In combination with in situ Raman spectroscopy, we characterise the defects formed in ozone treated graphene, confirming an increase in ionic current flow with defect density. This highlights the potential of our method for studying single molecule sensing and filtration.

Nanoscale ion sequestration to determine the polarity selectivity of ion conductance in carriers and channels.

The nanoscale spacing between a tethered lipid bilayer membrane (tBLM) and its supporting gold electrode can be utilized to determine the polarity selectivity of the conduction of ion channels and ion carriers embedded in a membrane. The technique relies upon a bias voltage sequestering or eliminating ions, of a particular polarity, into or out of the aqueous electrolyte region between the gold electrode and the tethered membrane. A demonstration is given, using ac swept frequency impedance spectrometry, of the bias polarity dependence of the ionophore conductance of gramicidin A, a cationic selective channel, and valinomycin, a potassium ion selective carrier. We further use pulsed amperometry to show that the intrinsic voltage dependence of the ion conduction is actually selective of the polarity of the transported ion and not simply of the direction of the ionic current flow.

SECM imaging of the cut edge corrosion of galvanized steel as a function of pH

Scanning electrochemical microscopy (SECM) and the scanning vibrating electrode technique (SVET) were employed to identify the local reactivity and the cathodes and anodes on a cut edge of galvanized steel. The SECM was used in the amperometric feedback mode, using a redox mediator, for sensing the conductivity of the surface and also in the redox competition mode for locating the depletion of the cathodic reactant. Good agreement was observed in acidic solution between the location of the conductive regions of the surface and the depletion of oxygen estimated from amperometric lines across the cut edge. In nearly neutral medium, non-uniform activity of the steel surface was observed and correlated well with the ionic current flows in solution and with the accumulation of zinc corrosion products on steel. In alkaline medium the entire steel surface operated as electron source for the regeneration cycle of the redox mediator. Irrespective of the pH of the solution, a maximum of the feedback observed over the cut edge is consentaneous with the thermodynamic stability of iron in the reduced form. SECM provided useful information regarding the steel conductivity, whereas the zinc anodes could only be resolved by the SVET.

Neurovascular regulation is critical for metabolic recovery from spreading depression.

This scientific commentary refers to ‘Inverse neurovascular coupling to cortical spreading depolarizations in severe brain trauma’ by Hinzman et al. (doi:10.1093/awu241). Long after Leao’s 1944 description of spreading depression in rabbit neocortex, scepticism remained over whether this phenomenon could be evoked or observed in the human brain (Somjen, 2001). Although many investigations have been carried out into the initiation, occurrence and spread of spreading depression, the mechanisms of ionic current flow underlying depolarization, and treatment paradigms (Pietrobon and Moskowitz, 2014), it is only recently that recording and imaging techniques have been able to confirm the occurrence of spreading depression in damaged human cortex, particularly in conditions involving trauma, subarachnoid haemorrhage, stroke, and possibly migraine headache with aura (Lauritzen et al. , 2011; Eikermann-Haerter et al. , 2012; Woitzik et al. , 2013). The intense depolarization and loss of ionic gradients in large volumes of brain tissue experiencing spreading depression means that significant substrate and metabolic capacity is required to generate energy for cell recovery (Somjen, 2001). If this metabolic need is unmatched by substrate supply (through neurovascular induction of increased blood flow), then propagation of brain damage can occur (Hossmann, 1994). In this issue of Brain , Hinzman and colleagues report a critical deficit in neurovascular coupling when spreading depression occurs near a traumatic brain lesion, in which decreased blood flow occurs in response to spreading depression (i.e. inverse neurovascular coupling) instead of increased blood flow, limiting the brain’s ability to meet the intense metabolic demand (Hinzman et al. , 2014). Although Hinzman and colleagues’ combined blood flow and electrocorticographic (ECoG) recording techniques only effectively worked in 5 of 24 patients, the spectrum of enhanced versus inverted neurovascular coupling in these five patients provides us with excellent examples of how proximity to a developing brain …

In situ monitoring of the electrochemical reactivity of aluminium alloy AA6060 using the scanning vibrating electrode technique

Localized electrochemical activation of aluminium alloy AA6060 surfaces during immersion in chloride-containing aqueous solution has been characterised using the scanning vibrating electrode technique (SVET). Ionic current flows in the electrolyte phase adjacent to corroding microcells are imaged in situ, allowing their evolution with time to be monitored with spatial resolution. A heterogeneous response due to the presence of intermetallic inclusions in the material is found on AA6060 surfaces. The highly localized anodic activity was thus detected, which has been interpreted as a result of the galvanic coupling between the matrix and the intermetallic particles. Metallic inclusions behave cathodically whereas the aluminium matrix undergoes metal dissolution due to the activation of anodic sites in the proximity of those inclusions. Hydrolysis of aluminium ions leads to local acidification of the electrolyte adjacent to the anodic sites, and it is accompanied by hydrogen evolution.

Effects of temperature on simulated electrotonic potentials and their current kinetics of human motor axons at 20°C–42°C

To expand our studies on accommodation in human motor nerve axons, the effects of temperature on polarizing nodal and internodal electrotonic potentials and their current kinetics are investigated. The computations use our temperature dependent multi-layered model of the myelinated human motor nerve fiber and the temperature is increased from 20°C to 42°C. The results show that for temperatures from 28°C to 37°C, the polarizing electrotonic potentials almost coincide, as the kinetics of their ionic currents is changed a little. The normal (at 37°C) resting membrane potential is further depolarized or hyperpolarized during hypothermia (≤ 25°C) or hyperthermia (≥ 40°C), respectively and its change is determined by the flow of ionic currents through the internodal axolemma during the polarizing current stimuli. The polarizing electrotonic potentials are more altered during hypothermia and are most altered during hyperthermia. During hyperthermia, the depolarizing nodal and internodal electrotonic potentials are determined by the nodal slow (I Ks ) and internodal fast (I Kf ) and slow (I Ks ) potassium currents. The hyperpolarizing internodal electrotonic potentials are determined by the activation of internodal channels, which are different during hyperthermia at 40°C and 42°C. These potentials are determined by the internodal I Ks current at 40°C and by the internodal inward rectifier (I IR ) and leakage (I Lk ) currents at 42°C. The difference in accommodation to hyperpolarizing currents during focal and uniform hyperthermia at 42°C is discussed. The present results are essential for the interpretation of mechanisms of threshold electrotonus measurements in subjects with symptoms of cooling, warming and fever, which can result from alterations in body temperature.

Bias Modulated Scanning Ion Conductance Microscopy

Nanopipets are versatile tools for nanoscience, particularly when used in scanning ion conductance microscopy (SICM) to determine, in a noncontact manner, the topography of a sample. We present a new method, applying an oscillating bias between a quasi-reference counter electrode (QRCE) in the SICM nanopipet probe and a second QRCE in the bulk solution, to generate a feedback signal to control the distance between the end of a nanopipet and a surface. Both the amplitude and phase of the oscillating ion current, induced by the oscillating bias and extracted using a phase-sensitive detector, are shown to be sensitive to the probe-surface distance and are used to provide stable feedback signals. The phase signal is particularly sensitive at high frequencies of the oscillating bias (up to 30 kHz herein). This development eliminates the need to physically oscillate the probe to generate an oscillating ion current feedback signal, as needed for conventional SICM modes. Moreover, bias modulation allows a feedback signal to be generated without any net ion current flow, ensuring that any polarization of the quasi reference counter electrodes, electro-osmotic effects, and perturbations of the supporting electrolyte composition are minimized. Both feedback signals, magnitude and phase, are analyzed through approach curve measurements to different surfaces at a range of distinct frequencies and via impedance measurements at different distances from a surface. The bias modulated response is readily understood via a simple equivalent circuit model. Bias modulated (BM)-SICM is compared to conventional SICM imaging through measurements of substrates with distinct topographical features and yields equivalent results. Finally, BM-SICM with both amplitude and phase feedback is used for topographical imaging of subtle etch features in a calcite crystal surface. The 2 modes yield similar results, but phase-detection opens up the prospect of faster imaging.

Characterization of Protein Unfolding with Solid-state Nanopores

In this work, we review the process of protein unfolding characterized by a solid-state nanopore based device. The occupied or excluded volume of a protein molecule in a nanopore depends on the protein's conformation or shape. A folded protein has a larger excluded volume in a nanopore thus it blocks more ionic current flow than its unfolded form and produces a greater current blockage amplitude. The time duration a protein stays in a pore also depends on the protein's folding state. We use Bovine Serum Albumin (BSA) as a model protein to discuss this current blockage amplitude and the time duration associated with the protein unfolding process. BSA molecules were measured in folded, partially unfolded, and completely unfolded conformations in solid-state nanopores. We discuss experimental results, data analysis, and theoretical considerations of BSA protein unfolding measured with silicon nitride nanopores. We show this nanopore method is capable of characterizing a protein's unfolding process at single molecule level. Problems and future studies in characterization of protein unfolding using a solid-state nanopore device will also be discussed.

Cylindrical Silicon on Insulator Solid State Nanopores for Charge Selective Nanoparticle Filtering

Rapid separation of specific biomolecules like virions and other nanoparticles through a solid state nanopore is of vital importance to various biomedical applications and bioanalytical studies. Several factors such as external applied transmembrane voltages, particle size and surface charge density of the nanopore are being investigated to improve the separation efficiency. However, in most cases the transmembrane electric field is not strong enough to pull the particles into the pore. Our goal is to use a voltage bias applied to the substrate of our specific silicon-on-insulator nanopore to significantly increase the nanoparticle translocation rate through the aperture, enhancing the performance of the device as a particle-selective filter.The ability to apply a substrate bias to single silicon-on-insulator cylindrical nanopores via the top silicon layer offers a tremendous advantage over regular silicon nitride nanopores. Moreover, the nanopore process flow is compatible with standard cleanroom facilities allowing a similar high throughput fabrication. The buried oxide layer provides a robust etch stop for the nanopore membrane and the sub-100nm aperture size is precisely controlled by electron beam lithography and thermal oxidation.The applied substrate bias changes the transverse conductance of the nanopore at low electrolyte concentrations (<10-4M HCl) when the Debye length is comparable to the dimensions of the nanopore. The bias depletes or attracts the H+ ions, being theions contributing to the ionic current flow within the nanopore, thereby decreasing or increasing the ionic current. When a positive substrate bias is applied to silicon device layer, it attracts negative charged nanoparticles such as polystyrene beads, which subsequently pass through the pore and repel positively charged particles away from the aperture entrance, acting as a charge-selective filter.

Impulses and pressure waves cause excitement and conduction in the nervous system

It is general accepted, that nerval excitement and conduction is caused by voltage changes.However, the influx of fluid into an elastical tube releases impulses or pressure waves. Therefore an influx of ion currents, respectively fluid motions into the elastic neuronal cells and fibres also induce impulses. This motion of charge carriers are measured by voltage devices as oscillations or action potentials, but the voltage changes may be an epiphenomenon of the (mechanical) impulses.Impulse waves can have a high speed. As stiffer or inelastic a tube wall, the greater is the speed of the impulse. Myelin sheaths cause a significant stiffening of the nerve fibre wall and myelinated fibres have a conduction velocity up to 120m/s. The influx of fluid at the nodes of Ranvier intensifies periodically the impulse wave in the nerve fibres.The authors suggest that also the muscle end-plate acts as a conductor of axonal impulses to the inner of the muscle fibres and that the exocytosis of acetylcholine into the synaptic cleft may be an amplifier of the axonal impulse. It is discussed that intracellular actin filaments may also influence motions at the neuronal membrane.Many sensory nerve cells are excited due to exogenous or endogenous mechanical impulses. It may plausible that such impulses are conducted directly to the sensory nerve cell bodies in the dorsal root ganglia without the transformation in electric energy. Excitation conduction happens without noteworthy energy consumption because the flow of ion currents through the membranes takes place equivalent to the concentration gradient.Impulse waves cause short extensions of the lipid membranes of the cell- and fibres walls and therefore they can induce opening and closing of the included ion channels. This mechanism acts to “voltage gated” and “ligand-gated” channels likewise.The concept of neuronal impulses can be helpful to the understanding of other points of neurophysiology or neuronal diseases. This includes e.g., the brain concussion and pathohistological findings in Alzheimer dementia.To verify the concept of (mechanical) impulses in the nervous system it is necessary to carry out biophysical or mechanical investigations in very small dimensions and the authors hope to give for this a sufficient stimulus.

A high-level, simulator independent, Python library for simulating small networks of multicompartmental neurons

We present a high level, simulator independent, Python library for building simulations of small populations of multi-compartmental neurons, in which membrane voltage is calculated from individual ionic current flows. The API allows the user to quickly construct simulations of small populations of neurons and synaptic connections, with particular focus on: (1) allowing simulation specification, with visualisation and analysis in a minimal, clean, human readable language; (2) reduction of complex simulation tool chains to a single python script; (3) promoting reproducible research through automatic self-documentation; (4) encourage the re-use of morphologies, neurons and channels in a way that specific and stochastic variation in parameters is simple; (5) transparent handling of different units; (6) allowing the use of established formats, (e.g. NEURON nmodl files[1]); (7) simplifying the definition and sharing of new channel types, including the possibility to support other libraries and standards easily (e.g. PyNN[2], 9ML, NeuroML[3]). Consider the following example: “We would like to build a network, of 30 neurons. Each soma should be 20(± 3) µm diameter, and axons are 1000µm long, have a hillock of radius 5um for the first 10µm, then taper to a radius 0.3µm. We will use a single compartment for the soma, divide the hillock into compartments of length 1um, and the axon into 100 compartments. We will use the sodium and potassium voltage-gated channels as specified by the equations and parameters in paper X, but use 3 times the density of sodium channels on the hillock. The neurons should be connected by gap junctions, distributed according to algorithm Y, with resistances of 1±0.5G Ohm. The neurons also excite other neurons in the population with AMPA synapses, with a probability of connections between any pair of 20%. We will stimulate this network with NMDA synaptic input to ~50% of the neurons at fixed times, as well as different levels of step current injections to cell 12, and plot graphs of the ionic currents flowing across the membrane of cells 2, 12, and any cells that spike, as well as the membrane voltage of all the neurons. We want to compare with the case when the gap junctions have been blocked.” The library allows the specification of this complete simulation and visualisation of the results in a single Python file of less than 100 lines, only requiring a single command to run. It is designed to make it possible to specify connection algorithms, morphologies, channel descriptions and simulation parameters as high-level objects, such that they can be reused in other simulations, without the need to copy and paste code. Units are handled transparently, reports of the simulation setup are automatically generated, and a clean separation between of simulation and visualisation is achieved through a mechanism of 'tagging' in the framework. The library is based on standard Python libraries, (numpy, matplotlib), making it easy to integrate with other libraries. The framework is under active development, with a NEURON backend, currently supporting everything in the above example. A first release is intended for July 2012.

Balanced excitation and inhibition: Model based analysis of local field potentials

We have developed a model of the local field potential (LFP) based on the conservation of charge, the independence principle of ionic flows and the classical Hodgkin-Huxley (HH) type intracellular model of synaptic activity. Insights were gained through the simulation of the HH intracellular model on the nonlinear relationship between the balance of synaptic conductances and that of post-synaptic currents. The latter is dependent not only on the former, but also on the temporal lag between the excitatory and inhibitory conductances, as well as the strength of the afferent signal. The proposed LFP model provides a method for decomposing the LFP recordings near the soma of layer IV pyramidal neurons in the barrel cortex of anaesthetised rats into two highly correlated components with opposite polarity. The temporal dynamics and the proportional balance of the two components are comparable to the excitatory and inhibitory post-synaptic currents computed from the HH model. This suggests that the two components of the LFP reflect the underlying excitatory and inhibitory post-synaptic currents of the local neural population. We further used the model to decompose a sequence of evoked LFP responses under repetitive electrical stimulation (5Hz) of the whisker pad. We found that as neural responses adapted, the excitatory and inhibitory components also adapted proportionately, while the temporal lag between the onsets of the two components increased during frequency adaptation. Our results demonstrated that the balance between neural excitation and inhibition can be investigated using extracellular recordings. Extension of the model to incorporate multiple compartments should allow more quantitative interpretations of surface Electroencephalography (EEG) recordings into components reflecting the excitatory, inhibitory and passive ionic current flows generated by local neural populations.

The Role of Separators in Lithium-Ion Cell Safety

As the use of lithium-ion cells for high power applications becomes increasingly widespread, safety and reliability of these cells and battery packs is of paramount importance. Many of the multilayer separators are designed with a shutdown feature, where two of the layers have different phase transition temperatures. As the temperature of a cell increases, the lower melting component melts and fills the pores of the other solid layer and stops ion transport and current flow in the cell. Separator designs for ensuring safety should be considered for a specific battery size, application, and potential abuse scenarios. New designs, detailed modeling, and robust testing are all essential to ensure separators selected to meet both the performance and safety requirements for a given application. Ceramic/polymer composites and high melting point polymer materials offer some improvement in thermal stability and abuse tolerance for lithium-ion cell separators but, in general, there needs to be more evaluation work dedicated to quantifying the safety impact of new separators

Extracellular Electrical Fields Direct Wound Healing and Regeneration

Endogenous DC electric fields (EFs) are important, fundamental components of development, regeneration, and wound healing. The fields are the result of polarized ion transport and current flow through electrically conductive pathways. Nullification of endogenous EFs with pharmacological agents or applied EFs of opposite polarity disturbs the aforementioned processes, while enhancement increases the rate of wound closure and the extent of regeneration. EFs are applied to humans in the clinic, to provide an overwhelming signal for the enhancement of healing of chronic wounds. Although clinical trials, spanning a course of decades, have shown that applied EFs enhance healing of chronic wounds, the mechanisms by which cells sense and respond to these weak cues remains unknown. EFs are thought to influence many different processes in vivo. However, under more rigorously controlled conditions in vitro, applied EFs induce cellular polarity and direct migration and outgrowth. Here we review the generation of endogenous EFs, the results of their alteration, and the mechanisms by which cells may sense these weak fields. Understanding the mechanisms by which native and applied EFs direct development and repair will enable current and future therapeutic applications to be optimized.