Propagation Of Electrical Activity Research Articles

Molecular Regulation of Cardiac Conduction System Development.

The cardiac conduction system, composed of pacemaker cells and conducting cardiomyocytes, orchestrates the propagation of electrical activity to synchronize heartbeats. The conduction system plays a crucial role in the development of cardiac arrhythmias. In the embryo, the cells of the conduction system derive from the same cardiac progenitors as the contractile cardiomyocytes and and the key question is how this choice is made during development. This review focuses on recent advances in developmental biology using the mouse as animal model to better understand the cellular origin and molecular regulations that control morphogenesis of the cardiac conduction system, including the latest findings in single-cell transcriptomics. The conducting cell fate is acquired during development starting with pacemaking activity and last with the formation of a complex fast-conducting network. Cardiac conduction system morphogenesis is controlled by complex transcriptional and gene regulatory networks that differ in the components of the cardiac conduction system.

SIMULATION OF PREMATURE VENTRICULAR CONTRACTIONS IN PATIENT SPECIFIC BIDOMAIN VENTRICULAR MODEL

The goal of the study was to simulate electrical activation of the heart ventricles and corresponding body surface potentials (BSPs) during premature ventricular contractions (PVC) using the patient specific realistic homogeneous model of cardiac ventricles and the torso. Real position of the initial ectopic activation during PVC was determined by intracardial measurement in the upper part of the right ventricle near the His bundle and confirmed by successful catheter ablation of the PVC origin. Simulated electrical activation in the ventricular model was started at the position of the initial ectopic activation as well as at several other sites at various distances from this position. The propagation of electrical activation in the ventricular model was modeled using bidomain reaction-diffusion (RD) equations with the ionic transmembrane current density defined by the modified FitzHugh-Nagumo (FHN) equations. The torso was modeled as a homogeneous passive volume conductor. The RD equations were numerically solved in the Comsol Multiphysics environment. Simulated ECG signals and BSPs were compared with those measured during PVC in a real patient. The polarity and shape of simulated and measured ECG leads as well as the BSP distribution during the PVC were in best agreement when the stimulated region was less than 10 mm from the position of the initial ectopic activation.

Distinct connectivity patterns in human medial parietal cortices: Evidence from standardized connectivity map using cortico-cortical evoked potential

The medial parietal cortices are components of the default mode network (DMN), which are active in the resting state. The medial parietal cortices include the precuneus and the dorsal posterior cingulate cortex (dPCC). Few studies have mentioned differences in the connectivity in the medial parietal cortices, and these differences have not yet been precisely elucidated. Electrophysiological connectivity is essential for understanding cortical function or functional differences. Since little is known about electrophysiological connections from the medial parietal cortices in humans, we evaluated distinct connectivity patterns in the medial parietal cortices by constructing a standardized connectivity map using cortico-cortical evoked potential (CCEP). This study included nine patients with partial epilepsy or a brain tumor who underwent chronic intracranial electrode placement covering the medial parietal cortices. Single-pulse electrical stimuli were delivered to the medial parietal cortices (38 pairs of electrodes). Responses were standardized using the z-score of the baseline activity, and a response density map was constructed in the Montreal Neurological Institutes (MNI) space. The precuneus tended to connect with the inferior parietal lobule (IPL), the occipital cortex, superior parietal lobule (SPL), and the dorsal premotor area (PMd) (the four most active regions, in descending order), while the dPCC tended to connect to the middle cingulate cortex, SPL, precuneus, and IPL. The connectivity pattern differs significantly between the precuneus and dPCC stimulation (p<0.05). Regarding each part of the medial parietal cortices, the distributions of parts of CCEP responses resembled those of the functional connectivity database. Based on how the dPCC was connected to the medial frontal area, SPL, and IPL, its connectivity pattern could not be explained by DMN alone, but suggested a mixture of DMN and the frontoparietal cognitive network. These findings improve our understanding of the connectivity profile within the medial parietal cortices. The electrophysiological connectivity is the basis of propagation of electrical activities in patients with epilepsy. In addition, it helps us to better understand the epileptic network arising from the medial parietal cortices.

A Simulation Study on Electrical Activity of Ventricular Endocardial Tissue due to SCN5A L812Q Mutation.

Brugada Syndrome is a rare arrhythmia, hereditary in nature. It is caused due to mutation in genes that encodes sodium ion channels and it results sudden cardiac death in young adults. This paper aims to model a two dimensional SCN5A L812Q mutated endocardial tissue by modifying the model equations for sodium ion channel in the Ten Tusscher model for human ventricular tissue. Results show that the propagation of electrical activity in the mutated cells is slower when compared to the normal cells of the endocardial tissue. From this it is concluded that there is a large reduction of sodium current in the mutated region of the endocardial tissue. This leads to reduction in the total ionic current as well and further reduces the membrane potential. It also leads to the slower propagation of action potential in the mutated region when compared to the normal endocardial tissue.Clinical Relevance- This establishes the propagation of electrical activity in endocardial tissue for SCN5A L812Q gene mutation that results in arrhythmia called Brugada Syndrome.

On Electrical Spiking of Ganoderma resinaceum

Fungi exhibit action-potential like spiking activity. Up to date, most electrical activity of oyster fungi has been characterized in sufficient detail. It remains unclear if there are any patterns of electrical activity specific only for a certain set of species or if all fungi share the same “language” of electrical signalling. We use pairs of differential electrodes to record extracellular electrical activity of the antler-like sporocarps of the polypore fungus Ganoderma resinaceum. The patterns of the electrical activity are analyzed in terms of frequency of spiking and parameters of the spikes. The indicators of the propagation of electrical activity are also highlighted.

New Insights into the Development and Morphogenesis of the Cardiac Purkinje Fiber Network: Linking Architecture and Function.

The rapid propagation of electrical activity through the ventricular conduction system (VCS) controls spatiotemporal contraction of the ventricles. Cardiac conduction defects or arrhythmias in humans are often associated with mutations in key cardiac transcription factors that have been shown to play important roles in VCS morphogenesis in mice. Understanding of the mechanisms of VCS development is thus crucial to decipher the etiology of conduction disturbances in adults. During embryogenesis, the VCS, consisting of the His bundle, bundle branches, and the distal Purkinje network, originates from two independent progenitor populations in the primary ring and the ventricular trabeculae. Differentiation into fast-conducting cardiomyocytes occurs progressively as ventricles develop to form a unique electrical pathway at late fetal stages. The objectives of this review are to highlight the structure–function relationship between VCS morphogenesis and conduction defects and to discuss recent data on the origin and development of the VCS with a focus on the distal Purkinje fiber network.

Dual Color, Live Imaging of Vesicular Transport in Axons of Cultured Sensory Neurons.

The function of neurons in afferent reception, integration, and generation of electrical activity relies on their strikingly polarized organization, characterized by distinct membrane domains. These domains have different compositions resulting from a combination of selective targeting and retention of membrane proteins. In neurons, most proteins are delivered from their site of synthesis in the soma to the axon via anterograde vesicular transport and undergo retrograde transport for redistribution and/or lysosomal degradation. A key question is whether proteins destined for the same domain are transported in separate vesicles for local assembly or whether these proteins are pre-assembled and co-transported in the same vesicles for delivery to their cognate domains. To assess the content of transport vesicles, one strategy relies on staining of sciatic nerves after ligation, which drives the accumulation of anterogradely and retrogradely transported vesicles on the proximal and distal side of the ligature, respectively. This approach may not permit confident assessment of the nature of the intracellular vesicles identified by staining, and analysis is limited to the availability of suitable antibodies. Here, we use dual color live imaging of proteins labeled with different fluorescent tags, visualizing anterograde and retrograde axonal transport of several proteins simultaneously. These proteins were expressed in rat dorsal root ganglion (DRG) neurons cultured alone or with Schwann cells under myelinating conditions to assess whether glial cells modify the patterns of axonal transport. Advantages of this protocol are the dynamic identification of transport vesicles and characterization of their content for various proteins that is not limited by available antibodies.

Nkx2-5 defines distinct scaffold and recruitment phases during formation of the murine cardiac Purkinje fiber network

The ventricular conduction system coordinates heartbeats by rapid propagation of electrical activity through the Purkinje fiber (PF) network. PFs share common progenitors with contractile cardiomyocytes, yet the mechanisms of segregation and network morphogenesis are poorly understood. Here, we apply genetic fate mapping and temporal clonal analysis to identify murine cardiomyocytes committed to the PF lineage as early as E7.5. We find that a polyclonal PF network emerges by progressive recruitment of conductive precursors to this scaffold from a pool of bipotent progenitors. At late fetal stages, the segregation of conductive cells increases during a phase of rapid recruitment to build the definitive PF network through a non-cell autonomous mechanism. We also show that PF differentiation is impaired in Nkx2-5 haploinsufficient embryos leading to failure to extend the scaffold. In particular, late fetal recruitment fails, resulting in PF hypoplasia and persistence of bipotent progenitors. Our results identify how transcription factor dosage regulates cell fate divergence during distinct phases of PF network morphogenesis.

Acute Isolation of Cells from Murine Sino-atrial Node

The cardiac conduction system allows the synchronized propagation of electrical activity through heart muscle. This is initiated by the spontaneous activity of the specialized pacemaker cells of the sino-atrial node (SAN). The SAN region underlies automaticity in mammals and therefore has a crucial role in the pathogenesis of cardiac disorders such as arrhythmia. Isolation of SAN tissue and SAN cells is critical to advance our understanding of SAN structure and function in health and disease. Initially, isolation of SAN tissue and SAN cells was carried out in the rabbit owing to its larger size and similar electrical properties to human. This protocol was optimized by Mangoni and Nargeot (2001) for use in mice to take advantage of advancements in transgenic models. Here, we provide a step-by-step guide to dissecting the SAN tissue and isolating pacemaker cardiomyocytes from mouse hearts using an enzyme digestion approach.

Voltage Sensing Comes to Rest

Voltage sensing by ion channels is the key event enabling the generation and propagation of electrical activity in excitable cells. In this issue of Cell, Wisedchaisri etal. provide a structural view of a voltage-gated sodium channel in its resting closed conformation.

Analysis of Unipolar and Bipolar 4x4 EHG Signal for Classifying Uterine Contraction

Proper evaluation and detection of uterine contraction is an important treat during gestation period. Uterine contraction happens by the generation of electrical activity from a given myometrial cell to the adjacent cell. There are various methods for monitoring uterine contraction but they lack to distinguish true labour contractions (efficient) from contractions that will not cause delivery (inefficient). One of the most accurate non-invasive technique for monitoring uterine contraction is the uterine electromyogram or Electrohysterogram (EHG). The main aim of this paper is to check whether it is possible to discriminate labour and pregnancy contraction by using 16 electrode database. And also to check bipolar signals give better classification rate than monopolar signals. Result shows that bipolar signal have better performance than monopolar signals.

Coupled lattice Boltzmann simulation method for bidomain type models in cardiac electrophysiology with multiple time-delays

In this work, we propose a mathematical model of the cardiac electrophysiology which take into account time delays in signal transmission, in order to capture the whole activities of macro- to micro-scale transport processes, and use this model to analyze the propagation of electrophysiological waves in the heart by using a developed coupling Lattice Boltzmann Method (LBM). The propagation of electrical activity in the heart is mathematically modeled by a modified bidomain system. As transmembrane potential evolves, the domain has anisotropical properties which are transposed into intracellular and extracellular conductivity. The new bidomain system is a multi-scale, stiff and strongly nonlinear coupled reaction-diffusion model in the shape of a set of ordinary differential equations coupled with a set of partial differential equations with multiple time delays. Due to delays, dynamic and geometry complexity, numerical simulation and implementation of this type of coupled systems are very ambitious mathematical and computational problems but are crucial in several biomedical applications. We introduce a modified LBM scheme, reliable, efficient, stable and easy to implement in the context of such bidomain systems with multiple time delays. Numerical tests to confirm effectiveness and accuracy of our approach are provided and, the influence and impact of delays to restore normal heart rhythm are analyzed.

Mathematical modeling and analysis of dynamic effects of multiple time-varying delays on electrophysiological wave propagation in the heart

In this work, we propose a mathematical model of the cardiac electrophysiology which takes into account time delays in signal transmission, in order to capture the whole activities of macro- to micro-scale transport processes, and use this model to analyze the propagation of electrophysiological waves in the heart. The propagation of electrical activity in the heart is mathematically modeled by a modified bidomain system. As transmembrane potential evolves, the domain has anisotropical properties which are transposed into intracellular and extracellular conductivity. The new bidomain system is a multi-scale, stiff and strongly nonlinear coupled reaction–diffusion model in the shape of a set of ordinary differential equations coupled with a set of partial differential equations with multiple time delays. First, the mathematical models are introduced. Afterward the existence and uniqueness of solution of the state equation are proved as well as stability result. A numerical calculation is performed by using a coupling Lattice Boltzmann Method.

Mechanosensitive Gene Regulation by Myocardin-Related Transcription Factors Is Required for Cardiomyocyte Integrity in Load-Induced Ventricular Hypertrophy.

Hypertrophic cardiomyocyte growth and dysfunction accompany various forms of heart disease. The mechanisms responsible for transcriptional changes that affect cardiac physiology and the transition to heart failure are not well understood. The intercalated disc (ID) is a specialized intercellular junction coupling cardiomyocyte force transmission and propagation of electrical activity. The ID is gaining attention as a mechanosensitive signaling hub and hotspot for causative mutations in cardiomyopathy. Transmission electron microscopy, confocal microscopy, and single-molecule localization microscopy were used to examine changes in ID structure and protein localization in the murine and human heart. We conducted detailed cardiac functional assessment and transcriptional profiling of mice lacking myocardin-related transcription factor (MRTF)-A and MRTF-B specifically in adult cardiomyocytes to evaluate the role of mechanosensitive regulation of gene expression in load-induced ventricular remodeling. We found that MRTFs localize to IDs in the healthy human heart and accumulate in the nucleus in heart failure. Although mice lacking MRTFs in adult cardiomyocytes display normal cardiac physiology at baseline, pressure overload leads to rapid heart failure characterized by sarcomere disarray, ID disintegration, chamber dilation and wall thinning, cardiac functional decline, and partially penetrant acute lethality. Transcriptional profiling reveals a program of actin cytoskeleton and cardiomyocyte adhesion genes driven by MRTFs during pressure overload. Indeed, conspicuous remodeling of gap junctions at IDs identified by single-molecule localization microscopy may partially stem from a reduction in Mapre1 expression, which we show is a direct mechanosensitive MRTF target. Our study describes a novel paradigm in which MRTFs control an acute mechanosensitive signaling circuit that coordinates cross-talk between the actin and microtubule cytoskeleton and maintains ID integrity and cardiomyocyte homeostasis in heart disease.

Autaptic modulation-induced neuronal electrical activities and wave propagation on network under electromagnetic induction

Based on an improved HR neuron model, the effects of electrical and chemical autapses on the firing activities of single neurons are studied, and the wave propagation in forward feedback neural network is also discussed by considering autapstic regulation under different intensities of electromagnetic induction. It is found that the electrical activities of single neuron can be changed by exerting excitatory or inhibitory of electrical and chemical autapses. With different feedback gains of electromagnetic induction current, membrane potential shows the oscillatory solutions and steady states. Under the condition of different autapse or electromagnetic induction, the propagation of electrical activities caused by the central neuron is transformed in the forward feedback network. Moreover, the spatial synchronization of the network will be changed by choosing different coupling intensities and feedback gains. It is proved that the electrical and chemical autapses play a significant role in firing modes of single neuron and the wave propagation of the forward feedback networks under the electromagnetic induction.

Connexin 26 Expression in Mammalian Cardiomyocytes

Connexins are a family of membrane-spanning proteins named according to their molecular weight. They are known to form membrane channels mediating cell-cell communication, which play an essential role in the propagation of electrical activity in the heart. Cx26 has been described in a number of tissues but not in the heart, and its mutations are frequently associated with deafness and skin diseases. The aim of this study was to assess the possible Cx26 expression in heart tissues of different mammalian species and to demonstrate its localization at level of cardiomyocytes. Samples of pig, human and rat heart and H9c2 cells were used for our research. Immunohistochemical and molecular biology techniques were employed to test the expression of Cx26. Interestingly, this connexin was found in cardiomyocytes, at level of clusters scattered over the cell cytoplasm but not at level of the intercalated discs where the other cardiac connexins are usually located. Furthermore, the expression of Cx26 in H9c2 myoblast cells increased when they were differentiated into cardiac-like phenotype. To our knowledge, the expression of Cx26 in pig, human and rat has been demonstrated for the first time in the present paper.

Temporal requirement of Nkx2-5 during cardiac conduction system development

During cardiac development, transient invaginations of the myocardium, termed trabeculae, appear at the inner surface of the ventricles, which disappeared by compaction to form a functional ventricular wall. Trabeculae also contain progenitor cells of the ventricular conduction system (VCS), a complex network of Purkinje fibers driving the rapid propagation of electrical activity in the ventricles. Defects in ventricular compaction and conduction have been observed in patients and mutant mice carrying mutations in NKX2-5, encoding a key transcriptional regulator of heart development. In order to analyze the link between trabecular fate and VCS differentiation, we carried out genetic tracing and prospective clonal analyses of trabeculae using Cx40-CreERT2 mice and Rosa26-Confetti mice. Our results show that the peripheral VCS segregates progressively during embryonic development. Cells exclusively fated to give rise to the VCS are present in the trabecular compartment as early as E9.5. Specification of new conductive myocytes within the trabecular compartment during subsequent development contributes to the formation of a complex Purkinje fiber network at birth. We performed the same lineage tracing experiments in Nkx2-5 heterozygous mice with severe hypoplasia of the Purkinje fiber network at adult stages. The number of Purkinje fibers originating from early Nkx2-5 hapolinsufficient progenitors is identical to control. In contrast, at later stages of development, we observed an increase in the number of trabecular cells that do not give rise to Purkinje fibers. This suggests that Nkx2-5 controls the progressive recruitment of trabecular cells into the VCS as well as the later maintenance of the conductive phenotype. Overall our study highlights the early segregation of the VCS lineage at the onset of trabeculation and the later role of Nkx2-5 in formation of the Purkinje fiber network.

Potentially Pathological Alpha-Pattern as a Variant of Vigilance EEG in Drug-Resistant Epilepsy

As a result of pathomorphosis affecting the mechanisms of electrical activity generation interictal EEG may show reduced epileptiform changes whereas clinically apparent epileptic seizures may be present. In these cases patterns of dominant alpha activity are sometimes recorded on the scalp. In this study variations of alpha activity in patients with refractory epilepsy are classified. A group of 50 refractory epilepsy patients aged between 20 and 55 years who were submitted to Polenov Russian Scientific Research Institute of Neurosurgery in 2014-2017 was included in this study. They underwent scalp EEG as a part of their presurgical assessment. In 12 cases patterns of potentially pathological alpha activity were observed. Three variations of alpha-patterns were described: 1) alpha-rhythm with decreased regional diversity and a marked synchronization in temporal areas; 2) alpha-rhythm with reduced epileptiform complexes integrated into the spindles, 3) decelerated non-rhythmic alpha activity distorted by the higher frequency components. Distinguished varieties of potentially pathological alpha-activity according to their order here represent gradual functional decline of normal thalamo-cortical interaction. Considering clinical manifestation of drug-resistant epilepsy with frequent seizures in these patients, reported varieties of alpha activity can not be interpreted as Landolt’s syndrome (forced normalization of EEG). Invasive electrocorticographic monitoring demonstrated that bursts of sharpened polyphasic waves coinciding with alpha-rhythm on scalp EEG are consistent with epileptic discharges on the brain cortex surface. This allows to think of these components as correlates of epileptic activity. Therefore, on a number of occasions in patients with epilepsy a dissonance between clinical signs and electroencephalographic patterns recorded during restful wakefulness may be observed, when epileptiform components are absent or reduced to nonspecific complexes.

A framework for simulating gastric electrical propagation in confocal microscopy derived geometries.

Interstitial Cells of Cajal (ICC) initiate and actively propagate electrical events in the gastrointestinal tract known as slow-waves. The slow-waves coordinate the contraction of the gastrointestinal tract necessary for breakdown and mixing of ingested food. Degradation of the ICC numbers has been linked to several gastrointestinal motility disorders. However, limitations in imaging techniques and techniques for the quantification of ICC network structure have hindered our understanding of these disorders. We evaluated different machine learning techniques to segment ICC networks imaged using confocal microscopy. The accuracy the segmented networks were then quantified and compared using numerical metrics. Structurally realistic finite element meshes were constructed and used to simulate the propagation of electrical activation over the tissue blocks. The presented framework provides a system to quantify the structure and function of an ICC tissue sample. These methods are also applicable to other biological tissues and networks.

Investigation of action potential propagation in a syncytium

Certain excitable cells, such as those in cardiac and smooth muscle, are known to form electrical syncytia. Cells within a syncytium are coupled to adjacent cells by means of structures known as gap junctions, which provide electrical continuity between cells. This results in the spread and propagation of electrical activity, such as action potentials (APs), from the originating cell to other cells in its syncytium. We propose that this ability of APs to propagate through an electrical syncytium depends on various syncytial features, and also the AP profile. The current study attempts to investigate these various factors using a computational approach. Simulations were conducted on a model of a three-dimensional syncytium using the NEURON simulation platform. The results confirm that the capacity of action potentials to propagate in a syncytium is influenced by the features of the action potential, and also the arrangement of cells within the syncytium. The excitability of biophysically identical cells was found to differ based on the size of the syncytium, their location within it, and the extent of gap junctional coupling between neighboring cells. Only a window of gap junctional coupling levels allowed both the initiation and propagation of action potentials. The results clearly exhibit the role of AP diversity and syncytial features in determining the spread of action potentials. This has significant implications for understanding the functioning of syncytial tissues, such as the detrusor smooth muscle, both in physiology and in disease.