Nerve Impulse Propagation Research Articles

Neosaxitoxin, a Paralytic Shellfish Poison toxin, effectively manages bucked shins pain, as a local long-acting pain blocker in an equine model

Local anesthesia is an effective method to control pain. Neosaxitoxin is a phycotoxin whose molecular mechanism includes a reversible inhibition of voltage–gated sodium channels at the axonal level, impeding nerve impulse propagation. The present study was designed to evaluate the clinical efficacy of Neosaxitoxin as a local long-acting pain blocker in horse bucked shins, and it was found to effectively control pain. While Neosaxitoxin and Gonyautoxin, another Paralytic Shellfish Poison (PSP) toxin, have been successfully used in humans as long-lasting pain blockers, this finding marks the first time a PSP has been shown to have an established effect in veterinary medicine.

The Generation of Nerve Impulse in Nerve Fiber Systems and its Transport Arising from the Bio-Energy Released by the Hydrolyses Reaction of ATP Molecules in Living Systems

The Generation of Nerve Impulse in Nerve Fiber Systems and its Transport Arising from the Bio-Energy Released by the Hydrolyses Reaction of ATP Molecules in Living Systems

Control of space-time chaos in a system of equations of the FitzHugh–Nagumo type

We perform an analytic and numerical study of a system of partial differential equations that describes the propagation of nerve impulses in the heart muscle. We show that, for fixed parameter values, the system has infinitely many distinct stable wave solutions running along the spatial axis at arbitrary velocities and infinitely many distinct modes of space-time chaos, where the bifurcation parameter is the velocity of running wave propagation along the spatial axis, which does not explicitly occur in the original system of equations. We suggest an algorithm for controlling the space-time chaos in the system, which permits one to stabilize any of its unstable periodic running waves.

Laser interference microscopy: a novel approach to the visualization of structural changes in myelin during the propagation of nerve impulses

We used 3D phase images obtained by laser interference microscopy (LIM) for ex vivo evaluation of changes in the structure of myelin during repetitive stimulation. In this work we propose a simple model of myelinated nerve fiber (mNF), which describes phase images as a result of different geometry and membrane-to-cytoplasm ratio in various regions, particularly, the internode and paranodal–nodal–paranodal region, including the node of Ranvier. Application of this model provides clear interpretation of the phase images and also demonstrates that repetitive action potentials are accompanied by structural changes in myelin in the internode and cytoplasmic modification in the node of Ranvier. The first 20 min of stimulation did not induce significant changes in the measured parameters, but then the optical path difference at the periphery of mNF and at the node of Ranvier declined reversibly. We believe that our model is also applicable to other modifications of interference and non-interference imaging.

Analogies between chemical and biological processes occurring in autowave mode

On the examples of frontal polymerization, tumor growth, and propagation of the nerve impulse, we examined nonlinear phenomena in chemistry and biology. The results of theoretical and experimental studies on the loss of stability of thermal waves of frontal polymerization were presented. The stationarity loss limits for the reactions of epoxide resin curing, polymerization of metal-containing acrylamide complexes, and copolymerization of methyl methacrylate and styrene in the presence of single-walled nanotubes were experimentally studied and theoretically calculated. It was shown that stability of the frontal process waves depends on the heat balance of the exothermic polymerization reaction. Nonlinear phenomena at variation of the polymerization kinetic parameters were studied. The limits of the transition from stationary to nonstationary mode were determined on the basis of experimental data and theoretical calculations. Theoretical study of a diffusion-kinetic model of tumor growth was discussed; the wave nature of the propagation of tumors was shown. The FitzHugh–Nagumo model was studied in view of the diffusion equation; the possibility of formation of the oscillatory modes during the nerve impulse propagation was demonstrated.

Spatio-temporal averaging for a class of hybrid systems and application to conductance-based neuron models

We obtain a limit theorem endowed with quantitative estimates for a general class of infinite dimensional hybrid processes with intrinsically two different time scales and including a population. As an application, we consider a large class of conductance-based neuron models describing the nerve impulse propagation along a neural cell at the scales of ion channels.

Beating of Gill Lateral Cell Cilia of Crassostrea virginica Involves Neuronal Innervation and the Presence of Gap Junctions

Suspension feeding bivalves use a ciliary pump driven by tracts of lateral cilia located on gill filaments to provide water currents for feeding, respiration and waste elimination. These cells in Crassostrea virginica are controlled by serotonergic‐dopaminergic innervation via the branchial nerve. Serotonin is the neurotransmitter that increases beating rates, while dopamine decreases it. Lateral cells of many other bivalves are similarly innervated. The cellular mechanism regulating lateral cell cilia beating is not fully explained. Second messenger systems are involved and gill filaments receive branches from the branchial nerve, but it is not known if each lateral cell is individually innervated. Lateral cells have gap junctions and questions arise if gap junctions are involved in controlling the rate or coordination of beating. We hypothesize gap junctions are involved in the cellular mechanism regulating lateral cell cilia beating rate and/or coordination to maintain the metachronal wave pattern. To study this we made immunohistological preparations using antibodies to visualize the gap junctions, and used the Sihler Whole Mount method to visualize nerves in gill filaments. We also set up preparations in which gill filaments were divided into proximal and distal sections by a petroleum jelly barrier, which prevented diffusion of drugs from one side to the other. We stimulated the branchial nerve entering the proximal end of the filaments with suction electrodes (5 hz, 2 msec, 10 – 20 volts), which causes a release of serotonin and increases beating rates. Stroboscopic microscopy was used to measure cilia beating rates. Drugs were applied to distal ends of preparations and beating rates of proximal and distal ends were compared. Applying procaine, a local anesthetic, to distal ends prevented electrical stimulation from increasing beating rates, while beating rate at the proximal ends increased, showing nerve impulse propagation is necessary for ciliary response. Using the same procedure, we tested 3 gap junction blockers, each with different mechanisms of action: lindane, diphenylborinic anhydride and mefloquine. Mefloquine had no effect on beating, but lindane and diphenylborinic anhydride both produced statistically significant reductions in beating rates at the distal ends. Lindane was stronger, causing a dose‐dependent (10−7 – 10−4M) blockage of beating, while diphenylborinic anhydride only blocked at a high dose of 10−4M. Results show neuronal innervation to filaments in conjunction with functioning gap junctions in the cells are necessary to increase cilia beating rates. Disrupting either one interfered with the normal response. Lindane is reported to reduce gap junction permeability and increase intracellular Ca2+ levels; either one or both of these actions may be responsible for the results we obtained.Support or Funding InformationThis work was supported in part by 2R25GM06003 of the Bridge Program of NIGMS and 0516041071 of NYSDOE.

Contactin-1 IgG4 antibodies cause paranode dismantling and conduction defects.

Paranodal axoglial junctions formed by the association of contactin-1, contactin-associated protein 1, and neurofascin-155, play important functions in nerve impulse propagation along myelinated axons. Autoantibodies to contactin-1 and neurofascin-155 define chronic inflammatory demyelinating polyradiculoneuropathy subsets of patients with specific clinical features. These autoantibodies are mostly of the IgG4 isotype, but their pathogenicity has not been proven. Here, we investigated the mechanisms how IgG subclasses to contactin-1 affect conduction. We show that purified anti-contactin-1 IgG1 and IgG4 bind to paranodes. To determine whether these isotypes can pass the paranodal barrier, we incubated isolated sciatic nerves with the purified antibody or performed intraneural injections. We found that IgG4 diffused into the paranodal regions in vitro or after intraneural injections. IgG4 infiltration was slow and progressive. In 24 h, IgG4 accessed the paranode borders near the nodal lumen, and completely fill the paranodal segments by 3 days. By contrast, control IgG, anti-contactin-1 IgG1, or even anti-contactin-associated-protein-2 IgG4 did not pass the paranodal barrier. To determine whether chronic exposure to these antibodies is pathogenic, we passively transferred anti-contactin-1 IgG1 and IgG4 into Lewis rats immunized with P2 peptide. IgG4 to contactin-1, but not IgG1, induced progressive clinical deteriorations combined with gait ataxia. No demyelination, axonal degeneration, or immune infiltration were observed. Instead, these animals presented a selective loss of the paranodal specialization in motor neurons characterized by the disappearance of the contactin-associated protein 1/contactin-1/neurofascin-155 complex at paranodes. Paranode destruction did not affect nodal specialization, but resulted in a moderate node lengthening. The sensory nerves and dorsal root ganglion were not affected in these animals. Electrophysiological examination further supported these results and revealed strong nerve activity loss affecting predominantly small diameter or slow conducting motor axons. These deficits partly matched with those found in patients: proximal motor involvement, gait ataxia, and a demyelinating neuropathy that showed early axonal features. The animal model thus seemed to replicate the early deteriorations in these patients and pointed out that paranodal loss in mature fibres results in conduction defects, but not conduction slowing. Our findings indicate that IgG4 directed against contactin-1 are pathogenic and are reliable biomarkers of a specific subset of chronic inflammatory demyelinating polyneuropathy patients. These antibodies appear to loosen the paranodal barrier, thereby favouring antibody progression and causing paranodal collapse.

The Pharmacokinetics of Potassium in Humans Is Unusual.

Potassium is critical for maintaining cellular tonicity, propagation of nerve impulses, contraction of cardiac, skeletal, and smooth muscles, and normal renal function. The focus of this review is on the pharmacokinetics of potassium, K(+) , after administration of liquid and solid formulations of potassium chloride, KCl, to healthy subjects. Potassium can be considered an endogenous and exogenous compound. The amounts of endogenous K(+) are kept constant by balancing intake and loss of exogenous K(+) . Food and ingestion of KCl-containing medicines are sources for exogenous K(+) . In the pharmacokinetic context exogenous K(+) from KCl-containing medicines, K(+) exo,dose , is of primary interest. The distinction between the different K(+) entities is critical for obtaining unbiased estimates of the kinetic parameters for K(+) exo,dose . A literature search using prespecified acceptance criteria was performed. Publications were selected that reported plasma and urine data of K(+) exo,dose directly or provided information allowing their determination. Additional criteria applied included that the studies used a randomized design and controlled for the important covariates. Most of the selected publications reported urinary excretion data. Only 2 publications also reported plasma concentrations. The excursions of the plasma concentrations of K(+) exo,dose were considered too small to be of use by most investigators. The aggregate results indicate that urinary recovery data have the potential for providing reliable estimates for bioavailability and bioequivalence of K(+) exo,dose with KCl-containing formulations. Absorption efficiency, peak rates, and corresponding times of K(+) exo,dose with liquid formulations are fairly consistent among studies. The mean absorption efficiency of K(+) exo,dose with solid and liquid formulations of KCl ranges between 70% and 90%. The absorption rate of liquid formulations is rapid, whereas the solid formulations show extended release characteristics. The time-averaged renal clearance of K(+) exo,dose is about 200 mL/min during daytime and significantly smaller around midnight. Circadian rhythm and delayed homeostatic control of potassium make the pharmacokinetics of K(+) exo,dose time dependent. The impact of these endogenous controls makes the pharmacokinetics of K(+) exo,dose unusual.

Glial Cells and Integrity of the Nervous System.

Today, there is enormous progress in understanding the function of glial cells, including astroglia, oligodendroglia, Schwann cells, and microglia. Around 150years ago, glia were viewed as a glue among neurons. During the course of the twentieth century, microglia were discovered and neuroscientists' views evolved toward considering glia only as auxiliary cells of neurons. However, over the last two to three decades, glial cells' importance has been reconsidered because of the evidence on their involvement in defining central nervous system architecture, brain metabolism, the survival of neurons, development and modulation of synaptic transmission, propagation of nerve impulses, and many other physiological functions. Furthermore, increasing evidence shows that glia are involved in the mechanisms of a broad spectrum of pathologies of the nervous system, including some psychiatric diseases, epilepsy, and neurodegenerative diseases to mention a few. It appears safe to say that no neurological disease can be understood without considering neuron-glia crosstalk. Thus, this book aims to show different roles played by glia in the healthy and diseased nervous system, highlighting some of their properties while considering that the various glial cell types are essential components not only for cell function and integration among neurons, but also for the emergence of important brain homeostasis.

Absence of galectin-3 attenuates neuroinflammation improving functional recovery after spinal cord injury.

After spinal cord injury (SCI), a cascade of events begins. At first, there is physical damage with disruption of the blood-brain barrier (BBB) and the integrity of the nervous tissue. The disruption of central nervous system (CNS) BBB alters the endothelial permeability, the protein and chemokines expression and the propensity to release in situ inflammatory cytokines, overcoming anti-inflammatory signals, facilitating the attraction and entry of immune system cells into the injured spinal cord parenchyma (Gaudet et al., 2011). As a result, there is a neuroinflammatory response with changes in blood flow, edema, cell infiltration, apoptosis and release of axonal growth inhibitory factors. Nerve function loss occurs when the nerve impulse propagation is interrupted and do not reach its target. This disorder encompasses neuron and glia apoptosis, accompanied by Wallerian degeneration of disconnected axons, and CNS cells exposure to a hostile microenvironment that hampers axon regeneration (Mautes et al., 2000; Harkey et al., 2003). Additionally, the damage spreads further in a phenomenon called progressive hemorrhagic necrosis – PHN, with the appearance of petechial hemorrhagic foci and deterioration in areas outside the lesion epicenter during the next 2 – 24 hours after the trauma (Simard et al., 2007). Our laboratory investigates the role of galectin-3, a protein linked to mechanisms of inflammation, behind the cellular mechanisms of neural degeneration/regeneration with perspectives of a novel treatment (Mostacada et al., 2015).

Asymptotic Approximation of the Stationary Solution with Internal Layer for FitzHugh–Nagumo System

Creating adequate mathematical models of processes in living nature is an important task of modern biophysics. Blood clotting, nerve impulse propagation, reduction of the heart muscle, the pattern-formation in nature are auto-wave processes. FitzHugh–Nagumo system of equations is used to describe the auto-wave processes in active media. Such math problems are usually solved by numerical methods. The use of resource-intensive algorithms is required in the case of auto-wave solutions with sharp gradients. Therefore, it is appropriate to use the analytical methods for this type of problems. In this paper, the asymptotic method of contrast structures theory is used to obtain an approximate solution of a singularly perturbed system of FitzHugh–Nagumo type. The method allows to reduce the non-linear system of equations to a number of problems that can be solved analytically or with a stable numerical algorithm. This study presents the asymptotic approximation of a stationary auto-wave solution of the considered system. Additionally, this paper provides a formula that specifies the location of internal transition layers. The results were compared with the numerical solution. The application of contrast structures theory to the study of active media models can be used for analytical studies of other such systems, improving existing models and increasing the efficiency of the numerical calculations.

Existence of Periodic Solutions of the FitzHugh--Nagumo Equations for an Explicit Range of the Small Parameter

The FitzHugh-Nagumo model describing propagation of nerve impulses in axon is given by fast-slow reaction-diffusion equations, with dependence on a parameter $\epsilon$ representing the ratio of time scales. It is well known that for all sufficiently small $\epsilon>0$ the system possesses a periodic traveling wave. With aid of computer-assisted rigorous computations, we prove the existence of this periodic orbit in the traveling wave equation for an explicit range $\epsilon \in (0, 0.0015]$. Our approach is based on a novel method of combination of topological techniques of covering relations and isolating segments, for which we provide a self-contained theory. We show that the range of existence is wide enough, so the upper bound can be reached by standard validated continuation procedures. In particular, for the range $\epsilon \in [1.5 \times 10^{-4}, 0.0015]$ we perform a rigorous continuation based on covering relations and not specifically tailored to the fast-slow setting. Moreover, we confirm that for $\epsilon=0.0015$ the classical interval Newton-Moore method applied to a sequence of Poincar\'e maps already succeeds. Techniques described in this paper can be adapted to other fast-slow systems of similar structure.

MECANISMOS DE DEPENDÊNCIA QUÍMICA NO TABAGISMO: REVISÃO DA LITERATURA

Introdução: O tabagismo está associado à dependência química da nicotina, a qual leva o fumante a manifestar características de abstinência, tolerância e abandono de atividades sociais. O fumo é também influenciado por fatores bioquímicos, genéticos e ambientais. Objetivo: Abordar os principais mecanismos de dependência química relacionados ao tabagismo. Metodologia: Foi realizada consulta à literatura médica através de meios eletrônicos e físicos. A consulta por meios eletrônicos se desenvolveu através de pesquisas nas bases de dados MEDLINE, LILACS e SciELO. Nas bases MEDLINE e LILACS foi utilizado como descritor “transtorno por uso de tabaco” (“tobacco use disorder”). Discussão: O mecanismo de dependência se relaciona com o alto poder de difusão da nicotina pelos alvéolos pulmonares e sua interação com receptores colinérgicos nicotínicos (nAchR) centrais. Isso possibilita indução e propagação do impulso nervoso até o sistema de recompensa cerebral, contribuindo com efeitos momentâneos de euforia e prazer, principalmente através da secreção de dopamina. A falta de nicotina no organismo leva o indivíduo à síndrome de abstinência, condição clínica desencadeada por alterações do número e estado dos receptores nicotínicos. A genética mostrou ter influência no início, na manutenção do hábito e no tratamento da dependência nicotínica, condicionada, no entanto, por fatores ambientais. Estudos mostraram também relação entre genes dos receptores nicotínicos e câncer de pulmão. Conclusão: A nicotina é o principal fator desencadeante da dependência ao tabaco, pois altera a conformação dos receptores colinérgicos nicotínicos. Estes influenciam na propagação do impulso nervoso até o sistema de recompensa cerebral, criando mecanismos de reforço positivo.

A cautionary note on the impact of protocol changes for genome-wide association SNP×SNP interaction studies: an example on ankylosing spondylitis.

Genome-wide association interaction (GWAI) studies have increased in popularity. Yet to date, no standard protocol exists. In practice, any GWAI workflow involves making choices about quality control strategy, SNP filtering, linkage disequilibrium (LD) pruning, analytic tool to model or to test for genetic interactions. Each of these can have an impact on the final epistasis findings and may affect their reproducibility in follow-up analyses. Choosing an analytic tool is not straightforward, as different tools exist and current understanding about their performance is based on often very particular simulation settings. In the present study, we wish to create awareness for the impact of (minor) changes in a GWAI analysis protocol can have on final epistasis findings. In particular, we investigate the influence of marker selection and marker prioritization strategies, LD pruning and the choice of epistasis detection analytics on study results, giving rise to 8 GWAI protocols. Discussions are made in the context of the ankylosing spondylitis (AS) data obtained via the Wellcome Trust Case Control Consortium (WTCCC2). As expected, the largest impact on AS epistasis findings is caused by the choice of marker selection criterion, followed by marker coding and LD pruning. In MB-MDR, co-dominant coding of main effects is more robust to the effects of LD pruning than additive coding. We were able to reproduce previously reported epistasis involvement of HLA-B and ERAP1 in AS pathology. In addition, our results suggest involvement of MAGI3 and PARK2, responsible for cell adhesion and cellular trafficking. Gene ontology biological function enrichment analysis across the 8 considered GWAI protocols also suggested that AS could be associated to the central nervous system malfunctions, specifically, in nerve impulse propagation and in neurotransmitters metabolic processes.

Solitary Waves in the Model of Active Media, Taking into Account Effects of Relaxation

We study a system of differential equation simulating transport phenomena in active structured media. The model is a generalization of the McKean s modification of the celebrated FitzHugh--Nagumo system, describing the nerve impulse propagation in axon. It takes into account the effects of memory, connected with the presence of internal structure. We construct explicitly the localized traveling wave solutions and analyze their stability.

First evidence of neosaxitoxin as a long-acting pain blocker in bladder pain syndrome.

Neosaxitoxin is a phycotoxin whose molecular mechanism of action shows a reversible inhibition of voltage-gated sodium channels at the axonal level, impeding nerve impulse propagation. This study was designed to evaluate the clinical efficacy of neosaxitoxin as a long-acting pain blocker in the treatment of bladder pain syndrome (BPS). Five patients with a diagnosis of BPS received a total dose of 80 µg of neosaxitoxin in an isoosmotic solution of 0.9 % NaCl, pH 6.5. Infiltration was performed via cystoscopy under spinal anesthesia. Questionnaires were administered immediately before and 7, 30 and 90 days after the procedure to measure the patients' reported pain severity and quality of life. This study, for the first time, showed the effect of blocking the neuronal transmission of pain by local infiltration of neosaxitoxin into the bladder submucosa. All five patients successfully responded to the treatment. Furthermore, the analgesic effect lasted for the entire 90 days of follow-up without the need for a second infiltration, and no adverse reactions to neosaxitoxin were detected. Neosaxitoxin infiltration was shown to be a safe and effective intervention to control pain related to BPS. It was well tolerated by patients, who experienced extended pain relief and associated beneficial effects over a follow-up of 90 days. These results confirm the effectiveness of neosaxitoxin as a long-acting local pain blocker.

The Case Against Delusional Parasitosis

Abstract: The body of knowledge on delusional parasitosis incriminates “delusional patients” as having imaginary external and/or internal symptoms that feel like parasite movements, dismisses them as psychiatric cases, and confuses cause with effect. The author is critical of these arguments and believes that the symptoms of crawling and pin-pricking are genuine; just misinterpreted as parasite movements. Based on the author’s research on over 1000 “delusional” patients since 1996 at the Parasitology Center, Inc. (PCI), the author has established that the symptoms of crawling and pin-pricking are caused by toxicity from exposure to incompatible dental materials, implants, environmental toxins among others that alter the propagation of normal nerve impulses. The author has also observed that external parasites/organisms including springtails (Collembola), other arthropods, bacteria, and fungi represent only opportunistic infections of skin sites compromised by the toxicity disorder involving the elimination of toxins through the skin. The author has described a new pathological disorder, Neuro-cutaneous Syndrome (NCS) primarily associated with dental toxicity to which “delusional parasitosis” and Morgellons disease cases could be assigned. The author has developed a protocol for the resolution of the symptoms of NCS cases. When followed to the letter, all symptoms of NCS, conventionally called delusional parasitosis, are invariably and irreversibly resolved; each individual’s unique circumstances taken into account. The author is also presenting a detailed case history of an NCS patient that has recovered from her experiential personal perspective.

Computational methods for a mathematical model of propagation of nerve impulses in myelinated axons

This paper is concerned with the approximate solution of a nonlinear mixed type functional differential equation (MTFDE) arising from nerve conduction theory. The equation considered describes conduction in a myelinated nerve axon. We search for a monotone solution of the equation defined in the whole real axis, which tends to given values at ±∞. We introduce new numerical methods for the solution of the equation, analyse their performance, and present and discuss the results of the numerical simulations.

Brain Na+, K+-ATPase Activity In Aging and Disease

Na+/K+ pump or sodium- and potassium-activated adenosine 5'-triphosphatase (Na+, K+-ATPase), its enzymatic version, is a crucial protein responsible for the electrochemical gradient across the cell membranes. It is an ion transporter, which in addition to exchange cations, is the ligand for cardenolides. This enzyme regulates the entry of K+ with the exit of Na+ from cells, being the responsible for Na+/K+ equilibrium maintenance through neuronal membranes. This transport system couples the hydrolysis of one molecule of ATP to exchange three sodium ions for two potassium ions, thus maintaining the normal gradient of these cations in animal cells. Oxidative metabolism is very active in brain, where large amounts of chemical energy as ATP molecules are consumed, mostly required for the maintenance of the ionic gradients that underlie resting and action potentials which are involved in nerve impulse propagation, neurotransmitter release and cation homeostasis. Protein phosphorylation is a key process in biological regulation. At nervous system level, protein phosphorylation is the major molecular mechanism through which the function of neural proteins is modulted in response to extracellular signals, including the response to neurotransmitter stimuli. It is the major mechanism of neural plasticity, including memory processing. The phosphorylation of Na+, K+-ATPase catalytic subunit inhibits enzyme activity whereas the inhibition of protein kinase C restores the enzyme activity. The dephosphorylation of neuronal Na+, K+-ATPase is mediated by calcineurin, a serine / threonine phosphatase. The latter enzyme is involved in a wide range of cellular responses to Ca2+ mobilizing signals, in the regulation of neuronal excitability by controlling the activity of ion channels, in the release of neurotransmitters and hormones, as well as in synaptic plasticity and gene transcription. In the present article evidence showing Na+, K+-ATPase involvement in signaling pathways, enzyme changes in diverse neurological diseases as well as during aging, have been summarized. Issues refer mainly to Na+, K+-ATPase studies in ischemia, brain injury, depression and mood disorders, mania, stress, Alzheimer´s disease, learning and memory, and neuronal hyperexcitability and epilepsy.