Conduction along myelinated and demyelinated nerve fibres during the recovery cycle: Model investigations

The membrane excitability changes as well as the underlying mechanisms of these changes in a normal and in a systematically paranodally demyelinated nerve fibre have been investigated by paired stimulation during the first 30 ms of the recovery cycle. The ionic current kinetics determining the observed changes in the action potential parameters are presented also. The simulation of the conduction in the normal fibre is based on the Frankenhaeuser and Huxley (1964) and Goldman and Albus (1968) equations, while in the case of a demyelinated fibre according to the same equations modified by Stephanova (1988a). It has been shown for the demyelinated membrane that increased demyelination increases both the threshold current for the second potential as well as the absolute refractory period. With increasing interpulse interval, the subnormality of the membrane excitability is followed by supernormality in the case of the demyelinated membrane. For the recovery cycle of 30 ms under consideration no supernormality of the normal membrane excitability is obtained. With interpulse interval from 8.8 to 10.9 ms, the highest degree of demyelination (l=30 m) is accompanied by a refractory period of transmission. The membrane properties of the normal and demyelinated fibres recover 20 ms after the first pulse. For short interpulse intervals, the amplitude of the second action potential is decreased, and a slower propagation velocity is obtained. The most sensitive phenomenon is the excitability of the demyelinated membrane, which remains unrecovered 30 ms after the first pulses has been applied.     

Transthoracic Doppler echocardiography – noninvasive diagnostic window for coronary flow reserve assessment

Background

Strain Rate Imaging shows the filling phases of the left ventricle to consist of a wave of myocardial stretching, propagating from base to apex. The propagation velocity of the strain rate wave is reduced in delayed relaxation. This study examined the relation between the propagation velocity of strain rate in the myocardium and the propagation velocity of flow during early filling.

Methods

12 normal subjects and 13 patients with treated hypertension and normal systolic function were studied. Patients and controls differed significantly in diastolic early mitral flow measurements, peak early diastolic tissue velocity and peak early diastolic strain rate, showing delayed relaxation in the patient group. There were no significant differences in EF or diastolic diameter.

Results

Strain rate propagation velocity was reduced in the patient group while flow propagation velocity was increased. There was a negative correlation (R = -0.57) between strain rate propagation and deceleration time of the mitral flow E-wave (R = -0.51) and between strain rate propagation and flow propagation velocity and there was a positive correlation (R = 0.67) between the ratio between peak mitral flow velocity/strain rate propagation velocity and flow propagation velocity.

Conclusion

The present study shows strain rate propagation to be a measure of filling time, but flow propagation to be a function of both flow velocity and strain rate propagation. Thus flow propagation is not a simple index of diastolic function in delayed relaxation.     

Identification of an endogenous glutamatergic transmitter system controlling excitability and conductivity of atrial cardiomyocytes

As an excitatory transmitter system, the glutamatergic transmitter system controls excitability and conductivity of neurons. Since both cardiomyocytes and neurons are excitable cells, we hypothesized that cardiomyocytes may also be regulated by a similar system. Here, we have demonstrated that atrial cardiomyocytes have an intrinsic glutamatergic transmitter system, which regulates the generation and propagation of action potentials. First, there are abundant vesicles containing glutamate beneath the plasma membrane of rat atrial cardiomyocytes. Second, rat atrial cardiomyocytes express key elements of the glutamatergic transmitter system, such as the glutamate metabolic enzyme, ionotropic glutamate receptors (iGluRs), and glutamate transporters. Third, iGluR agonists evoke iGluR-gated currents and decrease the threshold of electrical excitability in rat atrial cardiomyocytes. Fourth, iGluR antagonists strikingly attenuate the conduction velocity of electrical impulses in rat atrial myocardium both in vitro and in vivo. Knockdown of GRIA3 or GRIN1, two highly expressed iGluR subtypes in atria, drastically decreased the excitatory firing rate and slowed down the electrical conduction velocity in cultured human induced pluripotent stem cell (iPSC)-derived atrial cardiomyocyte monolayers. Finally, iGluR antagonists effectively prevent and terminate atrial fibrillation in a rat isolated heart model. In addition, the key elements of the glutamatergic transmitter system are also present and show electrophysiological functions in human atrial cardiomyocytes. In conclusion, our data reveal an intrinsic glutamatergic transmitter system directly modulating excitability and conductivity of atrial cardiomyocytes through controlling iGluR-gated currents. Manipulation of this system may open potential new avenues for therapeutic intervention of cardiac arrhythmias.Subject terms: Cell biology, Molecular biology     

Action potential propagation in inhomogeneous cardiac tissue: safety factor considerations and ionic mechanism

Heterogeneity of myocardial structure and membrane excitability is accentuated by pathology and remodeling. In this study, a detailed model of the ventricular myocyte in a multicellular fiber was used to compute a location-dependent quantitative measure of conduction (safety factor, SF) and to determine the kinetics and contribution of sodium current (I(Na)) and L-type calcium current [I(Ca(L))] during conduction. We obtained the following results. 1) SF decreases sharply for propagation into regions of increased electrical load (tissue expansion, increased gap junction coupling, reduced excitability, hyperkalemia); it can be <1 locally (a value indicating conduction failure) and can recover beyond the transition region to resume propagation. 2) SF and propagation across inhomogeneities involve major contribution from I(Ca(L)). 3) Modulating I(Na) or I(Ca(L)) (by blocking agents or calcium overload) can cause unidirectional block in the inhomogeneous region. 4) Structural inhomogeneity causes local augmentation of I(Ca(L)) and suppression of I(Na) in a feedback fashion. 5) Propagation across regions of suppressed I(Na) is achieved via a I(Ca(L))-dependent mechanism. 6) Reduced intercellular coupling can effectively compensate for reduced SF caused by tissue expansion but not by reduced membrane excitability.     

Velocity-curvature relationship of colliding spherical calcium waves in rat cardiac myocytes.

Colliding spherical calcium waves in enzymatically isolated rat cardiac myocytes develop new wavefronts propagating perpendicular to the original direction. When investigated by confocal laser scanning microscopy (CLSM), using the fluorescent Ca2+ indicator fluo-3 AM, "cusp"-like structures become visible that are favorably approximated by double parabolae. The time-dependent position of the vertices is used to determine propagation velocity and negative curvature of the wavefront in the region of collision. It is evident that negatively curved waves propagate faster than positively curved, single waves. Considering two perfectly equal expanding circular waves, we demonstrated that the collision of calcium waves is due to an autocatalytic process (calcium-induced calcium release), and not to a simple phenomenon of interference. Following the spatiotemporal organization in simpler chemical systems maintained under conditions far from the thermodynamic equilibrium (Belousov-Zhabotinskii reaction), the dependence of the normal velocity on the curvature of the spreading wavefront is given by a linear relation. The so-called velocity-curvature relationship makes clear that the velocity is enhanced by curvature toward the direction of forward propagation and decreased by curvature away from the direction of forward propagation (with an influence of the diffusion coefficient). Experimentally obtained velocity data of both negatively and positively curved calcium waves were approximated by orthogonal weighted regression. The negative slope of the straight line resulted in an effective diffusion coefficient of 1.2 x 10(-4) mm2/s. From the so-called critical radius, which must be exceeded to initiate a traveling calcium wave, a critical volume (with enhanced [Ca2+]i) of approximately 12 microm3 was calculated. This is almost identical to the volume that is occupied by a single calcium spark.     

Propagation through electrically coupled cells. Effects of a resistive barrier

Action potential propagation through cardiac tissue occurs in a spatially inhomogeneous three-dimensional electrical syncytium composed of discrete cells with regional variations in membrane properties and intercellular resistance. In comparison with axons, cardiac tissue presents some differences in the application of core conductor cable theory. We have used analytical and numerical techniques to contrast the propagation of action potentials along nerve axons and along cardiac strands, including an explicit inclusion of cellular anatomical factors (the surface-to-volume ratio), the strand radius, and the regional distribution of longitudinal resistance. A localized decrease in the number of gap junctions will produce a functional resistive barrier, which can lead to unidirectional block of propagation if the tissue on two sides of the barrier in either excitability or passive electrical load. However, in some circumstances, a resistive barrier separating regions of different electrical load can actually facilitate propagation into the region of larger electrical load.     

Modeling action potential generation and propagation in NRK fibroblasts

Normal rat kidney (NRK) fibroblasts change their excitability properties through the various stages of cell proliferation. The present mathematical model has been developed to explain excitability of quiescent (serum deprived) NRK cells. It includes as cell membrane components, on the basis of patch-clamp experiments, an inwardly rectifying potassium conductance (G_Kir), an L-type calcium conductance (G_CaL), a leak conductance (G_leak), an intracellular calcium-activated chloride conductance [G_Cl(Ca)], and a gap junctional conductance (G_gj), coupling neighboring cells in a hexagonal pattern. This membrane model has been extended with simple intracellular calcium dynamics resulting from calcium entry via G_CaL channels, intracellular buffering, and calcium extrusion. It reproduces excitability of single NRK cells and cell clusters and intercellular action potential (AP) propagation in NRK cell monolayers. Excitation can be evoked by electrical stimulation, external potassium-induced depolarization, or hormone-induced intracellular calcium release. Analysis shows the roles of the various ion channels in the ultralong (30 s) NRK cell AP and reveals the particular role of intracellular calcium dynamics in this AP. We support our earlier conclusion (De Roos A, Willems PH, van Zoelen EJ, and Theuvenet AP. Am J Physiol Cell Physiol 273: C1900–C1907, 1997) that AP generation and propagation may act as a rapid mechanism for the propagation of intracellular calcium waves, thus contributing to fast intercellular calcium signaling. The present model serves as a starting point to further analyze excitability changes during contact inhibition and cell transformation. Hodgkin-Huxley model; intracellular calcium dynamics; L-type calcium conductance; inward rectifier; calcium-activated chloride conductance; gap junctional coupling     

Mathematical models for excitable systems in biology and medicine.

The excitable systems play a very important role in Biology and Medicine. Phenomena such as the transmission of impulses between neurons, the cardiac arrhythmia, the aggregation of amoebas, the appearance of organized structures in the cortex of egg cells, all derive from the activity of excitable media. In the first part of this work a general definition of excitable system is given; we then analyze some cases of excitability, distinguishing between electrical and chemical excitability and comparing experimental observations with simulations carried out by appropriate mathematical models. Such models are almost always formulated by partial differential equations of "reaction-diffusion" type and they have the characteristic to describe propagations of electrical waves (neurons, pacemaker cardiac cells, pancreatic b-cells) or chemical and mechanical waves (propagation of Ca++ waves or mechanical waves in the endoplasmic reticulum). The aim is to put in evidence that the biological systems can show not only excitability of electrical type, but also excitability of chemical nature, which can be observed in the first steps of development of egg cells or, for example, in the formation of pigments in vertebrate skin or in clam shells.     

Bifurcations in the decremental propagation of a spike train in the Hodgkin-Huxley model of low excitability

Response of a nerve fiber of low excitability to periodic stimulus pulses is studied with computer simulation of the Hodgkin-Huxley model. The excitability of the Hodgkin-Huxley model is reduced by decreasing the equilibrium potential for the sodium ion and by increasing the temperature, so that the decremental propagation of spikes occurs in the refractory period. It is shown that, as the period of stimulus pulses is decreased, the propagation length of the spikes is continuously changed, and period-doubling bifurcations occur. The response of a nerve fiber of low excitability is then qualitatively different from that of a normal fiber. Received: 6 December 1996 / Accepted in revised form: 12 June 1998     

Asymmetry in Signal Propagation between the Soma and Dendrites Plays a Key Role in Determining Dendritic Excitability in Motoneurons

It is widely recognized that propagation of electrophysiological signals between the soma and dendrites of neurons differs depending on direction, i.e. it is asymmetric. How this asymmetry influences the activation of voltage-gated dendritic channels, and consequent neuronal behavior, remains unclear. Based on the analysis of asymmetry in several types of motoneurons, we extended our previous methodology for reducing a fully reconstructed motoneuron model to a two-compartment representation that preserved asymmetric signal propagation. The reduced models accurately replicated the dendritic excitability and the dynamics of the anatomical model involving a persistent inward current (PIC) dispersed over the dendrites. The relationship between asymmetric signal propagation and dendritic excitability was investigated using the reduced models while varying the asymmetry in signal propagation between the soma and the dendrite with PIC density constant. We found that increases in signal attenuation from soma to dendrites increased the activation threshold of a PIC (hypo-excitability), whereas increases in signal attenuation from dendrites to soma decreased the activation threshold of a PIC (hyper-excitability). These effects were so strong that reversing the asymmetry in the soma-to-dendrite vs. dendrite-to-soma attenuation, reversed the correlation between PIC threshold and distance of this current source from the soma. We propose the tight relation of the asymmetric signal propagation to the input resistance in the dendrites as a mechanism underlying the influence of the asymmetric signal propagation on the dendritic excitability. All these results emphasize the importance of maintaining the physiological asymmetry in dendritic signaling not only for normal function of the cells but also for biophysically realistic simulations of dendritic excitability.     

A novel application of capnography during controlled human exposure to air pollution

Background

A detailed contrast bolus propagation model is essential for optimizing bolus-chasing Computed Tomography Angiography (CTA). Bolus characteristics were studied using bolus-timing datasets from Magnetic Resonance Angiography (MRA) for adaptive controller design and validation.

Methods

MRA bolus-timing datasets of the aorta in thirty patients were analyzed by a program developed with MATLAB. Bolus characteristics, such as peak position, dispersion and bolus velocity, were studied. The bolus profile was fit to a convolution function, which would serve as a mathematical model of bolus propagation in future controller design.

Results

The maximum speed of the bolus in the aorta ranged from 5–13 cm/s and the dwell time ranged from 7–13 seconds. Bolus characteristics were well described by the proposed propagation model, which included the exact functional relationships between the parameters and aortic location.

Conclusion

The convolution function describes bolus dynamics reasonably well and could be used to implement the adaptive controller design.     

Potassium diffusive coupling in neural networks

Conventional neural networks are characterized by many neurons coupled together through synapses. The activity, synchronization, plasticity and excitability of the network are then controlled by its synaptic connectivity. Neurons are surrounded by an extracellular space whereby fluctuations in specific ionic concentration can modulate neuronal excitability. Extracellular concentrations of potassium ([K⁺]_o) can generate neuronal hyperexcitability. Yet, after many years of research, it is still unknown whether an elevation of potassium is the cause or the result of the generation, propagation and synchronization of epileptiform activity. An elevation of potassium in neural tissue can be characterized by dispersion (global elevation of potassium) and lateral diffusion (local spatial gradients). Both experimental and computational studies have shown that lateral diffusion is involved in the generation and the propagation of neural activity in diffusively coupled networks. Therefore, diffusion-based coupling by potassium can play an important role in neural networks and it is reviewed in four sections. Section 2 shows that potassium diffusion is responsible for the synchronization of activity across a mechanical cut in the tissue. A computer model of diffusive coupling shows that potassium diffusion can mediate communication between cells and generate abnormal and/or periodic activity in small (§3) and in large networks of cells (§4). Finally, in §5, a study of the role of extracellular potassium in the propagation of axonal signals shows that elevated potassium concentration can block the propagation of neural activity in axonal pathways. Taken together, these results indicate that potassium accumulation and diffusion can interfere with normal activity and generate abnormal activity in neural networks.     

Attraction and repulsion of spiral waves by inhomogeneity of conduction anisotropy—a model of spiral wave interaction with electrical remodeling of heart tissue

Various forms of heart disease are associated with remodeling of the heart muscle, which results in a perturbation of cell-to-cell electrical coupling. These perturbations may alter the trajectory of spiral wave drift in the heart muscle. We investigate the effect of spatially extended inhomogeneity of transverse cell coupling on the spiral wave trajectory using a simple active media model. The spiral wave was either attracted or repelled from the center of inhomogeneity as a function of cell excitability and gradient of the cell coupling. High levels of excitability resulted in an attraction of the wave to the center of inhomogeneity, whereas low levels resulted in an escape and termination of the spiral wave. The spiral wave drift velocity was related to the gradient of the coupling and the initial position of the wave. In a diseased heart, a region of altered transverse coupling corresponds with local gap junction remodeling that may be responsible for stabilization-destabilization of spiral waves and hence reflect potentially important targets in the treatment of heart arrhythmias.     

Velocity and Directionality of the Electrohysterographic Signal Propagation

Objective

The initiation of treatment for women with threatening preterm labor requires effective distinction between true and false labor. The electrohysterogram (EHG) has shown great promise in estimating and classifying uterine activity. However, key issues remain unresolved and no clinically usable method has yet been presented using EHG. Recent studies have focused on the propagation velocity of the EHG signals as a potential discriminator between true and false labor. These studies have estimated the propagation velocity of individual spikes of the EHG signals. We therefore focus on estimating the propagation velocity of the entire EHG burst recorded during a contraction in two dimensions.

Study Design

EHG measurements were performed on six women in active labor at term, and a total of 35 contractions were used for the estimation of propagation velocity. The measurements were performed using a 16-channel two-dimensional electrode grid. The estimates were calculated with a maximum-likelihood approach.

Results

The estimated average propagation velocity was 2.18 (±0.68) cm/s. No single preferred direction of propagation was found.

Conclusion

The propagation velocities estimated in this study are similar to those reported in other studies but with a smaller intra- and inter-patient variation. Thus a potential tool has been established for further studies on true and false labor contractions.     

An analysis of the relationships between subthreshold electrical properties and excitability in skeletal muscle

Skeletal muscle activation requires action potential (AP) initiation followed by its sarcolemmal propagation and tubular excitation to trigger Ca(2+) release and contraction. Recent studies demonstrate that ion channels underlying the resting membrane conductance (G(M)) of fast-twitch mammalian muscle fibers are highly regulated during muscle activity. Thus, onset of activity reduces G(M), whereas prolonged activity can markedly elevate G(M). Although these observations implicate G(M) regulation in control of muscle excitability, classical theoretical studies in un-myelinated axons predict little influence of G(M) on membrane excitability. However, surface membrane morphologies differ markedly between un-myelinated axons and muscle fibers, predominantly because of the tubular (t)-system of muscle fibers. This study develops a linear circuit model of mammalian muscle fiber and uses this to assess the role of subthreshold electrical properties, including G(M) changes during muscle activity, for AP initiation, AP propagation, and t-system excitation. Experimental observations of frequency-dependent length constant and membrane-phase properties in fast-twitch rat fibers could only be replicated by models that included t-system luminal resistances. Having quantified these resistances, the resulting models showed enhanced conduction velocity of passive current flow also implicating elevated AP propagation velocity. Furthermore, the resistances filter passive currents such that higher frequency current components would determine sarcolemma AP conduction velocity, whereas lower frequency components excite t-system APs. Because G(M) modulation affects only the low-frequency membrane impedance, the G(M) changes in active muscle would predominantly affect neuromuscular transmission and low-frequency t-system excitation while exerting little influence on the high-frequency process of sarcolemmal AP propagation. This physiological role of G(M) regulation was increased by high Cl(-) permeability, as in muscle endplate regions, and by increased extracellular [K(+)], as observed in working muscle. Thus, reduced G(M) at the onset of exercise would enhance t-system excitation and neuromuscular transmission, whereas elevated G(M) after sustained activity would inhibit these processes and thereby accentuate muscle fatigue.     

Conduction along myelinated and demyelinated nerve fibres with a reorganized axonal membrane during the recovery cycle: model investigations

The changes in the excitability of the reorganized axonal membrane in myelinated and demyelinated nerve fibres as well as the causes conditioning such changes have been investigated by paired stimulation during the first 30 ms of the recovery cycle. The variations of the action potential parameters (amplitude and velocity) are traced also. The simulation of the conduction along the normal fiber is based on the Frankenhaeuser and Huxley (1964) and Goldman and Albus (1968) equations, while the demyelination is considered to be an elongation of the nodes of Ranvier. The axonal membrane reorganization is achieved by means of potassium channel blocking and increase of the sodium-channel permeability. It is shown that potassium channels block decreases membrane excitability for the myelinated and demyelinated fibres in the cases of initial and paired stimulation. With increasing sodium-channel permeability on the background of the blocked potassium channels, the membrane excitability is increased. For the fibres with a reorganized membrane, a supernormality of the membrane excitability is obtained, the latter remaining unrecovered during the 30 ms cycle under investigation. The supernormality of the excitability grows from the demyelinated fibre without reorganized membrane to the demyelinated fibre with reorganized one. For short interstimulus intervals, the second action potential propagates along the fibres with a reduced velocity and a decreased amplitude. No supernormality of the potential parameters (amplitude, velocity) is observed during the cycle up to 30 ms. The membrane properties of the myelinated and demyelinated fibres with blocked potassium channels recover in the interval from 15 to 20 ms depending on whether the sodium channels' increase of the permeability is added on the background of the blocked potassium channel or not. In the recovery cycle, the axonal membrane reorganization leads to an improvement of the conduction along most severely demyelinated fibres.     

Effects of elevated extracellular potassium on the stimulation mechanism of diastolic cardiac tissue

During cardiac disturbances such as ischemia and hyperkalemia, the extracellular potassium ion concentration is elevated. This in turn changes the resting transmembrane potential and affects the excitability of cardiac tissue. To test the hypothesis that extracellular potassium elevation also alters the stimulation mechanism, we used optical fluorescence imaging to examine the mechanism of diastolic anodal unipolar stimulation of cardiac tissue under 4 mM (normal) and 8 mM (elevated) extracellular potassium. We present several visualization methods that are useful for distinguishing between anodal-make and anodal-break excitation. In the 4-mM situation, stimulation occurred by the make, or stimulus-onset, mechanism that involved propagation out of the virtual cathodes. For 8-mM extracellular potassium, the break or stimulus termination mechanism occurred with propagation out of the virtual anode. We conclude that elevated potassium, as might occur in myocardial ischemia, alters not only stimulation threshold but also the excitation mechanism for anodal stimulation.     

Acoustic radiation force impulse imaging for differentiation of thyroid nodules

Background

Acoustic Radiation Force Impulse (ARFI)-Imaging is an ultrasound-based elastography method enabling quantitative measurement of tissue stiffness. The aim of the present study was to evaluate sensitivity and specificity of ARFI-imaging for differentiation of thyroid nodules and to compare it to the well evaluated qualitative real-time elastography (RTE).

Methods

ARFI-imaging involves the mechanical excitation of tissue using acoustic pulses to generate localized displacements resulting in shear-wave propagation which is tracked using correlation-based methods and recorded in m/s. Inclusion criteria were: nodules ≥5 mm, and cytological/histological assessment. All patients received conventional ultrasound, real-time elastography (RTE) and ARFI-imaging.

Results

One-hundred-fifty-eight nodules in 138 patients were available for analysis. One-hundred-thirty-seven nodules were benign on cytology/histology, and twenty-one nodules were malignant. The median velocity of ARFI-imaging in the healthy thyroid tissue, as well as in benign and malignant thyroid nodules was 1.76 m/s, 1.90 m/s, and 2.69 m/s, respectively. While no significant difference in median velocity was found between healthy thyroid tissue and benign thyroid nodules, a significant difference was found between malignant thyroid nodules on the one hand and healthy thyroid tissue (p = 0.0019) or benign thyroid nodules (p = 0.0039) on the other hand. No significant difference of diagnostic accuracy for the diagnosis of malignant thyroid nodules was found between RTE and ARFI-imaging (0.74 vs. 0.69, p = 0.54). The combination of RTE with ARFI did not improve diagnostic accuracy.

Conclusions

ARFI can be used as an additional tool in the diagnostic work up of thyroid nodules with high negative predictive value and comparable results to RTE.     

Epileptic seizures in a heterogeneous excitatory network with short-term plasticity

Epilepsy involves a diverse group of abnormalities, including molecular and cellular disorders. These abnormalities prove to be associated with the changes in local excitability and synaptic dynamics. Correspondingly, the epileptic processes including onset, propagation and generalized seizure may be related with the alterations of excitability and synapse. In this paper, three regions, epileptogenic zone (EZ), propagation area and normal region, were defined and represented by neuronal population model with heterogeneous excitability, respectively. In order to describe the synaptic behavior that the strength was enhanced and maintained at a high level for a short term under a high frequency spike train, a novel activity-dependent short-term plasticity model was proposed. Bifurcation analysis showed that the presence of hyperexcitability could increase the seizure susceptibility of local area, leading to epileptic discharges first seen in the EZ. Meanwhile, recurrent epileptic activities might result in the transition of synaptic strength from weak state to high level, augmenting synaptic depolarizations in non-epileptic neurons as the experimental findings. Numerical simulation based on a full-connected weighted network could qualitatively demonstrate the epileptic process that the propagation area and normal region were successively recruited by the EZ. Furthermore, cross recurrence plot was used to explore the synchronization between neuronal populations, and the global synchronization index was introduced to measure the global synchronization. Results suggested that the synchronization between the EZ and other region was significantly enhanced with the occurrence of seizure. Interestingly, the desynchronization phenomenon was also observed during seizure initiation and propagation as reported before. Therefore, heterogeneous excitability and short-term plasticity are believed to play an important role in the epileptic process. This study may provide novel insights into the mechanism of epileptogenesis.     

The glial spike theory. I. On an active role of neuroglia in spreading depression and migraine.

The propagation mechanism of spreading depression (SD), which has been implicated in the pathophysiology of the neurological auras of migraine, remains enigmatic but is widely believed to depend primarily upon the behaviour of assemblies of neurons. It is proposed here, based upon a program of theoretical research, that the most essential constituent of SD is a slowly propagating, regenerative event in the neuroglial compartment. By altering the neuronal microenvironment, this glial spike helps trigger and coordinate the neuronal depolarization of SD; the glial spike is in turn facilitated by neuronally released agents acting at the neuroglial plasma membrane. The conduction velocity-determining propagation mechanism of SD is further proposed to be a wave of intracellular Ca(2+)-induced Ca2+ release (cytocal wave) that travels through the glial compartment of nervous tissue. Some implications for the improved understanding and clinical management of migraine are suggested. Excitability of glial cells of vertebrates has until now been demonstrated only in vitro, and its physiological significance has remained unknown. This work identifies a macroscopic reaction of neuronal tissue, known from the in vivo vertebrate brain for over 45 years, as a manifestation of neuroglial excitability.