Absolute Refractory Period Research Articles

Inferring Network Dynamics and Neuron Properties from Population Recordings

Understanding the computational capabilities of the nervous system means to “identify” its emergent multiscale dynamics. For this purpose, we propose a novel model-driven identification procedure and apply it to sparsely connected populations of excitatory integrate-and-fire neurons with spike frequency adaptation (SFA). Our method does not characterize the system from its microscopic elements in a bottom-up fashion, and does not resort to any linearization. We investigate networks as a whole, inferring their properties from the response dynamics of the instantaneous discharge rate to brief and aspecific supra-threshold stimulations. While several available methods assume generic expressions for the system as a black box, we adopt a mean-field theory for the evolution of the network transparently parameterized by identified elements (such as dynamic timescales), which are in turn non-trivially related to single-neuron properties. In particular, from the elicited transient responses, the input–output gain function of the neurons in the network is extracted and direct links to the microscopic level are made available: indeed, we show how to extract the decay time constant of the SFA, the absolute refractory period and the average synaptic efficacy. In addition and contrary to previous attempts, our method captures the system dynamics across bifurcations separating qualitatively different dynamical regimes. The robustness and the generality of the methodology is tested on controlled simulations, reporting a good agreement between theoretically expected and identified values. The assumptions behind the underlying theoretical framework make the method readily applicable to biological preparations like cultured neuron networks and in vitro brain slices.

Information geometry in neural spike sequences

An information geometrical method is developed for characterizing or classifying neurons in cortical areas whose spike rates fluctuate in time. The interspike intervals (ISIs) of a spike sequence of a neuron is modeled as a gamma process with a time-variant spike rate, a fixed shape parameter and a fixed absolute refractory period. We formulate the problem of estimating the fixed parameters as semiparametric estimation and apply an information geometrical method to derive the optimal estimators from a statistical viewpoint.

Optimization of the leak conductance in the squid giant axon

We report on a theoretical study showing that the leak conductance density, G{L} , in the squid giant axon appears to be optimal for the action potential firing frequency. More precisely, the standard assumption that the leak current is composed of chloride ions leads to the result that the experimental value for G{L} is very close to the optimal value in the Hodgkin-Huxley model, which minimizes the absolute refractory period of the action potential, thereby maximizing the maximum firing frequency under stimulation by sharp, brief input current spikes to one end of the axon. The measured value of G{L} also appears to be close to optimal for the frequency of repetitive firing caused by a constant current input to one end of the axon, especially when temperature variations are taken into account. If, by contrast, the leak current is assumed to be composed of separate voltage-independent sodium and potassium currents, then these optimizations are not observed.

Optimization of the squid giant axon leak conductance for repetitive firing

Recent work [1] indicates that the leak conductance (GL) in the squid giant axon is optimal for the action potential firing frequency. Assuming a chloride leak current, the measured GL of approximately 0.3 mS/cm2 is very close to the theoretical optimal value that minimizes the absolute refractory period, or equivalently, that maximizes the highest frequency at which action potentials can be generated. These results were obtained by simulating brief, sharp current injections at one end of a Hodgkin-Huxley axon model, consistent with the standard experimental technique for measuring refractory periods. However, it is known [2] that constant current inputs to one end of a spatially axon can also evoke repetitive firing over a relatively narrow range of input strength. We have therefore investigated the optimality of GL for constant input currents (IDC). We find that the repetitive firing frequency is indeed maximized near biological values of GL for lower values of IDC (Figure ​(Figure1).1). However, at higher values of IDC, the frequency-optimal GL goes to 0, and the firing frequency itself is even higher. Thus, solely from the point of view of maximizing repetitive firing frequency under constant current input, the combination of a high input current strength and little to no leak conductance would seem best. However, when one takes temperature into account, it suggests why evolution has not chosen this strategy. The ocean temperatures which a cold-blooded squid encounters can vary by as much as 10 degrees Celsius over a few months [3]. The repetitive firing of the axon therefore must be able to function over such a range. As shown in Figure ​Figure2,2, the range of GL-IDC parameter space over which repetitive firing can occur shrinks dramatically with increasing temperature. Since the value of GL is presumably unchangeable, the configuration which best preserves the ability of the axon to repetitively fire over the largest range of temperature favors GL values near the biological value. Figure 1 Repetitive firing frequency as function of leak conductance for a specific input current strength. Figure 2 Solid curves: boundaries in GL-IDC phase space outside of which repetitive firing is not possible under constant current input. Dashed curves: optimal GL values for each IDC

Effects of electric stimulations applied during absolute refractory period on cardiac function of rabbits with heart failure

The effects of electric currents applied during absolute refractory period (ARP) on the cardiac function of rabbits with heart failure due to myocardial infarction (MI), and the safety of this method were investigated. Thirty rabbits were randomly assigned equally to 3 groups: sham-operated group, LV-anterior wall cardiac contractility modulation (LV-CCM) group, and septum-CCM (S-CCM) group. A thoracotomy was performed on all the rabbits. Electric pulses were delivered during the ARP on the anterior wall of left ventricle in CCM group and in the septum in S-CCM group, respectively. The left ventricular systolic pressure (LVSP) and maximum positive left ventricular pressure change (+dp/dt(max)), heart rates, ventricular tachycardia, ventricular fibrillation were observed. It was found that, as compared with the baseline, LVSP, and +dp/dtmax were significantly increased, on average, by 15.2% and 19.5% in LV-CCM group (P<0.05), and by 8.5% and 10.8% in S-CCM group (P<0.05). LVEDP was significantly decreased and -dp/dt(max) increased both in LV-CCM group and S-CCM group (P<0.05). CCM had no effect on heart rate and induced no arrhythmia in short time. It is concluded that electric currents delivered during the ARP could significantly enhance the contractility of myocardium safely, suggesting that CCM stimulation is a novel potent method for contractility modulation.

Nerve excitability changes after intravenous immunoglobulin infusions in multifocal motor neuropathy and chronic inflammatory demyelinating neuropathy

Intravenous immunoglobulin (IVIg) infusions may provide clinical benefits in multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyneuropathy (CIDP). The short delay in the clinical response to IVIg therapy is not consistent with a process of remyelination or axonal regeneration. We assessed whether or not the efficacy of IVIg infusions in MMN and CIDP could reflect changes in axonal membrane properties and nerve excitability. Ulnar motor nerve excitability was studied before and after three to five consecutive days of IVIg infusions (0.4 g/kg/day) in 10 patients with MMN, 10 patients with CIDP, and 10 neurological controls (CTRLs). Excitability recovery cycle, stimulus–response and strength–duration properties were investigated. The recovery cycle parameters (absolute and relative refractory period durations, refractoriness and supernormality) were similar in all groups and did not change after IVIg infusions. At baseline, patients with CIDP, but not with MMN, showed a reduced strength–duration time constant (chronaxie) and increased rheobase when compared to CTRLs. After IVIg infusions, strength–duration time constant remained stable in CTRLs, but decreased in patients with MMN or CIDP. Rheobase increased in the three groups after treatment. The decreased strength–duration time constant after IVIg infusions in patients with MMN or CIDP could reflect a reduction of persistent Na + current, able to limit intraaxonal Na + accumulation and then to produce neuroprotective effects. However, this could also reflect compensatory mechanisms that did not directly underlie the therapeutic effect. Whatever the underlying process, this result revealed that IVIgs were able to produce early nerve excitability changes.

Patterns, Memory and Periodicity in Two-Neuron Delayed Recurrent Inhibitory Loops

We study the coexistence of multiple periodic solutions for an analogue of the integrate-and-fire neuron model of two-neuron recurrent inhibitory loops with delayed feedback, which incorporates the firing process and absolute refractory period. Upon receiving an excitatory signal from the excitatory neuron, the inhibitory neuron emits a spike with a pattern-related delay, in addition to the synaptic delay. We present a theoretical framework to view the inhibitory signal from the inhibitory neuron as a self-feedback of the excitatory neuron with this additional delay. Our analysis shows that the inhibitory feedbacks with firing and the absolute refractory period can generate four basic types of oscillations, and the complicated interaction among these basic oscillations leads to a large class of periodic patterns and the occurrence of multistability in the recurrent inhibitory loop. We also introduce the average time of convergence to a periodic pattern to determine which periodic patterns have the potential to be used for neural information transmission and cognition processing in the nervous system.

Electrophysiological Determinants for Arrhythmogenesis Following Premature Stimulation In Murine Hearts

Background: Circus type re-entry is classically associated with reduced action potential (AP) conduction velocity through partially refractory tissue resulting in unidirectional conduction block. We assessed the extent to which premature extrasystolic APs under such conditions resulted in ventricular arrhythmogenesis in isolated Langendorff-perfused murine hearts. Methods and Results: A novel programmed electrical stimulation (PES) protocol applied trains of 8 S1 stimuli at 100 ms intervals followed by extrasystolic S2 stimuli at successively decreasing S1S2 intervals. S2 stimulus strengths required to overcome refractoriness, reduce ventricular effective refractory period (VERP) and thereby elicit extrasystolic APs, increased with shortened S1S2 intervals, despite constant durations at 90% recovery (APD90) of the preceding APs. Critical interval, CI, the difference APD90-VERP, consequently increased with stimulus strength. The corresponding latencies and peak amplitudes of the extrasystolic APs consequently sharply increased and decreased respectively with CI thereby potentially replicating necessary conditions for re-entrant, circus-type, arrhythmia. The dependence of CI upon stimulus strength tended to consistent limiting values expected from approaches to absolute refractory periods. These values were greater in arrhythmogenic (mean CI 18.9±0.55 ms, n=4) than in non-arrhythmogenic hearts (mean CI 15.1±0.37, n=4; P=0.001, ANOVA), despite their statistically indistinguishable APD90 (arrhythmogenic hearts: 40.9±2.23 ms, n=4 vs non-arrhythmogenic hearts: 36.5±2.61ms, n=4; p>0.05, ANOVA) or VERP values (arrhythmogenic hearts: 22.5±2.66 ms, n=4 vs non-arrhythmogenic hearts: 21.8±2.53 ms, n=4; p>0.05, ANOVA). Conclusions: These findings suggest existence of a specific CI (CI∗) in turn corresponding to specific conditions of latency and action potential amplitude that would be sufficient to result in arrhythmogenesis.

Mechanism of postsystolic contraction and of multiple myocardial contractions during each single cardiac cycle

Postsystolic contraction and other forms of phenomenon of multiple myocardial contractions are characterised by secondary or even tertiary contraction that follow regular one during each single cardiac cycle, triggered by a single sinus node impulse. These additional contractions occur at circumscribed areas of different myocardial regions, in many cardiac patients and healthy subjects. The mechanism of onset and perpetuation of the phenomenon is unknown. Our hypothesis is based on idea of existence of accessory, dead-end, slow-conducting, low-voltage pathways, derived from atrioventricular node or the bundle of His. Secondary contraction could occur in the following way: sinus node impulse divides into two pathways, the main atrioventricular conduction axis that depolarises the entire myocardium and the accessory pathway that depolarises again target region of myocardium where it ends blindly. Slow conduction through such accessory pathway enables a delay of secondary depolarisation needed to overcome the absolute refractory period of the myocardium following the 'regular' contraction. Electrocardiographic signal of a postsystolic potential is not visible at body surface because the pathway is low-voltage. The purpose of multiple myocardial contractions could be, although rarely, completing of current ejection, but more often, in the case of postsystolic contraction it could be a postsystolic tightening of the myocardium which would influence the regular contraction of the next cardiac cycle with the aim to reverse or prevent ventricular remodelling. In those circumstances, regional pathological function of ventricles (deformation of remodelled ventricle during the contraction, maybe during the relaxation as well, and furthermore asynchronous, but otherwise suboptimal contraction as well) would be detected by hypothetical myocardial receptors for strain and stretch, which would activate and sustain the function of accessory dead-end pathways by a neuroendocrine feed-back mechanism. The hypothesis is supported by anatomical findings of dead-end tracts originating from atrioventricular node and disappearing in the muscular part of interventricular septum. Extensive differences in the velocity of impulse propagation, which exist along the conduction system, allow the possibility that the accessory pathways are of slow-conducting properties. Low-amplitude signal of such pathways was confirmed by our intracardiac electrophysiological recording. Feed-back mechanism based on myocardial receptors for strain and stretch is a relevant option, keeping in mind well-known receptor based regulatory mechanisms across the cardiovascular system. The phenomenon is easily detectible, but hard to explain, so even considering herein presented hypothesis implies a need for change of settled perception of myocardial kinetics, and of physiological and pathological function of conducting system.

Secretory cells of the supraoptic nucleus have central as well as neurohypophysial projections

Conventional neuroanatomical methods may fail to demonstrate the presence of axons that are finer than 1 microm in diameter because such processes are near or below the limit of resolution of the light microscope. The presence of such axons can, however, be readily demonstrated by recording. The most easily interpreted type of recording for this purpose is the demonstration of antidromic activation of the cell body following stimulation of the region through which the axon passes. We have exploited this technique in the hypothalamus and have demonstrated the presence of double axonal projections or axons branching very near the cell bodies of the secretory cells of the neurohypophysial system in the rat supraoptic nucleus. We found that a small proportion of supraoptic magnocellular cells could be antidromically activated both from the neural stalk and from elsewhere in the hypothalamus, including the suprachiasmatic nucleus (8 cells of a total of 182) and the antero-ventral third ventricular region (AV3V; 4 of 182 cells) near the organum vasculosum of the lamina terminalis (OVLT). Collision of antidromic and orthodromic spikes showed that the cells were clearly antidromically (rather than synaptically, or orthodromically) activated from both sites. A stimulus applied to one of the axons prevented propagation of a spike evoked by a pulse delivered to the other axon until sufficient time had elapsed after the first stimulus for the resultant spike to have propagated from the first stimulus site along one cell process (towards the cell body or branch point), and from this point along the other axonal branch to the second stimulus site (there was also a short additional delay period during which the axon at the site of the second stimulus recovered from its absolute refractory period). If the interval between the stimuli was progressively reduced, there came a point where the second spike failed. Such a clear demonstration of dual projections in a system where the cells were previously thought to have only a single axon raises the possibility that many nerve cells in the CNS have previously unsuspected projections.

Firing rate of noisy integrate-and-fire neurons with synaptic current dynamics

We derive analytical formulas for the firing rate of integrate-and-fire neurons endowed with realistic synaptic dynamics. In particular, we include the possibility of multiple synaptic inputs as well as the effect of an absolute refractory period into the description. The latter affects the firing rate through its interaction with the synaptic dynamics.

Electrophysiology of neurones projections from the rat A1 noradrenergic region to the medial preoptic/anterior hypothalamic area: lack of effect of the oestrous cycle on their excitability.

The neuronal excitability of presumed A1 noradrenergic neurones in the ventrolateral medulla (VLM) which directly project to the medial preoptic/anterior hypothalamic area was analysed in pro-oestrous and metoestrous female rats under urethane anaesthesia. No significant difference was detected between the two groups for the antidromic activation threshold, absolute refractory period, frequency of successful antidromic propagation into the somatodendritic membrane, duration of post-stimulus inhibition, or spontaneous firing rate of these neurones. These results do not support the idea that the neuronal somata of A1 noradrenergic neurones in the VLM show a pro-oestrous increase in excitability during the oestrous cycle, although limitations of the methodology employed do not completely rule out this possibility.

Optimal coupling in noisy feed forward leaky integrate and fire network

We study the stochastic resonance (SR) phenomenon in feed-forward networks of leaky integrate and fire (LIF) neurons. It is shown for various input frequencies, amplitudes and network sizes that the appropriate coupling strength can improve the output signal to noise ratio (SNR). We demonstrate that the value of the optimal coupling strength in the content of SR depends primarily on the absolute refractory period. Other circumstances, signal frequency, amplitude and network size play minor role to determine this value (see Figure 1), consequently it is possible to optimally pretune the system. The optimal coupling strength jumps to discrete values as the noise increases and we discuss the background of this phenomenon.

Modelled temperature-dependent excitability behaviour of a generalised human peripheral sensory nerve fibre

The objective of this study was to determine if a recently developed human Ranvier node model, which is based on a modified version of the Hodgkin-Huxley model, could predict the excitability behaviour in human peripheral sensory nerve fibres with diameters ranging from 5.0 to 15.0 microm. The Ranvier node model was extended to include a persistent sodium current and was incorporated into a generalised single cable nerve fibre model. Parameter temperature dependence was included. All calculations were performed in Matlab. Sensory nerve fibre excitability behaviour characteristics predicted by the new nerve fibre model at different temperatures and fibre diameters compared well with measured data. Absolute refractory periods deviated from measured data, while relative refractory periods were similar to measured data. Conduction velocities showed both fibre diameter and temperature dependence and were underestimated in fibres thinner than 12.5 microm. Calculated strength-duration time constants ranged from 128.5 to 183.0 micros at 37 degrees C over the studied nerve fibre diameter range, with chronaxie times about 30% shorter than strength-duration time constants. Chronaxie times exhibited temperature dependence, with values overestimated by a factor 5 at temperatures lower than body temperature. Possible explanations include the deviated absolute refractory period trend and inclusion of a nodal strangulation relationship.

Ca2+‐Binding Proteins in Dogs with Heart Failure: Effects of Cardiac Contractility Modulation Electrical Signals

In dogs with heart failure (HF), chronic therapy with cardiac contractility modulation (CCM) electrical signals delivered to left ventricular (LV) muscle during the absolute refractory period improves LV function. This study examined the effects of CCM therapy on the expression of calcium (Ca(2+))-binding proteins (CBPs) in dogs with HF. Studies were performed in LV tissue from seven CCM-treated HF dogs, seven untreated HF dogs, and six normal (NL) dogs. mRNA expression of S100A1, sorcin, presenillin-1 (PS1), PS2, histidine-rich Ca(2+)-binding protein (HRC), and 18S ribosomal RNA (18S), a housekeeping gene, was measured using RT-PCR. Protein levels of CBPs and calsequestrin (CSQ) were determined by Western blotting. No difference was observed in the expression of 18S and CSQ among study groups. Compared with NL, the expression of S100A1, sorcin, and HRC was decreased, whereas the expression of PS2 was increased in untreated HF dogs. CCM therapy normalized the expression of S100A1, sorcin, and PS2 but not of HRC. No change was seen in the expression of PS1 among study groups. CCM therapy restores LV expression of S100A1, PS2, and sorcin. Normalization of CBPs may partly contribute to improved LV function in HF following CCM therapy.

A model of auditory spiral ganglion neurons

Event Abstract Back to Event A model of auditory spiral ganglion neurons Paul Wilhelm-Bade1, Marek Rudnicki1* and Werner Hemmert2, 3 1 Technische Universitat Munich, Fakultat fur Elektrotechnik und Informationstechnik, Germany 2 Bernstein Center for Computational Neuroscience, Germany 3 Technische Universitat Munich, Institute for Medical Engineering, Germany Our study focuses on biophysical modeling of the auditory periphery and initial stages of neural processing. We examined in detail synaptic excitation between inner hair cells and spiral ganglion type I neurons. Spiral ganglion neurons encode and convey information about sound to the central nervous system in the form of action potentials. For the purpose of our study we utilized a biophysical model of the auditory periphery proposed by Sumner (2002). It consists of outer/middle ear filters, a basilar membrane filter bank, an inner hair cell model coupled with complex vesicle pool dynamics at the presynaptic membrane. Finally, fusion of vesicles, modelled with a probabilistic function, releases neurotransmitter into the synaptic cleft. Response of auditory nerve fibers is modeled with a spike generator. The absolute refractory period is set to 0.75 ms and the relative refractory period is modelled with an exponentially decaying function. In our approach we substituted the artificial spike generation and refraction model with a more realistic spiral ganglion neuron model with Hodgkin-Huxley type ion channels proposed by Negm and Bruce (2008). The model included several channels also found in cochlear nucleus neurons (K_A, K_ht, K_lt). Our model consisted of the postsynaptic bouton (1.5x1.7µm) from high-spontaneous rate fibers. We coupled the model of the synapse with the spiral ganglion neuron using a synaptic excitation model fitted to results from Glowatzki and Fuchs' (2002) experiments, who conducted patch clamp measurements at the afferent postsynapse. We verified our hybrid model against various experiments, mostly pure tone stimulation. Rate intensity functions fitted experimental data well, rates varied from about 40 spikes/s to a maximum of 260 spikes/s. Adaptation properties were investigated with peri-stimulus time histograms (PSTH). As adaptation is mainly governed by vesicle pool dynamics, only small changes occurred compared with the statistical spike generation model and adaptation was consistent with experiments. Interestingly, Hodgkin-Huxley models of spiral ganglion neurons exhibited a notch visible in the PSTH after rapid adaptation that could also be observed in experiments. This was not revealed by the statistical spike generator. The fiber's refractory period was investigated using inter-spike interval histograms. The refractory period varied with simulus intensity from 1ms (spontaneous activity) to 0.7ms (84dB_SPL). We also analyzed phase locking with the synchronization index. It was slightly lower compared to the statistical spike generator. By varying the density of K_lt and K_A channels, we could replicate heterogenity of auditory nerve fibers as shown by Adamson et al. (2002). In summary, replacing the statistical spike generation model with a more realistic model of the postsynaptic membrane obsoletes the introduction of non-physiologic parameters for absolute and relative refraction. It improves the refractory behaviour and provides more realistic spike trains of the auditory nerve. Acknowledgments:Supported by within the Munich Bernstein Center for Computational Neuroscience by the German Federal Ministry of Education and Research (reference numbers 01GQ0441 and 01GQ0443). Conference: Bernstein Conference on Computational Neuroscience, Frankfurt am Main, Germany, 30 Sep - 2 Oct, 2009. Presentation Type: Poster Presentation Topic: Sensory processing Citation: Wilhelm-Bade P, Rudnicki M and Hemmert W (2009). A model of auditory spiral ganglion neurons. Front. Comput. Neurosci. Conference Abstract: Bernstein Conference on Computational Neuroscience. doi: 10.3389/conf.neuro.10.2009.14.131 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Aug 2009; Published Online: 27 Aug 2009. * Correspondence: Marek Rudnicki, Technische Universitat Munich, Fakultat fur Elektrotechnik und Informationstechnik, Munich, Germany, marek.rudnicki@tum.de Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Paul Wilhelm-Bade Marek Rudnicki Werner Hemmert Google Paul Wilhelm-Bade Marek Rudnicki Werner Hemmert Google Scholar Paul Wilhelm-Bade Marek Rudnicki Werner Hemmert PubMed Paul Wilhelm-Bade Marek Rudnicki Werner Hemmert Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Verbesserung der linksventrikulären Kontraktilität durch Stimulation in der absoluten Refraktärperiode –

Cardiac contractility modulation (CCM) is a treatment option for patients with systolic ventricular dysfunction, independent of QRS duration, moderate to severe systolic heart failure and symptoms despite optimal medical therapy. In contrast to cardiac resynchronization therapy (CRT) which has been an established therapy in patients with wide QRS and ventricular asynchrony, CCM can enhance cardiac contractility in patients independent of QRS duration. Whereas inotropic drugs increase oxygen demand, CCM works without additional myocardial oxygen need and without reference to asynchrony. Non-excitatory signals applied during the absolute refractory period have been shown to enhance the strength of left ventricular contraction in animals and humans with heart failure probably due to normalization of myocardial gene expression. Several multicenter studies have demonstrated safety and efficacy of CCM in patients with medically refractory heart failure. We describe the specific technical aspects and conditions in clinical application of CCM.

Cardiac contractility modulation in non-responders to cardiac resynchronization therapy

Cardiac resynchronization therapy (CRT) has become a standard therapy in cases of heart failure and asynchrony. Unfortunately, 20-30% of patients were non-responsive (NR) to CRT. In this report we used cardiac contractility modulation (CCM) as an adjunctive measure in NR patients. Sixteen NR patients, mean age 65 +/- 9 years, mean ejection fraction 27.3 +/- 7.4%, and New York Heart Association (NYHA) class III (n = 9) or IV (n = 7) despite CRT plus optimized medical therapy, received an additional CCM-implantation contra-lateral to the existing CRT system (OPTIMIZER III, Impulse Dynamics, Orangeburg, NY, USA). Cardiac contractility modulation delivers non-excitatory high-energy stimulatory impulses during the absolute refractory period, thus improving contractility [left ventricular (LV) dp/dt)] by stimulating the septum with two screw-in leads and one additional atrial lead for triggering the impulses. Acute LV dp/dt changes induced by CCM stimulation were measured by 5F Millar catheters placed in the LV during the implantation procedure in 14 of 16 cases. Patients were followed prospectively. Left ventricular dp/dt increased from a mean of 568 +/- 153 to 646 +/- 147 mmHg/s (+14%, P < 0.001) in the acute intraoperative testing. We noted the following complications and events during a follow-up of an average of 147 +/- 80 days (range 68-326) after CCM: intraoperative ventricular flutter needing cardioversion (n = 1), atrial lead dislocation (n = 1), coronary sinus (CS) lead dislocation (n = 1), painful stimulation requiring repositioning of septal leads (n = 1), true defibrillator shocks (n = 3), cardiac decompensations (n = 3), atrial fibrillation (n = 4), renal failure (n = 1), and pneumonia (n = 2). NYHA class improved from 3.4 to 2.8 (P < 0.01), and the ejection fraction increased from 27.3 +/- 5 to 31.1 +/- 6 (P < 0.01). Three patients (19%) died suddenly presumably due to electromechanical dissociation after 318, 104, and 81 days. No electrical interference was observed between the CCM and CRT systems, and in particular, at no time was the CRT-implantable cardioverter-defibrillator found to be delivering inadequate shocks. The CCM method is feasible and could be applied with calculated risks as a possible useful adjunct in CRT-NR when no other options are available; however, mortality and event rates are high in this very sick population.

A randomized controlled trial to evaluate the safety and efficacy of cardiac contractility modulation in patients with systolic heart failure: Rationale, design, and baseline patient characteristics

Cardiac contractility modulation (CCM) signals are nonexcitatory electrical signals delivered during the cardiac absolute refractory period that enhance the strength of cardiac muscular contraction. Prior research in experimental and human heart failure has shown that CCM signals normalize phosphorylation of key proteins and expression of genes coding for proteins involved in regulation of calcium cycling and contraction. The results of prior clinical studies of CCM have supported its safety and efficacy. A large-scale clinical study, the FIX-HF-5 study, is currently underway to test the safety and efficacy of this treatment. In this article, we provide an overview of the system used to deliver CCM signals, the implant procedure, and the details and rationale of the FIX-HF-5 study design. Baseline characteristics for patients randomized in this trial are also presented.

Identifying essential conditions for refractoriness of Leão's spreading depression—Computational modeling

A mathematical description of the restoring ionic mechanisms in a compartmentalized electrochemical model of neuronal tissues was developed aiming at studying the essential conditions for refractoriness of Leão's spreading depression (SD). The model comprehends the representation of a plexiform layer, composed by synaptic terminals and glial process immersed in an extracellular space where the space-temporal variations of the ionic concentrations were described by electrodiffusion equations. The synaptic transmission was described by differential equations representing the corresponding chemical reactions associated with the neurotransmitter release, diffusion, binding to its receptor in the postsynaptic membrane and the uptake by the presynaptic terminals. The effect of the neurotransmitter binding to the receptor induces changes in the permeability of the postsynaptic membrane and the corresponding transmembrane fluxes were calculated. The fluxes promote changes in the external ionic concentrations, changing the ionic electrodiffusion through the extracellular space. The description of these mechanisms provides the reaction-diffusion structure of the model and allows simulating the wave propagation. The simulations of experimental maneuvers of application of two consecutive stimuli for inducing SD suggest: (i) the extracellular space acts coupling the postsynaptic terminals and glial cells recovery mechanisms in such a way that the extracellular ionic concentrations change only during the wave front; (ii) the potassium removed from the extracellular by the glial cells, originated from the depolarization of the synaptic terminals returns slowly limited by the glial release, contributing for the refractoriness of the tissue; (iii) critical points for sodium and potassium transmembrane fluxes could be identified, allowing proposing specific conditions for the interplay between channels and pumps fluxes for determining the absolute and relative refractory periods.