Single fibre action potentials in skeletal muscle related to recording distances

Single muscle fibre action potentials (SFAPs) are considered to be functions of a bioelectrical source and electrical conductivity parameters of the medium. In most model studies SFAPs are computed as a convolution of the bioelectrical source with a transfer function. Calculated peak-to-peak amplitudes of SFAPs decrease with increasing recording distances. In this paper an experimental validation of model results is presented. Experiments were carried out on the m. extensor digitorum longus (EDL) of the rat. Using a method including fluorescent labelling of the active fibre, the distance between the active fibre and the recording electrode was derived. With another method, the decline of the peak-to-peak amplitude of SFAPs detected along a multi-electrode was obtained. With both experimental methods, in general peak-to-peak amplitudes of SFAPs decreased with increasing recording distances, as was found in model results with present volume conduction theory. However, this behaviour was not found in all experiments. The rate of decline of the peak-to-peak amplitudes with recording distance was always less than in models

Multiscale Modeling of the Ventricles: From Cellular Electrophysiology to Body Surface Electrocardiograms

This work is focused on different aspects within the loop of multiscale modeling: On the cellular level, effects of adrenergic regulation and the Long-QT syndrome have been investigated. On the organ level, a model for the excitation conduction system was developed and the role of electrophysiological heterogeneities was analyzed. On the torso level a dynamic model of a deforming heart was created and the effects of tissue conductivities on the solution of the forward problem were evaluated

Neuroelectronic interfacing with cultured multielectrode arrays toward a cultured probe

Efficient and selective electrical stimulation and recording of neural activity in peripheral, spinal, or central pathways requires multielectrode arrays at micrometer scale. ¿Cultured probe¿ devices are being developed, i.e., cell-cultured planar multielectrode arrays (MEAs). They may enhance efficiency and selectivity because neural cells have been grown over and around each electrode site as electrode-specific local networks. If, after implantation, collateral sprouts branch from a motor fiber (ventral horn area) and if they can be guided and contacted to each ¿host¿ network, a very selective and efficient interface will result. Four basic aspects of the design and development of a cultured probe, coated with rat cortical or dorsal root ganglion neurons, are described. First, the importance of optimization of the cell-electrode contact is presented. It turns out that impedance spectroscopy, and detailed modeling of the electrode-cell interface, is a very helpful technique, which shows whether a cell is covering an electrode and how strong the sealing is. Second, the dielectrophoretic trapping method directs cells efficiently to desired spots on the substrate, and cells remain viable after the treatment. The number of cells trapped is dependent on the electric field parameters and the occurrence of a secondary force, a fluid flow (as a result of field-induced heating). It was found that the viability of trapped cortical cells was not influenced by the electric field. Third, cells must adhere to the surface of the substrate and form networks, which are locally confined, to one electrode site. For that, chemical modification of the substrate and electrode areas with various coatings, such as polyethyleneimine (PEI) and fluorocarbon monolayers promotes or inhibits adhesion of cells. Finally, it is shown how PEI patterning, by a stamping technique, successfully guides outgrowth of collaterals from a neonatal rat lumbar spinal cord explant, after six days in cultur

Nonlinear physics of electrical wave propagation in the heart: a review

The beating of the heart is a synchronized contraction of muscle cells (myocytes) that are triggered by a periodic sequence of electrical waves (action potentials) originating in the sino-atrial node and propagating over the atria and the ventricles. Cardiac arrhythmias like atrial and ventricular fibrillation (AF,VF) or ventricular tachycardia (VT) are caused by disruptions and instabilities of these electrical excitations, that lead to the emergence of rotating waves (VT) and turbulent wave patterns (AF,VF). Numerous simulation and experimental studies during the last 20 years have addressed these topics. In this review we focus on the nonlinear dynamics of wave propagation in the heart with an emphasis on the theory of pulses, spirals and scroll waves and their instabilities in excitable media and their application to cardiac modeling. After an introduction into electrophysiological models for action potential propagation, the modeling and analysis of spatiotemporal alternans, spiral and scroll meandering, spiral breakup and scroll wave instabilities like negative line tension and sproing are reviewed in depth and discussed with emphasis on their impact in cardiac arrhythmias.Peer ReviewedPreprin

Restoring Upper Extremity Mobility through Functional Neuromuscular Stimulation using Macro Sieve Electrodes

The last decade has seen the advent of brain computer interfaces able to extract precise motor intentions from cortical activity of human subjects. It is possible to convert captured motor intentions into movement through coordinated, artificially induced, neuromuscular stimulation using peripheral nerve interfaces. Our lab has developed and tested a new type of peripheral nerve electrode called the Macro-Sieve electrode which exhibits excellent chronic stability and recruitment selectivity. Work presented in this thesis uses computational modeling to study the interaction between Macro-Sieve electrodes and regenerated peripheral nerves. It provides a detailed understanding of how regenerated fibers, both on an individual level and on a population level respond differently to functional electrical stimulation compared to non-disrupted axons. Despite significant efforts devoted to developing novel regenerative peripheral interfaces, the degree of spatial clustering between functionally related fibers in regenerated nerves is poorly understood. In this thesis, bioelectrical modeling is also used to predict the degree of topographical organization in regenerated nerve trunks. In addition, theoretical limits of the recruitment selectivity of the device is explored and a set of optimal stimulation paradigms used to selectively activate fibers in different regions of the nerve are determined. Finally, the bioelectrical model of the interface/nerve is integrated with a biomechanical model of the macaque upper limb to study the feasibility of using macro-sieve electrodes to achieve upper limb mobilization

Functional characterization of murine muscle spindles

Coordinated movements require proprioceptive information, such as information about muscle tone as well as position and movement of extremities in space. The primary proprioceptive sensory receptors are muscle spindles. Muscle spindles are complex stretch-sensitive mechanoreceptors. They detect how much and how fast a muscle is lengthened. Muscle spindles consist of specialised skeletal muscle fibers, so called intrafusal fibers. In their central part, these fibers are surrounded by a proprioceptive afferent sensory neuron in an annulospiral shape. Here the speed as well as the length of the stretch is translated into action potential frequencies, which are proportional to the length change and the speed thereof. Both polar endings are innervated by efferent γ-motoneurons. Previously it was shown that AChRs are concentrated in the polar region at the contact site between intrafusal fiber and sensory neuron. To investigate the function of these AChRs, extracellular recordings from single unit proprioceptive-afferents of wildtype murine extensor digitorum longus muscles in the absence of γ-motoneuron activity was performed. I investigated the response during ramp-and-hold stretches as well as during sinusoidal vibrations in the presence and absence of the AChR inhibitors d-tubocurarine, α-bungarotoxin or of the choline reuptake inhibitor hemicholinium-3. In the presence of either drug, the resting action potential discharge frequency was not altered but the stretch-evoked action potential frequencies were increased. Additionally, the firing rate during sinusoidal vibrations at low amplitudes was higher in the presence of α-bungarotoxin compared to control spindles. These results indicate that ACh modulates muscle spindle function during stretch in the central region of intrafusal fibers by possibly fine-tuning muscle spindle sensitivity. As a second project, I investigated the morphology and function of muscle spindles from murine models of muscular dystrophies. Muscular dystrophies comprise a heterogeneous group of hereditary diseases, which are all characterised by progressive degeneration and weakness of skeletal muscles. Murine model systems for two distinct types of muscular dystrophy with very different disease etiologies, i.e. dystrophin- and dysferlin-deficient mice, were analysed. The total number and the overall structure of muscle spindles in soleus muscles of these mice appeared unchanged. Immunohistochemical analyses of wildtype muscle spindles revealed a concentration of dystrophin and β-dystroglycan in intrafusal fibers outside the region of contact to the sensory neuron. Moreover, extracellular recordings from single units of sensory afferents from muscle spindles of the extensor digitorum longus muscle were performed during ramp-and-hold stretches, as well as during sinusoidal vibrations. I demonstrate that mouse models for muscular dystrophy have an increased resting discharge but no change during the dynamic or static phase of ramp-and-hold stretches. Mutant muscle spindles show a higher action potential firing rate during sinusoidal vibrations with small amplitudes and low frequencies. I observed no exacerbated phenotype in DMDmdx- dysf-/- double transgenic mice compared to either single transgenic animal. These results demonstrate that a lack of dystrophin and or dysferlin lead to a change in muscle spindle function and suggest that an impaired proprioceptive feedback might contribute to the instable gait and the frequent falls in patients with muscular dystrophy. To test the hypothesis that an increased intracellular calcium ion concentration [Ca2+] in dystrophic muscles could cause the impaired proprioceptive function, extracellular recordings from single units of sensory afferents from muscle spindles of the extensor digitorum longus muscle were performed during ramp-and-hold stretches, as well as during sinusoidal vibrations in the presence and absence of the AChE inhibitor neostigmine and the calcium channel blocker nifedipine. After nifedipine and neostigmine administration an increased resting discharge but no change during the dynamic or static phase of ramp-and-hold stretches as well as a higher action potential firing rate during sinusoidal vibrations after neostigmine administration with small amplitudes and low frequencies was observed. Overall, I show that murine models of muscular dystrophy have an impaired muscle spindle function, which could contribute to the instable gait and posture observed in patients with muscular dystrophy, that these changes could be due to an increased intracellular [Ca2+] in muscles and that the AChR in the central part of the muscle spindles negatively modulates muscle spindle responses during stretch

Functional characterization of murine muscle spindles

Coordinated movements require proprioceptive information, such as information about muscle tone as well as position and movement of extremities in space. The primary proprioceptive sensory receptors are muscle spindles. Muscle spindles are complex stretch-sensitive mechanoreceptors. They detect how much and how fast a muscle is lengthened. Muscle spindles consist of specialised skeletal muscle fibers, so called intrafusal fibers. In their central part, these fibers are surrounded by a proprioceptive afferent sensory neuron in an annulospiral shape. Here the speed as well as the length of the stretch is translated into action potential frequencies, which are proportional to the length change and the speed thereof. Both polar endings are innervated by efferent γ-motoneurons. Previously it was shown that AChRs are concentrated in the polar region at the contact site between intrafusal fiber and sensory neuron. To investigate the function of these AChRs, extracellular recordings from single unit proprioceptive-afferents of wildtype murine extensor digitorum longus muscles in the absence of γ-motoneuron activity was performed. I investigated the response during ramp-and-hold stretches as well as during sinusoidal vibrations in the presence and absence of the AChR inhibitors d-tubocurarine, α-bungarotoxin or of the choline reuptake inhibitor hemicholinium-3. In the presence of either drug, the resting action potential discharge frequency was not altered but the stretch-evoked action potential frequencies were increased. Additionally, the firing rate during sinusoidal vibrations at low amplitudes was higher in the presence of α-bungarotoxin compared to control spindles. These results indicate that ACh modulates muscle spindle function during stretch in the central region of intrafusal fibers by possibly fine-tuning muscle spindle sensitivity. As a second project, I investigated the morphology and function of muscle spindles from murine models of muscular dystrophies. Muscular dystrophies comprise a heterogeneous group of hereditary diseases, which are all characterised by progressive degeneration and weakness of skeletal muscles. Murine model systems for two distinct types of muscular dystrophy with very different disease etiologies, i.e. dystrophin- and dysferlin-deficient mice, were analysed. The total number and the overall structure of muscle spindles in soleus muscles of these mice appeared unchanged. Immunohistochemical analyses of wildtype muscle spindles revealed a concentration of dystrophin and β-dystroglycan in intrafusal fibers outside the region of contact to the sensory neuron. Moreover, extracellular recordings from single units of sensory afferents from muscle spindles of the extensor digitorum longus muscle were performed during ramp-and-hold stretches, as well as during sinusoidal vibrations. I demonstrate that mouse models for muscular dystrophy have an increased resting discharge but no change during the dynamic or static phase of ramp-and-hold stretches. Mutant muscle spindles show a higher action potential firing rate during sinusoidal vibrations with small amplitudes and low frequencies. I observed no exacerbated phenotype in DMDmdx- dysf-/- double transgenic mice compared to either single transgenic animal. These results demonstrate that a lack of dystrophin and or dysferlin lead to a change in muscle spindle function and suggest that an impaired proprioceptive feedback might contribute to the instable gait and the frequent falls in patients with muscular dystrophy. To test the hypothesis that an increased intracellular calcium ion concentration [Ca2+] in dystrophic muscles could cause the impaired proprioceptive function, extracellular recordings from single units of sensory afferents from muscle spindles of the extensor digitorum longus muscle were performed during ramp-and-hold stretches, as well as during sinusoidal vibrations in the presence and absence of the AChE inhibitor neostigmine and the calcium channel blocker nifedipine. After nifedipine and neostigmine administration an increased resting discharge but no change during the dynamic or static phase of ramp-and-hold stretches as well as a higher action potential firing rate during sinusoidal vibrations after neostigmine administration with small amplitudes and low frequencies was observed. Overall, I show that murine models of muscular dystrophy have an impaired muscle spindle function, which could contribute to the instable gait and posture observed in patients with muscular dystrophy, that these changes could be due to an increased intracellular [Ca2+] in muscles and that the AChR in the central part of the muscle spindles negatively modulates muscle spindle responses during stretch

Cardiac electrophysiology and mechanoelectric feedback : modeling and simulation

Cardiac arrhythmia such as atrial and ventricular fibrillation are characterized by rapid and irregular electrical activity, which may lead to asynchronous contraction and a reduced pump function. Besides experimental and clinical studies, computer simulations are frequently applied to obtain insight in the onset and perpetuation of cardiac arrhythmia. In existing models, the excitable tissue is often modeled as a continuous two-phase medium, representing the intracellular and interstitial domains, respectively. A possible drawback of continuous models is the lack of flexibility when modeling discontinuities in the cardiac tissue. We introduce a discrete bidomain model in which the cardiac tissue is subdivided in segments, each representing a small number of cardiac cells. Active membrane behavior as well as intracellular coupling and interstitial currents are described by this model. Compared with the well-known continuous bidomain equations, our Cellular Bidomain Model is better aimed at modeling the structure of cardiac tissue, in particular anisotropy, myofibers, fibrosis, and gap junction remodeling. An important aspect of our model is the strong coupling between cardiac electrophysiology and cardiomechanics. Mechanical behavior of a single segment is modeled by a contractile element, a series elastic element, and a parallel elastic element. Active force generated by the sarcomeres is represented by the contractile element together with the series elastic element. The parallel elastic element describes mechanical behavior when the segment is not electrically stimulated. Contractile force is related to the intracellular calcium concentration, the sarcomere length, and the velocity of sarcomere shortening. By incorporating the influence of mechanical deformation on electrophysiology, mechanoelectric feedback can be studied. In our model, we consider the immediate influence of stretch on the action potential by modeling a stretch-activated current. Furthermore, we consider the adap- tation of ionic membrane currents triggered by changes in mechanical load. The strong coupling between cardiac electrophysiology and cardiac mechanics is a unique property of our model, which is reflected by its application to obtain more insight in the cause and consequences of mechanical feedback on cardiac electrophysiology. In this thesis, we apply the Cellular Bidomain Model in five different simulation studies to cardiac electrophysiology and mechanoelectric feedback. In the first study, the effect of field stimulation on virtual electrode polarization is studied in uniform, decoupled, and nonuniform cardiac tissue. Field stimulation applied on nonuniform tissue results in more virtual electrodes compared with uniform tissue. Spiral waves can be terminated in decoupled tissue, but not in uniform, homogeneous tissue. By gradually increasing local differences in intracellular conductivities, the amount and spread of virtual electrodes increases and spiral waves can be terminated. We conclude that the clinical success of defibrillation may be explained by intracellular decoupling and spatial heterogeneity present in normal and in pathological cardiac tissue. In the second study, the role of the hyperpolarization-activated inward current If is investigated on impulse propagation in normal and in pathological tissue. The effect of diffuse fibrosis and gap junction remodeling is simulated by reducing cellular coupling nonuniformly. As expected, the conduction velocity decreases when cellular coupling is reduced. In the presence of If, the conduction velocity increases both in normal and in pathological tissue. In our simulations, ectopic activity is present in regions with high expression of If and is facilitated by cellular uncoupling. We also found that an increased If may facilitate propagation of the action potential. Hence, If may prevent conduction slowing and block. Overexpression of If may lead to ectopic activity, especially when cellular coupling is reduced under pathological conditions. In the third study, the influence of the stretch-activated current Isac is investigated on impulse propagation in cardiac fibers composed of segments that are electrically and mechanically coupled. Simulations of homogeneous and inhomogeneous cardiac fibers have been performed to quantify the relation between conduction velocity and Isac under stretch. Conduction slowing and block are related to the amount of stretch and are enhanced by contraction of early-activated segments. Our observations are in agreement with experimental results and explain the large differences in intra-atrial conduction, as well as the increased inducibility of atrial fibrillation in acutely dilated atria. In the fourth study, we investigate the hypothesis that electrical remodeling is triggered by changes in mechanical work. Stroke work is determined for each segment by simulating the cardiac cycle. Electrical remodeling is simulated by adapting the L-type Ca2+ current ICa,L such that a homogeneous distribution of stroke work is obtained. With electrical remodeling, a more homogeneous shortening of the fiber is obtained, while heterogeneity in APD increases and the repolarization wave reverses. These results are in agreement with experimentally observed distributions of strain and APD and indicate that electrical remodeling leads to more homogeneous shortening during ejection. In the fifth study, we investigate the effect of stretch on the vulnerability to AF. The human atria are represented by a triangular mesh obtained from MRI data. To model acute dilatation, overall stretch is applied to the atria. In the presence of Isac, the membrane potential depolarizes, which causes inactivation of the sodium channels and results in conduction slowing or block. Inducibility of AF increases under stretch, which is explained by an increased dispersion in refractory period, conduction slowing, and local conduction block. Our observations explain the large differences in intra-atrial conduction measured in experiments and provide insight in the vulnerability to AF in dilated atria. In conclusion, our model is well-suited to describe cardiac electrophysiology and mechanoelectric feedback. For future applications, the model may be improved by taking into account new insights from cellular physiology, a more accurate geometry, and hemodynamics

Statistical Optimizations of Muscle Action Potentials Based on Modeling and Analysis of Ion Channel Dynamics

An Electromyogram (EMG) is an electrical signal, which is measured from a skeletal muscle during voluntary and involuntary contractions. EMGs are useful in interpreting pathological states of the musculoskeletal system. In particular, EMGs offer valuable information concerning the timing of muscular activity and its relative intensity. Various EMG models have developed with many different purposes from a pure mathematical model to a pattern structure model [17,46]. Sophisticated EMG models are necessary to examine the effects of small changes in muscular morphology and activities [46]. Due to the crucial importance of EMG models, all factors in the model should be precise and accurate. Especially, an intracellular action potential (IAP) model, the starting point of an EMG model, should be precisely generated because of its importance as the main component for an EMG model. Generally, the Rosenfalck IAP model [75,89] has been used because of its computational simplicity [59,72,77]. However, the Rosenfalck IAP model oversimplifies a real IAP, which has been experimentally measured, and it results in mismatching amplitudes and time duration between a real and modeled IAP. This research proposes a mathematical IAP model using a series of modified gamma and erlang probability density functions. The optimization of the proposed IAP model was conducted by several different numerical methods, namely Gauss-Newton, Steepest Descent, and Conjugate Gradient methods. These optimizing methods for the proposed muscle IAP model were validated by applying them to the experimental results of the Hudgkin and Huxley neuron action potential [11]. Due to the similarity in the mechanism of both nerve and muscle IAP generations, the validation shows that the methods and results are reasonably applied and obtained in the proposed muscle model, which for the first time incorporates properties that explain ion channel behavior in IAP generation

三次元心臓モデルと不均一振動モデルによる心臓活動電位のコンピュータシミュレーション

Tohoku University西條芳文論