Inversion of the current-distance relationship by transientdepolarization

The objective of this research was to develop a technique to excite selectively nerve fibers distant from an electrode without exciting nerve fibers close to the electrode. The shape of the stimulus current waveform was designed based on the nonlinear conductance properties of neuronal sodium channels. Models of mammalian peripheral myelinated axons and experimental measurements on cat sciatic nerve were used to determine the effects of subthreshold polarization on neural excitability and recruitment. Subthreshold membrane depolarization generated a transient decrease in neural excitability and thus an increase in the threshold for stimulation by a subsequent stimulus pulse. The decrease in excitability increased as the duration and amplitude of the subthreshold depolarization were increased, and the increase in threshold was greater for fibers close to the electrode. When a depolarizing stimulus pulse was applied immediately after the subthreshold depolarization, nerve fibers far from the electrode could be stimulated without stimulating fibers close to the electrode. Subthreshold depolarizing prepulses inverted the current-distance relationship and allowed selective stimulation of nerve fibers far from the electrode     

The effect of stimulus parameters on the recruitment characteristics of direct nerve stimulation

The effect of stimulus parameters on the recruitment characteristics of motor nerve was studied for regulated current monophasic and balanced charge biphasic stimuli. Results of a nerve model investigation indicated that the threshold difference between different diameter nerve fibers would be dependent on pulse width, the choice between monophasic and biphasic stimuli, and the delay between the primary cathodic and secondary anodic pulses. Threshold difference increased with decreasing pulse width, the greatest effects evident for pulses less than 100 ?s. Biphasic stimulation with no delay between pulses provided greater threshold separation than monophasic stimulation or biphasic stimulation with delay. Animal experiments, in which recruitment in a nerve trunk composed of mixed diameter nerve fibers was examined, showed a decrease in recruitment slope with a decrease in pulse width and with the use of a biphasic, zero delay pulse. These results were examined through muscle force measurements using both a metal loop electrode encircling the nerve trunk and a nerve cuff electrode, i. e., a loop electrode in an insulating tube.     

Sensitivity and selectivity of intraneural stimulation using a silicon electrode array

Artificial electrical stimulation of peripheral nerves needs the development of multielectrode devices which stimulate individual fibers or small groups in a selective and sensitive way. To this end, a multielectrode array in silicon technology has been developed, as well as experimental paradigms and model calculations for sensitivity and selectivity measures. The array consists of twelve platinum electrode sites (10 x 50 microns at 50 microns interdistance) on a 45 microns thick tip-shaped silicon substrate and a Si3N4 insulating glass cover layer. The tip is inserted in the peroneal nerve of the rat during acute experiments to stimulate alpha motor fibers of the extensor digitorum longus muscle. Sensitivity calculations and experiments show a cubic dependence of the number of stimulated motor units on current amplitude of the stimulatory pulse (recruitment curves), starting at single motor level. Selectivity was tested by a method based on the refractory properties of neurons. At the lowest stimulus levels (for one motor unit) selectivity is maximal when two electrodes are separated by 200-250 microns, which was estimated also on theoretical grounds. The study provides clues for future designs of two- and three-dimensional devices.     

Electrical stimulation of cardiac tissue: a bidomain model withactive membrane properties

Numerical calculations simulated the response of cardiac muscle to stimulation by electrical current. The bidomain model with unequal anisotropy ratios represented the tissue, and parallel leak and active sodium channels represented the membrane conductance. The speed of the wavefront was faster in the direction parallel to the myocardial fibers than in the direction perpendicular to them. However, for cathodal stimulation well above threshold, the wavefront originated farther from the cathode in the direction perpendicular to the myocardial fibers than in the direction parallel to them, consistent with observations of a dog-bone-shaped virtual cathode made by Wikswo et al., (Circ. Res., vol.68, p.513-30, 1991). The model showed that the virtual cathode size and shape were dependent upon both membrane and tissue conductivities. Increasing the peak Na conductance or reducing the transverse intracellular conductivity accentuated the dog-bone shape, while the opposite change caused the virtual cathode to become more elliptical, with the major axis of the ellipse transverse to the fiber direction. A cathodal stimulus created regions of hyperpolarization that slowed conduction of the wavefront propagating parallel to the fibers. An anodal stimulus evoked a wavefront with a complex shape; activation originated from two depolarized regions 1 to 2 mm from the stimulus site along the fiber direction. The threshold current strength (0.5 ms duration pulse) for a cathodal stimulus was 0.048 mA, and for an anodal stimulus was 0.67 mA. When the model was modified to simulate the effect of electropermeabilization, which may be present, when the transmembrane potential reaches very large values near the stimulating electrode, the authors' qualitative conclusions remained unchanged     

Modeling the effects of electric fields on nerve fibers: influenceof tissue electrical properties

The effects of anisotropy and inhomogeneity of the electrical conductivity of extracellular tissue on excitation of nerve fibers by an extracellular point source electrode were determined by computer simulation. Analytical solutions to Poison's equation were used to calculate potentials in anisotropic infinite homogeneous media and isotropic semi-infinite inhomogeneous media, and the net driving function was used to calculate excitation thresholds for nerve fibers. The slope and intercept of the current-distance curve in anisotropic media were power functions of the ratio and product of the orthogonal conductivities, respectively. Excitation thresholds in anisotropic media were also dependent on the orientation of the fibers, and in strongly anisotropic media (sigma z/sigma xy > 4) there were reversals in the recruitment order between different diameter fibers and between fibers at different distances from the electrode. In source-free regions of inhomogeneous media (two regions of differing conductivity separated by a plane boundary), the current-distance relationship of fibers parallel to the interface was dependent only on the average conductivity, whereas in regions containing the source the current-distance relationship was dependent on the individual values of conductivity. Reversals in recruitment order between fibers at different distances from the electrode and between fibers of differing diameter were found in inhomogeneous media. The results of this simulation study demonstrate that the electrical properties of the extracellular medium can have a strong influence on the pattern of neuronal excitation generated by extracellular electric fields, and indicate the importance of tissue electrical properties in interpreting results of studies employing electrical stimulation applied in complex biological volume conductors.     

Analysis of a Model for Excitation of Myelinated Nerve

Excellent models have been presented in the literature which relate membrane potential to transverse membrane current and which describe the propagation of action potentials along the axon, for both myelinated and nonmyelinated fibers. There is not, however, an adequate model for nerve excitation which allows one to compute the threshold of a nerve fiber for pulses of finite duration using electrodes that are not in direct contact with the fiber. This paper considers this problem and presents a model of the electrical properties of myelinated nerve which describes the time course of events following stimulus application up to the initiation of the action potential. The time-varying current and potential at all nodes can be computed from the model, and the strength-duration curve can be determined for arbitrary electrode geometries, although only the case of a monopolar electrode is considered in this paper. It is shown that even when the stimulus is a constant-current pulse, the membrane current at the nodes varies considerably with time. The strength-duration curve calculated from the model is consistent with previously published experimental data, and the model provides a quantitative relationship between threshold and fiber diameter which shows there is less selectivity among fibers of large diameter than those of small diameter.     

A novel nerve bundle containing thin muscle fibers in the posterior cricoarytenoid muscle of the marmoset

We examined a novel nerve bundle in the posterior cricoarytenoid muscle of the marmoset. This intramuscular nerve bundle contained two thin muscle fibers about 10 microm in diameter, like intrafusal muscle fibers in the muscle spindle. These thin muscle fibers were individually surrounded by nerve bundles consisting of numerous nonmyelinated nerve fibers. Individual nerve axons contained clear synaptic vesicles and large granulated vesicles, being possibly cholinergic (parasympathetic) in nature. These nerve axons were often in contact with the muscle fiber with and without an interposing basal lamina. Two thin muscle fibers gradually terminated in the endoneural connective tissue around myelinated and nonmyelinated nerve fibers during their course. The innervation of thin muscle fibers in the novel nerve bundle is briefly discussed.     

Selective activation of small motor axons by quasitrapezoidalcurrent pulses

We have found a method to activate electrically smaller nerve fibers without activating larger fibers in the same nerve trunk. The method takes advantage of the fact that action potentials are blocked with less membrane hyperpolarization in larger fibers than in smaller fibers. In our nerve stimulation system, quasitrapezoidal-shaped current pulses were delivered through a tripolar cuff electrode to effect differential block by membrane hyperpolarization. The quasitrapezoidal-shaped pulses with a square leading edge, a 350 microsecond(s) plateau, and an exponential trailing phase ensured the block of propagating action potentials and prevented the occurrence of anodal break excitation. The tripolar cuff electrode design restricted current flow inside the cuff and thus eliminated the undesired nerve stimulation due to a "virtual cathode." Experiments were performed on 13 cats. The cuff electrode was placed on the medial gastrocnemius nerve. Both compound and single fiber action potentials were recorded from L7 ventral root filaments. The results demonstrated that larger alpha motor axons could be blocked at lower current levels than smaller alpha motor axons, and that all alpha fibers could be blocked at lower current levels than gamma fibers. A statistical analysis indicated that the blocking threshold was correlated with the axonal conduction velocity or fiber diameter. This method could be used in physiological experiments and neural prostheses to achieve a small-to-large recruitment order in motor or sensory systems.     

Band-tunable and multiplexed integrated circuits for simultaneous recording and stimulation with microelectrode arrays

Two thin-film microelectrode arrays with integrated circuitry have been developed for extracellular neural recording in behaving animals. An eight-site probe for simultaneous neural recording and stimulation has been designed that includes on-chip amplifiers that can be individually bypassed, allowing direct access to the iridium sites for electrical stimulation. The on-probe amplifiers have a gain of 38.9 dB, an upper-cutoff frequency of 9.9 kHz, and an input-referred noise of 9.2 microV rms integrated from 100 Hz to 10 kHz. The low-frequency cutoff of the amplifier is tunable to allow the recording of field potentials and minimize stimulus artifact. The amplifier consumes 68 microW from +/- 1.5 V supplies and occupies 0.177 mm2 in 3 microm features. In vivo recordings have shown that the preamplifiers can record single-unit activity 1 ms after the onset of stimulation on sites as close as 20 microm to the stimulating electrode. A second neural recording array has been developed which multiplexes 32 neural signals onto four output data leads. Providing gain on this array eliminates the need for bulky headmounted circuitry and reduces motion artifacts. The time-division multiplexing circuitry has crosstalk between consecutive channels of less than 6% at a sample rate of 20 kHz per channel. Amplified, time-division-multiplexed multichannel neural recording allows the large-scale recording of neuronal activity in freely behaving small animals with minimum number of interconnect leads.     

Selective activation of distant nerve by surface electrode array

Neural prostheses for restoring lost functions can benefit from selective activation of nerves with limited number and density of electrodes. Here, we show by simulations and animal experiments that multipoint simultaneous stimulation with a surface electrode array can selectively activate nerves in a bundle at a desired location in between the array or at a desired depth, which are referred to as lateral or depth-wise gating stimulation, respectively. The stimulation broadly generates action potentials with cathodic source electrodes, and simultaneously blocks unnecessary propagation with downstream anodic gate electrodes. In general, stimulation with a small diameter electrode can affect a nearly hemispherical region, while a large electrode is effective at a more vertically compressed region, i.e., a surface of nerve bundle. The gating stimulation takes advantage of the size effects by utilizing an asymmetrical electrode array. The array of the lateral gating stimulation is designed to have four electrodes; a pair of large source electrodes and a pair of small gate electrodes. The depth-wise gating stimulation array consists of two electrodes; a large gate and small source electrodes. The simulation first demonstrated that appropriate combination of currents at the source and gate electrodes can change recruitment patterns of nerves with lateral or depth-wise selectivity as desired. We then applied the lateral gating stimulation on the rat spinal cords and obtained a preliminary support for the feasibility.     

Analysis of models for extracellular fiber stimulation

This paper presents the mathematical basis for analysis as well as for the computer simulation of the stimulus/response characteristics of nerve or muscle fibers. The results follow from the extracellular potential along the fiber as a function of electrode geometry. The theory is of a general nature but special investigations are made on monopolar, bipolar, and ring electrodes. Stimulations with monopolar electrodes show better recruitment characteristics than ring electrodes.     

Different pulse shapes to obtain small fiber selective activation by anodal blocking--a simulation study

The aim of this study was to investigate whether it is possible to reduce a charge per pulse, which is needed for selective nerve stimulation. Simulation is performed using a two-part simulation model: a volume conductor model to calculate the electrical potential distribution inside a tripolar cuff electrode and a human fiber model to simulate the fiber response to simulation. Selective stimulation is obtained by anodal block. To obtain anodal block of large fibers, long square pulses (> 350 micros) with a relatively high currents (1-2.5 mA) are usually required. These pulses might not be safe for a long-term application because of a high charge per pulse. In this study, several pulse shapes are proposed that have less charge per pulse compared with the conventional square pulse and would therefore be safer in a chronic application. Compared with the conventional square pulse, it was possible to reduce the charge with all proposed pulse shapes, but the best results are obtained with a combination of a square depolarizing pulse and a blocking pulse. The charge per pulse was up to 32% less with that pulse shape than with a square pulse. Using a hyperpolarizing anodal prepulse preceding a square pulse, it was not possible to block nerve fibers in a whole nerve bundle and to obtain reduction of a charge per phase. Reduction of the charge could be achieved only with spatially selective blocking. The charge per phase was larger for the combination of a hyperpolarizing anodal prepulse and a two-step pulse than for the two-step pulse alone.     

利用单电极不对称双向脉冲刺激实现哺乳动物有髓神经纤维选择性兴奋的仿真研究

本研究的目的是要从理论上探讨利用单电极双向脉冲刺激实现哺乳动物神经纤维选择性刺激,(即当刺激一束神经时,不兴奋粗神经而兴奋细神经)的可能性.双向脉冲刺激可以降低刺激脉冲对神经纤维产生的电化学损伤.为研究哺乳动物有髓神经纤维的电特性,建立了一个基于简单的无穷大、各向同性的容积导体模型的仿真系统.利用该仿真系统,采用"不对称但电荷平衡"的双向脉冲刺激,计算了神经纤维的兴奋和阻断阈值与纤维直径、纤维-电极间距离的关系.结果表明:在距电极一定距离内采用该双向脉冲刺激模式确实可以实现哺乳动物有髓神经纤维的选择性兴奋.     

Simulation analysis of conduction block in myelinated axons induced by high-frequency biphasic rectangular pulses

Nerve conduction block induced by high-frequency biphasic rectangular pulses was analyzed using a lumped circuit model of the myelinated axon based on Frankenhaeuser-Huxley (FH) equations. At the temperature of 37 degrees C, axons of different diameters (2-20 microm) can be blocked completely at supra-threshold intensities when the stimulation frequency is above 10 kHz. However, at stimulation frequencies between 6 kHz and 9 kHz, both nerve block and repetitive firing of action potentials can be observed at different stimulation intensities. When the stimulation frequency is below 6 kHz, nerve block does not occur regardless of stimulation intensity. Larger diameter axons have a lower threshold intensity to induce conduction block. When temperature is reduced from 37 degrees C to 20 degrees C, the lowest frequency to completely block large axons (diameters 10-20 microm) decreased from 8 kHz to 4 kHz. This simulation study can guide future animal experiments as well as optimize stimulation waveforms for electrical nerve block in clinical applications.     

Modulation of Muscle Force by Recruitment During Intramuscular Stimulation

The input?output relationships for modulation of force by recruitment during intramuscular electrical stimulation were examined for cat sleus muscles and human finger and thumb muscles. Recruitment was modulated by varying either the pulsewidth or amplitude of a monophasic, rectangular, cathodal current pulse train. Force was a nonlinear function of either pulsewidth or amplitude, and the shape of the nonlinearity was the same regardless of which parameter was modulated. The charge per stimulus pulse was lowest if pulsewidth was modulated with a fixed, high amplitude stimulus. The shape of the nonlinear relationship between pulsewidth and force (recruitment characteristic) depended on stimulus amplitude, electrode location in the muscle and muscle length. In most applications the amplitude and location would be fixed, so force would be a two-dimensional nonlinear function of pulsewidth and muscle length. The results are discussed with respect to possible mechanisns of recruitment during intramuscular stimulation, and the implications of the nonlinearities on the proportional control of orthoses employing electrically stimulated muscles.     

Recording from a Single Motor Unit During Strong Effort

During strong voluntary effort it is rarely possible to identify the action potentials from single motor units. In large muscles the most selective recordings are obtained with bipolar wire electrodes. To elucidate this experimental finding we have calculated the extracellular field around a single muscle fiber from an intracellular muscle action potential. This model showed that the selectivity of a bipolar electrode is high provided: i) the diameter of the recording surfaces is less than half the diameter of the muscle fibers; ii) the center distance between the recording surfaces is of the same order or smaller than the diameter of the muscle fibers, and when iii) the center-line between the recording surfaces is oriented perpendicular to the direction of the muscle fibers.     

A method to effect physiological recruitment order in electricallyactivated muscle

A new stimulation method has been utilized to achieve physiological recruitment order of small-to-large motor units in electrically activated muscles. The use of quasitrapezoidal-shaped pulses and a tripolar cuff electrode made selective activation of small motor axons possible, thus recruiting slow-twitch, fatigue-resistant muscle units before fast-twitch, fatigable units in a heterogeneous muscle. Isometric contraction force from the medial gastrocnemius muscle was measured in five cats. The physiological recruitment order was evidenced by larger twitch widths at lower force levels and smaller twitch widths at higher force levels in the muscles tested. In addition, force modulation process was more gradual and fused contractions were obtained at lower stimulation frequencies when the new stimulation method was employed. Furthermore, muscles activated by the new method were more fatigue-resistant under repetitive activation at low force levels. This stimulation method is simpler to implement and has fewer adverse effects on the neuromuscular system than previous blocking methods. Therefore, it may have applications in future functional neuromuscular stimulation systems.     

A polyimide pressure-contact multielectrode array for implantation along a submillimeter neural process in small animals

We describe a microelectrode system for recordings from nerve bundles with diameters ranging from 20-200 microm. A novel polyimide structure allows for a planar microfabricated device to constrain a free neural process against several recording sites. This polyimide array contains multiple zigzag vias through which a small nerve process may be woven while remaining functionally intact in a live preparation. Our electrode construct features the benefits of nerve cuffs (evenly spaced electrodes in a polymer) and the functionality of a nerve hook (ability to connect to submillimeter processes). The device records extracellular action potentials in the red-swamp crayfish, Procambarus clarkii. Action potential propagation is monitored at several sites along a constrained nerve in this model organism's peripheral nervous system. Details of temporal accuracy and error sources in absolute conduction velocity measurements from microelectrode arrays are discussed.     

Long-term intramuscular electrical activation of the phrenic nerve:efficacy as a ventilatory prosthesis

The efficacy of a system for long-term intramuscular activation of the phrenic nerve as a ventilatory prosthesis was evaluated in seven dogs. Five dogs underwent chronic bilateral intramuscular diaphragm stimulation (IDS) for 61 to 183 days at stimulus parameters selected to evoke at least 120% of the animal's basal ventilation. Two dogs maintained as controls did not undergo chronic stimulation. The ability of IDS to provide long-term ventilation without diaphragm fatigue was evaluated in terms of the ventilatory capacity of IDS, the effects of chronic IDS on diaphragm contractile properties, and the phrenic nerve recruitment properties of chronic IDS electrodes. Hemi-diaphragms with electrodes placed within 2 cm of the phrenic nerve trunk could be completely activated by 25 mA pulses having a 100 μs pulse width. The tidal volume evoked by IDS in this study was 167% (±48 s.d.) of that required for full-time basal ventilation without diaphragm fatigue. Evoked tidal volume increased after 8 to 9 weeks of chronic IDS for stimulus pulse intervals longer than 50 ms. Electrode recruitment properties were stable for both active and passive implanted electrodes. It is concluded from these studies that with properly placed electrodes IDS is capable of providing reliable full-time ventilatory support without fatiguing the diaphragm     

Electrical stimulation of the auditory nerve: direct current measurement in vivo

Neural prostheses use charge recovery mechanisms to ensure the electrical stimulus is charge balanced. Nucleus cochlear implants short all stimulating electrodes between pulses in order to achieve charge balance, resulting in a small residual direct current (DC). In the present study we sought to characterize the variation of this residual DC with different charge recovery mechanisms, stimulation modes, and stimulation parameters, and by modeling, to gain insight into the underlying mechanisms. In an acute study with anaesthetised guinea pigs, DC was measured in four platinum intracochlear electrodes stimulated using a Nucleus C124M cochlear implant at moderate to high pulse rates (1200-14,500 pulses/s) and stimulus intensities (0.2-1.75 mA at 26-200 microseconds/phase). Both monopolar and bipolar stimulation modes were used, and the effects of shorting or combining a capacitor with shorting for charge recovery were investigated. Residual DC increased as a function of stimulus rate, stimulus intensity, and pulse width. DC was lower for monopolar than bipolar stimulation, and lower still with capacitively coupled monopolar stimulation. Our model suggests that residual DC is a consequence of Faradaic reactions which allow charge to leak through the electrode tissue interface. Such reactions and charge leakage are still present when capacitors are used to achieve charge recovery, but anodic and cathodic reactions are balanced in such a way that the net charge leakage is zero.