Endoneural selective stimulating using wire-microelectrode arrays.

In acute experiments eight 5- to 24-wire-microelectrode arrays were inserted into the common peroneal nerve of the rat, to investigate whether the electrodes could selectively stimulate motor units of the extensor digitorum longus (EDL) muscle. Twitch-force-recruitment curves were measured from the EDL for each array electrode. The curves were plotted on a double-logarithmic scale and parameterized by the low-force slope (which represents the power p in the power-law relationship of force F versus stimulus current I, or F approximately I(p)) and the threshold current. The slopes and threshold currents measured with array electrodes did not differ significantly from those obtained with randomly inserted single wire-microelectrodes. This indicates that, although involving a more invasive insertion procedure, electrode arrays provide neural contacts with low-force recruitment properties similar to those of single wires. Array results revealed partial blocking of neural conduction, similar to that reported with microneurographic insertion with single needles. The efficiency of the array was defined as the fraction of array electrodes selectively contacting a motor unit and evoking the corresponding threshold force. Efficiency thus expresses the practical value of the used electrode array in terms of the total number of distinct threshold forces that can be stimulated by selecting the appropriate electrodes. The eight arrays were capable of evoking threshold forces selectively with an average efficiency of 0.81 (or 81%).

Validity and reproducibility of crutch force and heart rate measurements to assess energy expenditure of paraplegic gait.

OBJECTIVE: To determine the validity and reproducibility of heart rate (HR) and crutch force measurements to estimate energy expenditure during paraplegic walking. Usefulness of these outcome measures in comparative trials was assessed in terms of responsiveness. DESIGN: Cross-sectional validity was determined using one single (first) measurement. Longitudinal validity as well as reproducibility were calculated using repeated measurements. SETTING: Oxygen uptake and HR during steady state as well as axial crutch load were measured at subjects' self-selected walking speeds. PATIENTS: Ten subjects with thoracic-level spinal cord injury were included in the study. All subjects had considerable experience with ambulation in the advanced reciprocating gait orthosis (ARGO). MAIN OUTCOME MEASURES: Oxygen uptake (VO2, mL/min) and oxygen cost (EO2, mL/m) were used as criterion standards. Crutch peak force (CPF), crutch force time integral (CFTI), HR, and physiological cost index (PCI) were used to estimate energy expenditure. RESULTS: The PCI was found to be sensitive to detect differences between sessions in criterion standard (r = .86). Smallest detectable difference (ie, point where difference exceeds measurement error) ranged from approximately 15% for CPF to 33.7% and 41.8% for EO2 and PCI, respectively. CONCLUSIONS: Although PCI is expected to be a valid measure for within-patient differences in VO2, responsiveness was lower compared to EO2 and CPF. The limited number of patients who can be included in studies on paraplegic locomotion requires reproducible outcome measures. Therefore, CPF and EO2 are advocated in favor of PCI.

A model of the electrical behaviour of myelinated sensory nerve fibres based on human data.

Calculation of the response of human myelinated sensory nerve fibres to spinal cord stimulation initiated the development of a fibre model based on electrophysiological and morphometric data for human sensory nerve fibres. The model encompasses a mathematical description of the kinetics of the nodal membrane, and a non-linear fibre geometry. Fine tuning of only a few, not well-established parameters was performed by fitting the shape of a propagating action potential and its diameter-dependent propagation velocity. The quantitative behaviour of this model corresponds better to experimentally determined human fibre properties than other mammalian, nonhuman models do. Typical characteristics, such as the shape of the action potential, the propagation velocity and the strength-duration behaviour show a good fit with experimental data. The introduced diameter-dependent parameters did not result in a noticeable diameter dependency of action potential duration and refractory period. The presented model provides an improved tool to analyse the electrical behaviour of human myelinated sensory nerve fibres.

Comparative trials on hybrid walking systems for people with paraplegia: an analysis of study methodology.

A new orthosis (SEPRIX) which combines user friendliness with low energy cost of walking has been developed and will be subject to a clinical comparison with conventional hip-knee-ankle-foot orthoses. In designing such comparative trials it was considered it may be worthwhile to use previous clinical studies as practical examples. A literature search was conducted in order to select all comparative trials which have studied two walking systems (hip-knee-ankle-foot orthoses) for patients with a complete thoracic lesion. Study population, intervention, study design, outcome measurement and statistical analyses were examined. Statistical power was calculated where possible. Of 12 selected studies, 7 were simple A-B comparisons, 2 A-B comparisons with a replication, 2 cross-over trials and 1 nonrandomised parallel group design, the last of which was considered internally invalid due to severe confounding by indication. All A-B comparisons were considered internally invalid as well, since they have not taken into account that a comparison of two orthoses requires a control for aspecific effects (like test effects) which may cause a difference. Statistical power could only be examined in 4 studies and the highest statistical power achieved in one study was 47%. It is concluded that statistical power was too low to be able to detect differences. Even analysis through interval estimation showed that the estimation of the difference was too imprecise to be useful. Since the majority of the surveyed papers have reported small studies (of only 4-6 patients), it is assumed that lack of statistical power is a more general problem. Three possibilities are discussed in order to enhance statistical power in comparative trials, i.e. multicentre studies, statistical pooling of results and improving the efficiency of study design by means of interrupted time series designs.

Quantitative aspects of the clinical performance of transverse tripolar spinal cord stimulation.

A multicenter study was initiated to evaluate the performance of the transverse tripolar system for spinal cord stimulation. Computer modeling had predicted steering of paresthesia with a dual channel stimulator to be the main benefit of the system. The quantitative analysis presented here includes the results of 484 tests in 30 patients. For each test, paresthesia coverage as a function of voltage levels was stored in a computerized database, including a body map which enabled calculation of the degree of paresthesia coverage of separate body areas, as well as the overlap with the painful areas. The results show that with the transverse tripolar system steering of the paresthesia is possible, although optimal steering requires proper placement of the electrode with respect to the spinal cord. Therefore, with this steering ability as well as a larger therapeutic stimulation window as compared to conventional systems, we expect an increase of the long-term efficacy of spinal cord stimulation. Moreover, in view of the stimulation-induced paresthesia patterns, the system allows selective stimulation of the medial dorsal columns.

Speed dependence of crutch force and oxygen uptake: implications for design of comparative trials on orthoses for people with paraplegia.

OBJECTIVE: To determine speed dependence of crutch force and oxygen uptake, and to discuss the implications of differences in self-selected walking speed between orthoses in a comparative trial. DESIGN: Cross-sectional comparison. SETTING: Treadmill experiments and gait laboratory experiments were performed at five and three different imposed walking speeds, respectively. PATIENTS: Five paraplegic subjects with lesions between T9 and T12 were included. All subjects had experience with ambulation using the advanced reciprocating gait orthosis (ARGO) as well as walking on a treadmill. MAIN OUTCOME MEASURES: Crutch force time integral (CFTI), crutch peak force on stance and swing side (CPFstance and CPFswing), oxygen uptake (VO2), oxygen cost (EO2). RESULTS: VO2, EO2, and CFTI were strongly dependent on walking speed. CPFstance and CPFswing were less dependent. However, depending on the clinically relevant difference that should be detected in a comparative trial, the peak forces can still be confounded by walking speed. CONCLUSION: CFTI, CPFswing, VO2, and EO2 should be adjusted for walking speed if differences in walking speed between orthoses are found, but this correction is relevant only if there is no effect modification. Such modification (different slopes between orthoses) cannot be excluded for the studied outcome measures. In addition, because determination of effect modification is difficult in small studies, standardization of walking speed, by means of a three-point design, is recommended.

Estimation of fiber diameters in the spinal dorsal columns from clinical data.

Lack of human morphometric data regarding the largest nerve fibers in the dorsal columns (DC's) of the spinal cord has lead to the estimation of the diameters of these fibers from clinical data retrieved from patients with a new spinal cord stimulation (SCS) system. These patients indicated the perception threshold of stimulation induced paresthesia in various body segments, while the stimulation amplitude was increased. The fiber diameters were calculated with a computer model, developed to calculate the effects of SCS on spinal nerve fibers. This computer model consists of two parts: 1) a three-dimensional (3-D) volume conductor model of a spinal cord segment in which the potential distribution due to electrical stimulation is calculated and 2) an electrical equivalent cable model of myelinated nerve fiber, which uses the calculated potential field to determine the threshold stimulus needed for activation. It is shown that the largest fibers in the medial DC's are significantly smaller than the largest fibers in the lateral parts. This finding is in accordance with the fiber distribution in cat, derived from the corresponding propagation velocities. Moreover, it is shown that the mediolateral increase in fiber diameter is mainly confined to the lateral parts of the DC's. Implementation of this mediolateral fiber diameter distribution of the DC's in the computer model enables the prediction of the recruitment order of dermatomal paresthesias following increasing electrical stimulation amplitude.

Extracellular potentials from active myelinated fibers inside insulated and noninsulated peripheral nerve.

A model is presented that calculates the single-fiber extracellular field and action potential (ap) of an active myelinated nerve fiber placed centrally or eccentrically inside a nerve with a cylindrical geometry, representing essentially a one-fascicle nerve. This one-fascicle nerve has the dimensions and conductivities of the rat peroneal nerve branch. The results show a wide variety of wave shapes to be measured, depending on the position of the intraneural electrode with respect to the fiber axis and to the nodes of Ranvier and depending on the presence of an isolating cuff around the nerve. Action potential shapes may range from the "classical" quasi-biphasic one, to more triphasic, or even more complicated in the case of a short insulating cuff being present around the nerve. In the latter case, when measured bipolarly, ap-wave shapes become almost monophasic.

Transverse tripolar stimulation of peripheral nerve: a modelling study of spatial selectivity.

Various anode-cathode configurations in a nerve cuff are modelled to predict their spatial selectivity characteristics for functional nerve stimulation. A 3D volume conductor model of a monofascicular nerve is used for the computation of stimulation-induced field potentials, whereas a cable model of myelinated nerve fibre is used for the calculation of the excitation thresholds of fibres. As well as the usual configurations (monopole, bipole, longitudinal tripole, 'steering' anode), a transverse tripolar configuration (central cathode) is examined. It is found that the transverse tripole is the only configuration giving convex recruitment contours and therefore maximises activation selectivity for a small (cylindrical) bundle of fibres in the periphery of a monofascicular nerve trunk. As the electrode configuration is changed to achieve greater selectivity, the threshold current increases. Therefore threshold currents for fibre excitation with a transverse tripole are relatively high. Inverse recruitment is less extreme than for the other configurations. The influences of several geometrical parameters and model conductivities of the transverse tripole on selectivity and threshold current are analysed. In chronic implantation, when electrodes are encapsulated by a layer of fibrous tissue, threshold currents are low, whereas the shape of the recruitment contours in transverse tripolar stimulation does not change.

Analysis of current density and related parameters in spinal cord stimulation.

A volume conductor model of the spinal cord and surrounding anatomical structures is used to calculate current (and current density) charge per pulse, and maximum charge density per pulse at the contact surface of the electrode in the dorsal epidural space, in the dorsal columns of the spinal cord and in the dorsal roots. The effects of various contact configurations (mono-, bi-, and tripole), contact area and spacing, pulsewidth and distance between contacts and spinal cord on these electrical parameters were investigated under conditions similar to those in clinical spinal cord stimulation. At the threshold stimulus of a large dorsal column fiber, current density and charge density per pulse at the contact surface were found to be highest (1.9.10(5) microA/cm2 and 39.1 microC/cm2.p, respectively) when the contact surface was only 0.7 mm2. When stimulating with a pulse of 500 microseconds, highest charge per pulse (0.92 microC/p), and the largest charge density per pulse in the dorsal columns (1.59 microC/cm2. p) occurred. It is concluded that of all stimulation parameters that can be selected freely, only pulsewidth affects the charge and charge density per pulse in the nervous tissue, whereas both pulsewidth and contact area strongly affect these parameters in the nonnervous tissue neighboring the electrode contacts.

Force-current relationships in intraneural stimulation: role of extraneural medium and motor fibre clustering.

Animal experiments and model simulations of monopolar, intrafascicular nerve stimulation are presented to study force-current relationships (recruitment curves). The conductivity of the extraneural medium is of prime importance to the resulting recruitment cures: an insulating extraneural medium generally leads to steeper curves with lower threshold currents than a well-conducting extraneural medium. Extensive statistical comparison of experimental and model results suggests the occurrence of clustering of alpha-motoneurons within the fascicle, manifesting itself mainly by an increased spread in threshold currents, as opposed to the situation where the fibres are distributed uniformly throughout the entire fascicle.

Rupture of the arterial wall causes deflection in pressure time course during ex vivo balloon angioplasty.

A relation between restenosis and arterial lesions resulting from balloon angioplasty has been suggested in literature. Nevertheless, it is unclear to what extent angioplasty-induced arterial wall lesions contribute to the occurrence of restenosis. One problem is that arterial ruptures cannot be detected during balloon inflation. This study describes a method to detect ruptures in the arterial wall, based on deflections observable in the development of the balloon pressure. We performed ex vivo angioplasty with constant strain rate on 28 human femoral artery segments, showing deflections in 21 cases. In 20 cases wall rupture was confirmed histologically. From seven cases not showing deflections, four showed intact wall at microscopy. These figures result in a selectivity of the proposed method of 87 +/- 7% and a predictive value of the positive test of 95 +/- 5%. We conclude that this method can enhance detection of arterial rupture during ex vivo angioplasty and may become important clinically.

The influence of the reciprocal cable linkage in the advanced reciprocating gait orthosis on paraplegic gait performance.

A wide variety of mechanical orthoses is available to provide ambulation to paraplegic patients. Evaluation of energy cost during walking in each of these devices has been acknowledged as an important topic in this field of research. In order to investigate the benefits of a ballistic swing on gait performance in the Advanced Reciprocating Gait Orthosis (ARGO) a study was conducted in which the ARGO was compared with an orthosis with freely swinging legs. This Non Reciprocally linked Orthosis (NRO) was obtained by removing the reciprocal linkage in the subjects' own ARGOs. Subsequently, flexion/extension limits were mounted to permit adjustment of stride length. Six male paraplegic subjects with lesions ranging from T4 to T12 were included in the study. A single case experimental design (B-A-B-A) was conducted in order to improve internal validity. Biomechanical and physiological parameters were assessed and the subjects' preference for either ARGO or NRO was determined. It was found that large inter-individual differences produced insufficient evidence in this study to draw general conclusions about difference in energy expenditure between both orthoses. However, individual analysis of the results showed a reduction of oxygen cost (range: 4%-14%) in the NRO in T9 and T12 lesions, while oxygen cost in subjects with T4 lesions increased markedly (22% and 40%). It is concluded that patients with low level lesions could benefit in terms of oxygen lost from removing the reciprocal cable linkage in the ARGO. However, only one subject preferred the NRO for walking, whereas none of the subject chose the NRO for use in daily living activities. Removal of the reciprocal cable linkage in the ARGO may not be desirable for these patients.

Influence of inhomogeneities in muscle tissue on single-fibre action potentials: a model study.

The influence of changes in electrical conductivity, due to the muscle boundary, layers and compartments of intramuscular connective tissue and blood vessels, on computed single-muscle fibre action potentials (SFAPs) in rat hindleg muscle is calculated. The position of the active fibre is varied throughout the muscle. For fibres close to the muscle boundary, peak-to-peak voltages of SFAPs increase by up to a factor of 3 compared with the unbounded situation. For inner fibres, the presence of nearby connective tissue compartments causes an increase of up to 40%. A blood vessel in the neighbourhood of the active fibre leads to a decrease of at most 20%, for recording sites between the active fibre and the blood vessel. For recording sites beyond the blood vessel, peak-to-peak voltages increase by up to 20%.

The influence of voluntary upper body exercise on the performance of stimulated paralysed human quadriceps.

In this study the influence of voluntary upper body exercise on the performance of stimulated paralysed human quadriceps was investigated in five subjects with spinal cord lesions in the thoracic spine. The experimental setup consisted of computer-controlled stimulation of the quadriceps using electrodes on the surface of the skin, a dynamometer for isometric or isokinetic loading of the lower leg, and a rowing ergometer for upper body exercise. In all subjects, quadriceps fatigue tests were conducted to study the influence of upper body exercise on knee torque during sustained continuous or intermittent stimulation of quadriceps. The relative asymptotic torque appeared to be significantly higher with the presence of upper body exercise than without. This was consistently found both between trials (starting with or without upper body exercise) as well as within trials, when upper body exercise was started or stopped during the trial. No significant influence of upper body exercise on the time constant of initial torque decline was found.

The influence of the reciprocal hip joint link in the Advanced Reciprocating Gait Orthosis on standing performance in paraplegia.

The effect of reciprocally linking the hip hinges of a hip-knee-ankle-foot orthosis on standing performance was studied in a comparative trial of the Advanced Reciprocating Gait Orthosis (ARGO) and an ARGO in which the Bowden cable was removed (A_GO). Six male subjects with spinal cord injury (SCI) at T4 to T12 level participated in the study, which was conducted using a single case experimental design. Standing balance, the ability to handle balance disturbances (standing stability), and the performance of a functional hand task during standing were assessed in both orthosis configurations in the order A_GO-ARGO-A_GO-ARGO. No significant differences with respect to standing performance were found for the two orthosis configurations. However, the results indicate that the crutch force needed for maintaining balance during various tasks, especially for quiet standing with two crutches, may be much higher in the orthosis without Bowden cable. Therefore, it is very likely that the reciprocal hip joint link in the ARGO provides a substantial and clinically relevant reduction of upper body effort required for standing under functional conditions.

Force recruitment during electrical nerve stimulation with multipolar intrafascicular electrodes.

Experimentally, during electrical nerve stimulation, the influence is examined of two intrafascicular anodes on the force recruitment with one intrafascicular cathode. It is found that the anodes suppress recruitment and that this effect is more pronounced when the distance of the anodes to the cathode is decreased, or when the anodal currents are increased. The measured recruitment curve patterns can be qualitatively explained by a nerve stimulation model that calculates theoretical recruitment curves for intrafascicular multi-electrode configurations. Discrepancies between the experimental and the theoretical recruitment curves are seen, but these can be understood by taking into account a non-uniform fibre distribution.

Cycle-to-cycle control of swing phase of paraplegic gait induced by surface electrical stimulation.

Parameterised swing phase of gait in paraplegics was obtained using surface electrical stimulation of the hip flexors, hamstrings and quadriceps; the hip flexors were stimulated to obtain a desired hip angle range, the hamstrings to provide foot clearance in the forward swing, and the quadriceps to acquire knee extension at the end of the swing phase. We report on two main aspects; optimisation of the initial stimulation parameters, and parameter adaptation (control). The initial stimulation patterns were experimentally optimised in two paraplegic subjects using a controlled stand device, resulting in an initial satisfactory swinging motion in both subjects. Intersubject differences appeared in the mechanical output (torque joint) per muscle group. During a prolonged open-loop controlled trial with the optimised but unregulated stimulation onsets and burst duration for the three muscle groups, the hip angle range per cycle initially increased above the desired value and subsequently decreased below it. The mechanical performance of the hamstrings and quadriceps remained relatively unaffected. A cycle-to-cycle controller was then designed, operating on the basis of the hip angle ranges obtained in previous swings. This controller successfully adapted the burst duration of the hip flexors to maintain the desired hip angle range.

Ionic currents during action potentials in mammalian skeletal muscle fibers analyzed with loose patch clamp.

The loose patch-clamp technique was applied to analyze transmembrane currents during propagating action potentials in superficial fibers of musculi extensor digitorum longus of the mouse in vitro. Experimentally three components were identified in the transmembrane current: 1) a capacitive, 2) an inward sodium, and 3) an outward potassium current. Other components were negligible. The capacitive current was similar in shape to the first derivative of the intracellularly measured action potential. Tetrodotoxin, tetraethylammonium, and 4-aminopyridine, applied in the pipette, were used to identify the contribution in the current by sodium and potassium ions. With extracellularly applied depolarization steps only a sodium current was observed, not a potassium current. Occasionally found outward currents were artifactual. The behaviour of delayed rectifier potassium channels in muscle fiber membranes is discussed in the light of these unexpected findings. We conclude that potassium channel activity contributing to and measured during action potential generation is in some way inaccessible to loose patch extracellular voltage-clamp stimulation and that loose patch action current recording is a useful noninvasive method to analyze membrane conductances involved in action potential generation.