Intraspinal microstimulation produces over-ground walking in anesthetized cats.

OBJECTIVE: Spinal cord injury causes a drastic loss of motor, sensory and autonomic function. The goal of this project was to investigate the use of intraspinal microstimulation (ISMS) for producing long distances of walking over ground. ISMS is an electrical stimulation method developed for restoring motor function by activating spinal networks below the level of an injury. It produces movements of the legs by stimulating the ventral horn of the lumbar enlargement using fine penetrating electrodes (≤50 µm diameter). APPROACH: In each of five adult cats (4.2-5.5 kg), ISMS was applied through 16 electrodes implanted with tips targeting lamina IX in the ventral horn bilaterally. A desktop system implemented a physiologically-based control strategy that delivered different stimulation patterns through groups of electrodes to evoke walking movements with appropriate limb kinematics and forces corresponding to swing and stance. Each cat walked over an instrumented 2.9 m walkway and limb kinematics and forces were recorded. MAIN RESULTS: Both propulsive and supportive forces were required for over-ground walking. Cumulative walking distances ranging from 609 to 835 m (longest tested) were achieved in three animals. In these three cats, the mean peak supportive force was 3.5 ± 0.6 N corresponding to full-weight-support of the hind legs, while the angular range of the hip, knee, and ankle joints were 23.1 ± 2.0°, 29.1 ± 0.2°, and 60.3 ± 5.2°, respectively. To further demonstrate the viability of ISMS for future clinical use, a prototype implantable module was successfully implemented in a subset of trials and produced comparable walking performance. SIGNIFICANCE: By activating inherent locomotor networks within the lumbosacral spinal cord, ISMS was capable of producing bilaterally coordinated and functional over-ground walking with current amplitudes <100 µA. These exciting results suggest that ISMS may be an effective intervention for restoring functional walking after spinal cord injury.

Real-time control of walking using recordings from dorsal root ganglia.

OBJECTIVE: The goal of this study was to decode sensory information from the dorsal root ganglia (DRG) in real time, and to use this information to adapt the control of unilateral stepping with a state-based control algorithm consisting of both feed-forward and feedback components. APPROACH: In five anesthetized cats, hind limb stepping on a walkway or treadmill was produced by patterned electrical stimulation of the spinal cord through implanted microwire arrays, while neuronal activity was recorded from the DRG. Different parameters, including distance and tilt of the vector between hip and limb endpoint, integrated gyroscope and ground reaction force were modelled from recorded neural firing rates. These models were then used for closed-loop feedback. MAIN RESULTS: Overall, firing-rate-based predictions of kinematic sensors (limb endpoint, integrated gyroscope) were the most accurate with variance accounted for >60% on average. Force prediction had the lowest prediction accuracy (48 ± 13%) but produced the greatest percentage of successful rule activations (96.3%) for stepping under closed-loop feedback control. The prediction of all sensor modalities degraded over time, with the exception of tilt. SIGNIFICANCE: Sensory feedback from moving limbs would be a desirable component of any neuroprosthetic device designed to restore walking in people after a spinal cord injury. This study provides a proof-of-principle that real-time feedback from the DRG is possible and could form part of a fully implantable neuroprosthetic device with further development.

Feed forward and feedback control for over-ground locomotion in anaesthetized cats.

The biological central pattern generator (CPG) integrates open and closed loop control to produce over-ground walking. The goal of this study was to develop a physiologically based algorithm capable of mimicking the biological system to control multiple joints in the lower extremities for producing over-ground walking. The algorithm used state-based models of the step cycle each of which produced different stimulation patterns. Two configurations were implemented to restore over-ground walking in five adult anaesthetized cats using intramuscular stimulation (IMS) of the main hip, knee and ankle flexor and extensor muscles in the hind limbs. An open loop controller relied only on intrinsic timing while a hybrid-CPG controller added sensory feedback from force plates (representing limb loading), and accelerometers and gyroscopes (representing limb position). Stimulation applied to hind limb muscles caused extension or flexion in the hips, knees and ankles. A total of 113 walking trials were obtained across all experiments. Of these, 74 were successful in which the cats traversed 75% of the 3.5 m over-ground walkway. In these trials, the average peak step length decreased from 24.9 ± 8.4 to 21.8 ± 7.5 (normalized units) and the median number of steps per trial increased from 7 (Q1 = 6, Q3 = 9) to 9 (8, 11) with the hybrid-CPG controller. Moreover, within these trials, the hybrid-CPG controller produced more successful steps (step length ≤ 20 cm; ground reaction force ≥ 12.5% body weight) than the open loop controller: 372 of 544 steps (68%) versus 65 of 134 steps (49%), respectively. This supports our previous preliminary findings, and affirms that physiologically based hybrid-CPG approaches produce more successful stepping than open loop controllers. The algorithm provides the foundation for a neural prosthetic controller and a framework to implement more detailed control of locomotion in the future.

Neuro-fuzzy decoding of sensory information from ensembles of simultaneously recorded dorsal root ganglion neurons for functional electrical stimulation applications.

Functional electrical stimulation (FES) is used to improve motor function after injury to the central nervous system. Some FES systems use artificial sensors to switch between finite control states. To optimize FES control of the complex behavior of the musculo-skeletal system in activities of daily life, it is highly desirable to implement feedback control. In theory, sensory neural signals could provide the required control signals. Recent studies have demonstrated the feasibility of deriving limb-state estimates from the firing rates of primary afferent neurons recorded in dorsal root ganglia (DRG). These studies used multiple linear regression (MLR) methods to generate estimates of limb position and velocity based on a weighted sum of firing rates in an ensemble of simultaneously recorded DRG neurons. The aim of this study was to test whether the use of a neuro-fuzzy (NF) algorithm (the generalized dynamic fuzzy neural networks (GD-FNN)) could improve the performance, robustness and ability to generalize from training to test sets compared to the MLR technique. NF and MLR decoding methods were applied to ensemble DRG recordings obtained during passive and active limb movements in anesthetized and freely moving cats. The GD-FNN model provided more accurate estimates of limb state and generalized better to novel movement patterns. Future efforts will focus on implementing these neural recording and decoding methods in real time to provide closed-loop control of FES using the information extracted from sensory neurons.

Limb-state feedback from ensembles of simultaneously recorded dorsal root ganglion neurons.

Functional electrical stimulation (FES) holds great potential for restoring motor functions after brain and spinal cord injury. Currently, most FES systems are under simple finite state control, using external sensors which tend to be bulky, uncomfortable and prone to failure. Sensory nerve signals offer an interesting alternative, with the possibility of continuous feedback control. To test feasibility, we recorded from ensembles of sensory neurons with microelectrode arrays implanted in the dorsal root ganglion (DRG) of walking cats. Limb position and velocity variables were estimated accurately (average R2 values >0.5) over a range of walking speeds (0.1-0.5 m s(-1)) using a linear combination of firing rates from 10 or more neurons. We tested the feasibility of sensory control of intraspinal FES by recording from DRG neurons during hindlimb movements evoked by intraspinal microstimulation of the lumbar spinal cord in an anesthetized cat. Although electrical stimulation generated artifacts, this problem was overcome by detecting and eliminating events that occurred synchronously across the array of microelectrodes. The sensory responses to limb movement could then be measured and decoded to generate an accurate estimate of the limb state. Multichannel afferent recordings may thus provide FES systems with the feedback needed for adaptive control and perturbation compensation, though long-term stability remains a challenge.

Movements generated by intraspinal microstimulation in the intermediate gray matter of the anesthetized, decerebrate, and spinal cat.

The intermediate laminae of the lumbosacral spinal cord are suggested to contain a small number of specialized neuronal circuits that form the basic elements of movement construction ("movement primitives"). Our aim was to study the properties and state dependence of these hypothesized circuits in comparison with movements elicited by direct nerve or muscle stimulation. Microwires for intraspinal microstimulation (ISMS) were implanted in intermediate laminae throughout the lumbosacral enlargement. Movement vectors evoked by ISMS were compared with those evoked by stimulation through muscle and nerve electrodes in cats that were anesthetized, then decerebrated, and finally spinalized. Similar movements could be evoked under anesthesia by ISMS and nerve and muscle stimulation, and these covered the full work space of the limb. ISMS-evoked movements were associated with the actions of nearby motoneuron pools. However, after decerebration and spinalization, ISMS-evoked movements were dominated by flexion, with few extensor movements. This indicates that the outputs of neuronal networks in the intermediate laminae depend significantly on descending input and on the state of the spinal cord. Frequently, the outputs also depended on stimulus intensity. These experiments suggest that interneuronal circuits in the intermediate and ventral regions of the spinal cord overlap and their function may be to process reflex and descending activity in a flexible manner for the activation of nearby motoneuron pools.

Encoding mechanisms for sensory neurons studied with a multielectrode array in the cat dorsal root ganglion.

Recent advances in microelectrode array technology now permit a direct examination of the way populations of sensory neurons encode information about a limb's position in space. To address this issue, we recorded nerve impulses from about 100 single units simultaneously in the L6 and L7 dorsal root ganglia (DRG) of the anesthetized cat. Movement sensors, placed near the hip, knee, ankle, and foot, recorded passive movements of the cat's limb while it was moved pseudo-randomly. The firing rate of the neurons was correlated with the position of the limb in various coordinate systems. The firing rates were less correlated to the position of the foot in Cartesian coordinates (x, y) than in joint angular coordinates (hip, knee, ankle), or in polar coordinates. A model was developed in which position and its derivatives are encoded linearly, followed by a nonlinear spike-generating process. Adding the nonlinear portion significantly increased the correlations in all coordinate systems, and the full models were able to accurately predict the firing rates of various types of sensory neurons. The observed residual variability is captured by a simple stochastic model. Our results suggest that compact encoding models for primary afferents recorded at the DRG are well represented in polar coordinates, as has previously been suggested for the cortical and spinal representation of movement. This study illustrates how sensory receptors encode a sense of limb position, and it provides a general framework for modeling sensory encoding by populations of neurons.

Functional electrical stimulation using microstimulators to correct foot drop: a case study.

This paper presents a case study that tested the feasibility and efficacy of using injectable microstimulators (BIONs) in a functional electrical stimulation (FES) device to correct foot drop. Compared with surface stimulation of the common peroneal nerve, stimulation with BIONs provides more selective activation of specific muscles. For example, stimulation of the tibialis anterior (TA) and extensor digitorum longus (EDL) muscles with BIONs produces ankle flexion without excessive inversion or eversion of the foot (i.e., balanced flexion). Efficacy was assessed using a 3-dimensional motion analysis of the ankle and foot trajectories during walking with and without stimulation. Without stimulation, the toe on the affected leg drags across the ground. BION stimulation of the TA muscle and deep peroneal nerve (which innervates TA and EDL) elevates the foot such that the toe clears the ground by 3 cm, which is equivalent to the toe clearance in the less affected leg. The physiological cost index (PCI) measured effort during walking. The PCI equals the change in heart rate (from rest to activity) divided by the walking speed; units are beats per metre. The PCI is high without stimulation (2.29 +/- 0.37, mean +/- SD) and greatly reduced with surface (1.29 +/- 0.10) and BIONic stimulation (1.46 +/- 0.24). Also, walking speed increased from 9.4 +/- 0.4 m/min without stimulation to 19.6 +/- 2.0 m/min with surface and 17.8 +/- 0.7 m/min with BIONic stimulation. These results suggest that FES delivered by a BION is an alternative to surface stimulation and provides selective control of muscle activation.

Coding of position by simultaneously recorded sensory neurones in the cat dorsal root ganglion.

Muscle, cutaneous and joint afferents continuously signal information about the position and movement of individual joints. How does the nervous system extract more global information, for example about the position of the foot in space? To study this question we used microelectrode arrays to record impulses simultaneously from up to 100 discriminable nerve cells in the L6 and L7 dorsal root ganglia (DRG) of the anaesthetized cat. When the hindlimb was displaced passively with a random trajectory, the firing rate of the neurones could be predicted from a linear sum of positions and velocities in Cartesian (x, y), polar or joint angular coordinates. The process could also be reversed to predict the kinematics of the limb from the firing rates of the neurones with an accuracy of 1-2 cm. Predictions of position and velocity could be combined to give an improved fit to limb position. Decoders trained using random movements successfully predicted cyclic movements and movements in which the limb was displaced from a central point to various positions in the periphery. A small number of highly informative neurones (6-8) could account for over 80% of the variance in position and a similar result was obtained in a realistic limb model. In conclusion, this work illustrates how populations of sensory receptors may encode a sense of limb position and how the firing of even a small number of neurones can be used to decode the position of the limb in space.

The role of neuromuscular properties in determining the end-point of a movement.

How does the activation of several muscles combine to produce reliable multijoint movements? To study this question, we stimulated up to six sites in muscles, nerves, and the spinal cord. Flexion and extension of the hip, knee, and ankle were elicited in anesthetized and decerebrate cats. The movements occurred largely in the sagittal plane against a constant spring load and covered most of the passive range of motion of the cat's limb. The movements of the end-point (foot) were compared with predictions based on vectorial summation of end-point movements elicited by stimulating single electrodes. The lengths of the movements produced by stimulating more than one site exceeded what was expected from linear summation for small movements (<3 cm) and showed a less than linear summation for large movements (>11 cm). The data were compared with muscle and limb models. Since the deviations from linearity were predictable as a function of distance, adjustments might easily be learned by trial and error. The summation was less complete for spinal stimulation, compared to nerve and muscle stimulation, so spinal circuits do not appear to compensate for the nonlinearities. Movements were elicited from positions of the limb not only in a neutral position, but also in front and behind the neutral position. A degree of convergence was seen, even with stimulation of some individual muscles, but the convergence increased as more muscles were stimulated and more joints were actively involved. This suggests that convergence to an equilibrium-point arises at least partly from muscle properties. In conclusion, there are deviations from linear vectorial summation, and these deviations increase when more muscles are stimulated. The convergence to an equilibrium-point may simplify the computations needed to produce movements involving many muscles.

BIONic WalkAide for correcting foot drop.

The goal of this study was to test the feasibility and efficacy of using microstimulators (BIONs) to correct foot drop, the first human application of BIONs in functional electrical stimulation (FES). A prototype BIONic foot drop stimulator was developed by modifying a WalkAide2 stimulator to control BION stimulation of the ankle dorsiflexor muscles. BION stimulation was compared with surface stimulation of the common peroneal nerve provided by a normal WalkAide2 foot drop stimulator. Compared to surface stimulation, we found that BION stimulation of the deep peroneal nerve produces a more balanced ankle flexion movement without everting the foot. A 3-D motion analysis was performed to measure the ankle and foot kinematics with and without stimulation. Without stimulation, the toe on the affected leg drags across the ground. The BIONic WalkAide elevates the foot such that the toe clears the ground by 3 cm, which is equivalent to the toe clearance in the unaffected leg. The physiological cost index (PCI) was used to measure effort during walking. The PCI is high without stimulation (2.29 +/- 0.37; mean +/- S.D.) and greatly reduced with surface (1.29 +/- 0.10) and BION stimulation (1.46 +/- 0.24). Also, walking speed is increased from 9.4 +/- 0.4 m/min. without stimulation to 19.6 +/- 2.0 m/min. with surface and 17.8 +/- 0.7 m/min. with BION stimulation. We conclude that functional electrical stimulation with BIONs is a practical alternative to surface stimulation and provides more selective control of muscle activation.

A wheelchair modified for leg propulsion using voluntary activity or electrical stimulation.

A commercially available wheelchair has been modified for propulsion by movements of the lower legs. The feet are attached securely to a foot rest that can rotate around the knee joint. Movement is generated either with residual voluntary activation of the quadriceps (knee extensor) and hamstring (knee flexor) muscles, or with electrical stimulation of these muscles, if voluntary control is absent. Either a chain or a lever can couple the movements through a gearbox to the wheel to propel the wheelchair forward. Control of a wheelchair with the legs is more efficient than using the arms and has the potential to increase the mobility and whole-body fitness of many wheelchair users, but there is considerable variability between subjects. To address this variability, we measured for individual subjects the passive properties of the legs and foot at rest (effective stiffness and viscosity), the length-tension (torque-angle) properties of the active muscle groups, as well as their force-velocity curve and their activation and fatigue rates. The measured values were then inserted into a model of the leg-propelled wheelchair. The purpose of this paper is to test whether the model could predict the performance of individual subjects accurately and could be used, for example, to optimize the speed of the wheelchair for a given subject.

Limb movements generated by stimulating muscle, nerve and spinal cord.

We have compared the movements generated by stimulation of muscle, nerve, spinal roots and spinal cord in anesthetized, decerebrate and spinalized cats. Each method produced a full range of movements of the cat's hind limb in the sagittal plane against a spring load, except for stimulation of the roots. Stimulation of the dorsal roots produced movements that were mainly up and forward, whereas stimulation of the ventral roots produced complementary movements (down and backward). Results from stimulation in the intermediate areas of the spinal cord were compared to predictions of the "movement primitives" hypothesis. We could not confirm that the directions were independent of stimulus amplitude or the state of descending inputs. Pros and cons of stimulating at some sites were provisionally considered for the reliable control of limb movements with functional electrical stimulation (FES) in clinical conditions.

Effects of cholinergic and noradrenergic agents on locomotion in the mudpuppy (Necturus maculatus).

Some neurotransmitters act consistently on the central pattern generator (CPG) for locomotion in a wide range of vertebrates. In contrast, acetylcholine (ACh) and noradrenaline (NA) have various effects on locomotion in different preparations. The roles of ACh and NA have not been studied in amphibian walking, so we examined their effects in an isolated spinal cord preparation of the mudpuppy ( Necturus maculatus). This preparation contains a CPG that produces locomotor activity when N-methyl- D-aspartic acid (NMDA), an excitatory amino acid agonist, is added to the bath. The addition of carbachol, a long acting ACh agonist, to the bath disrupted the walking rhythm induced by NMDA, while not changing the level of activity in flexor and extensor motoneurons. Adding clonidine, an alpha(2)-noradrenergic agonist, had no effect on the NMDA-induced walking rhythm. Physostigmine, an ACh-esterase inhibitor, disrupted the walking rhythm, presumably by potentiating the effects of endogenously released ACh. Atropine, an ACh antagonist that binds to muscarinic ACh receptors, blocked the effects of carbachol, indicating that the action is mediated, at least in part, by muscarinic receptors. In the absence of carbachol, atropine had no effect. Locomotion was not induced by carbachol, atropine or clonidine in a resting spinal cord preparation. Cholinergic actions do not seem to be essential to the CPG for walking in the mudpuppy, but ACh may convert a rhythmic walking state to a more tonic state with occasional bursts of EMG activity for postural adjustments.

Toe flexor muscle spindle discharge and stretch modulation during locomotor activity in the decerebrate cat.

In order to investigate the nature (i.e. static or dynamic) of fusimotor drive to the flexor hallucis longus (FHL) and flexor digitorum longus (FDL) muscles during locomotion we recorded Ia and group II muscle spindle afferent responses to sinusoidal stretch (0.25 and 1 mm amplitude, respectively, 4-5 Hz) in a decerebrate cat preparation. FHL Ia and group II afferents generally had increased discharge rates and decreased modulation to stretch throughout the step cycle, compared to rest, suggesting raised static gamma drive at all locomotor phases. Although the modulation of Ia afferents was reduced during locomotion, most (13 of 18) showed a clear increasing trend during homonymous muscle activity (extension). This was consistent with phasic dynamic gamma drive to FHL spindles linked with alpha drive. In agreement with previous reports, FHL gave a single burst of EMG activity during the step cycle while FDL alpha drive had two components. One was related to extension while the other comprised a brief burst around the end of this phase. Typically FDL Ia and group II afferents also had elevated firing rates and reduced modulation at all locomotor phases, again implicating static gamma drive. Half the afferents (seven Ia, three group II) showed increased discharge during extension, suggesting phasic static gamma drive. There was no gamma drive associated with the late FDL alpha burst. In conclusion, the gamma drives to FHL and FDL differed during locomotion. FHL, which has the alpha drive of a classic extensor, received gamma drive that closely resembled other extensors. The gamma drive of FDL, which exhibits both extensor and flexor alpha synergies, did not match either muscle type. These observations are compatible with the view that fusimotor drive varies in different muscles during locomotion according to the prevailing sensorimotor requirements.

Differential distribution of interneurons in the neural networks that control walking in the mudpuppy (Necturus maculatus) spinal cord.

Locomotor behavior is believed to be produced by interneuronal networks that are intrinsically organized to generate the underlying complex spatiotemporal patterns. In order to study the temporal correlation between the firing of individual interneurons and the pattern of locomotion, we utilized the spinal cord-forelimb preparation from the mudpuppy, in which electrophysiological recordings of neuronal activity were achieved during walking-like movement of the forelimb induced by bath application of N-methyl- D-aspartate (NMDA). Intra- and extracellular recordings were made in the C2 and C3 segments of the spinal cord. These segments contain independent flexor and extensor centers for the forelimb movement about the elbow joint during walking. Among the 289 cells recorded in the intermediate gray matter (an area between the ventral and dorsal horns) of the C2 and C3 segments, approximately 40% of the cells fired rhythmically during "walking." The firing rates were 6.4+/-0.4 impulses/s (mean +/- SE). These rhythmically active cells were classified into four types based on their phase of activity during a normalized step cycle. About half the rhythmic cells fired in phase with either the flexor (F) or extensor (E) motoneurons. The rest fired in the transitions between the two phases (F-->E and E-->F). Longitudinal distributions of the four types of interneurons along the spinal cord were in agreement with observations that revealed distinct but overlapping flexor and extensor centers for walking. Some cells triggered short-latency responses in the elbow flexor or extensor muscles and may be last-order interneurons. These observations suggest that there is a differential distribution of phase-specific interneurons in the central pattern generator of the mudpuppy spinal cord for walking.

Improved efficiency with a wheelchair propelled by the legs using voluntary activity or electric stimulation.

OBJECTIVE: To determine whether a new leg-propelled wheelchair provides enhanced efficiency and mobility to wheelchair users. DESIGN: Observational; subjects were tested while wheeling with the arms and legs and while walking (where possible) for 4-minute periods in random order with approximately 10-minute rest periods between exercise sets. SETTING: Tests were done on an indoor 200-meter track. PATIENTS: Group 1, 13 controls; group 2, 9 persons with complete spinal cord injury (SCI); group 3, 13 persons with other motor disorders (retaining some voluntary control of the legs). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Physiological Cost Index (PCI), (computed as change in heart rate divided by velocity of movement) and oxygen consumption (VO(2)) RESULTS: Arm wheeling took significantly more effort (mean PCI =.52 beats/m) than walking (.33 beats/m) in control subjects. Leg wheeling was most efficient (.23), requiring less than half the effort of arm wheeling and 30% less effort than walking. For SCI subjects, leg wheeling with functional electric stimulation (FES) required less than half the effort (.18) of arm wheeling (.40). The FES group could not walk. Subjects in group 3 could walk, but with substantial effort (1.81) compared with arm (.76) or leg wheeling (.64). Results for VO(2) were similar. CONCLUSIONS: Better wheelchair efficiency can be obtained for many disabled individuals, by moving the leg muscles voluntarily or with FES.

Integrating anti-tumor necrosis factor therapy in inflammatory bowel disease: current and future perspectives.

Crohn's disease and ulcerative colitis are two idiopathic inflammatory disorders of the GI tract. Manifestations of disease can be severe and lead to long term therapy with a variety of medications and/or surgery. Standard medical therapy consists of agents that either treat suppurative complications or modulate the inflammatory cascade in a nonspecific manner. Many specific chemokine and cytokine effectors that promote intestinal inflammation have been identified. Such work has led to experimental clinical trials with a variety of cytokine antagonists. Compounds directed against one such cytokine, tumor necrosis factor alpha (TNF), have demonstrated the greatest clinical efficacy to date. This is consistent with scientific observations that suggest a central role for TNF in the inflammatory cascade. Infliximab is a chimeric monoclonal antibody against TNF that has been demonstrated to be effective for the treatment of Crohn's disease. Infliximab is Food and Drug Administration approved for the treatment of Crohn's disease. There exist several other TNF antagonists in various phases of investigation, including the monoclonal antibody CDP 571, the fusion peptide etanercept, the phosphodiesterase inhibitor oxpentifylline, and thalidomide. The clinical efficacy of these agents and the role of TNF in the pathogenesis of inflammatory bowel disease is reviewed.

Selective stimulation of cat sciatic nerve using an array of varying-length microelectrodes.

Restoration of motor function to individuals who have had spinal cord injuries or stroke has been hampered by the lack of an interface to the peripheral nervous system. A suitable interface should provide selective stimulation of a large number of individual muscle groups with graded recruitment of force. We have developed a new neural interface, the Utah Slanted Electrode Array (USEA), that was designed to be implanted into peripheral nerves. Its goal is to provide such an interface that could be useful in rehabilitation as well as neuroscience applications. In this study, the stimulation capabilities of the USEA were evaluated in acute experiments in cat sciatic nerve. The recruitment properties and the selectivity of stimulation were examined by determining the target muscles excited by stimulation via each of the 100 electrodes in the array and using force transducers to record the force produced in these muscles. It is shown in the results that groups of up to 15 electrodes were inserted into individual fascicles. Stimulation slightly above threshold was selective to one muscle group for most individual electrodes. At higher currents, co-activation of agonist but not antagonist muscles was observed in some instances. Recruitment curves for the electrode array were broader with twitch thresholds starting at much lower currents than for cuff electrodes. In these experiments, it is also shown that certain combinations of electrode pairs, inserted into an individual fascicle, excite fiber populations with substantial overlap, whereas other pairs appear to address independent populations. We conclude that the USEA permits more selective stimulation at much lower current intensities with more graded recruitment of individual muscles than is achieved by conventional cuff electrodes.

Medical therapy for Crohn's disease: the state of the art.

Various medications are used to control the symptoms of Crohn's disease. This article reviews the traditional medical therapies of Crohn's disease, including aminosalicylates and corticosteroids, and the broad armamentarium of immune modulators and biologic agents that are becoming increasingly important in the management of Crohn's disease.