Vivian K. Mushahwar

Intraspinal microstimulation generates functional movements after spinal-cord injury

Restoring locomotion after spinal-cord injury has been a difficult problem to solve with traditional functional electrical stimulation (FES) systems. Intraspinal microstimulation (ISMS) is a novel approach to FES that takes advantage of spinal-cord locomotor circuits by stimulating in the spinal cord directly. Previous studies in spinal-cord intact cats showed near normal recruitment order, reduced fatigue, and functional, synergistic movements induced by stimulation through a few microwires implanted over a 3-cm region in the lumbosacral cord , . The present study sought to test the feasibility of ISMS for restoring locomotion after complete spinal-cord transection. In four adult male cats, the spinal cord was severed at T10, T11, or T12. Two to four weeks later, 30 wires (30 /spl mu/m, stainless steel) were implanted, under anesthesia, in both sides of the lumbosacral cord. The cats were then decerebrated. Stimulus pulses (40 - 50 Hz, 200 /spl mu/s, biphasic) with amplitudes ranging from 1 - 4x threshold (threshold = 32 /spl plusmn/19 /spl mu/A) were delivered through each unipolar electrode. Kinetics, kinematics, and electromyographic (EMG) measurements were obtained with the cats suspended over a stationary treadmill with embedded force platforms for the hindlimbs. Phasic, interleaved stimulation through electrodes generating flexor or extensor movements produced bilateral weight-bearing stepping of the hindlimbs with ample foot clearance during swing. Minimal changes in kinematics and little fatigue were seen during episodes of 40 consecutive steps. The results indicate that ISMS is a promising technique for restoring locomotion after injury.

Intraspinal micro stimulation generates locomotor-like and feedback-controlled movements

Intraspinal microstimulation (ISMS) may provide a means for improving motor function in people suffering from spinal cord injuries, head trauma, or stroke. The goal of this study was to determine whether microstimulation of the mammalian spinal cord could generate locomotor-like stepping and feedback-controlled movements of the hindlimbs. Under pentobarbital anesthesia, 24 insulated microwires were implanted in the lumbosacral cord of three adult cats. The cats were placed in a sling leaving all limbs pendent. Bilateral alternating stepping of the hindlimbs was achieved by stimulating through as few as two electrodes in each side of the spinal cord. Typical stride lengths were 23.5 cm, and ample foot clearance was achieved during swing. Mean ground reaction force during stance was 36.4 N, sufficient for load-bearing. Feedback-controlled movements of the cats foot were achieved by reciprocally modulating the amplitude of stimuli delivered through two intraspinal electrodes generating ankle flexion and extension such that the distance between a sensor on the cats foot and a free sensor moved back and forth by the investigators was minimized.. The foot tracked the displacements of the target sensor through its normal range of motion. Stimulation through electrodes with tips in or near lamina IX elicited movements most suitable for locomotion. In chronically implanted awake cats, stimulation through dorsally located electrodes generated paw shakes and flexion-withdrawals consistent with sensory perception but no weight-bearing extensor movements. These locations would not be suitable for ISMS in incomplete spinal cord injuries. Despite the complexity of the spinal neuronal networks, our results demonstrate that by stimulating through a few intraspinal microwires, near-normal bipedal locomotor-like stepping and feedback-controlled movements could be achieved.

Strategies for Generating Prolonged Functional Standing Using Intramuscular Stimulation or Intraspinal Microstimulation

Spinal cord injury (SCI) often results in the loss of the ability to stand. The goal of this study was to implement a functional electrical stimulation (FES) system for restoring prolonged periods of standing after SCI. For this purpose, we tested two control strategies: open-loop and closed-loop control, and two stimulation paradigms: non-interleaved intramuscular stimulation (IM-S) and interleaved intraspinal microstimulation (ISMS). The experiments were conducted in anesthetized cats. Stimulation was applied to the muscles through IM-S electrodes implanted in the main knee and ankle extensor muscles, or to the spinal cord through ultra-fine ISMS wires implanted within the ventral horn of the lumbosacral enlargement. The cats were partially supported over parallel force plates and accelerometers were secured to the hindlimbs above and below the ankle joint. Ground reaction forces and knee and ankle joint angles were measured by the force plates and accelerometers, respectively. The closed-loop controller used these feedback signals to modulate the amplitude of stimulation applied to the extensor muscles. The open-loop controller applied constant levels of stimulation which were determined before the onset of each trial. The duration of standing achieved using closed-loop control of IM-S was significantly longer than that achieved with open-loop control (~2 times longer). The increase in the duration of standing corresponded with a decrease in the rate of force decay and a lower average injected current during closed-loop control. Standing was further improved with the use of ISMS. Closed-loop control of interleaved ISMS resulted in a period of standing > 3 times longer than the best trial generated using non-interleaved IM-S. There was also a significant improvement in the balance of force between the two hindlimbs. The results suggest that a system which uses closed-loop control in conjunction with interleaved ISMS could achieve prolonged FES standing in people with SCI.

Management of Spasticity After Spinal Cord Injury: Current Techniques and Future Directions

Spasticity, resulting in involuntary and sustained contractions of muscles, may evolve in patients with stroke, cerebral palsy, multiple sclerosis, brain injury, and spinal cord injury (SCI). The authors critically review the neural mechanisms that may contribute to spasticity after SCI and assess their likely degree of involvement and relative significance to its pathophysiology. Experimental data from patients and animal models of spasticity as well as computer simulations are evaluated. The current clinical methods used for the management of spasticity and the pharmacological actions of drugs are discussed in relation to their effects on spinal mechanisms. Critical assessment of experimental findings indicates that increased excitability of both motoneurons and interneurons plays a crucial role in pathophysiology of spasticity. New interventions, including forms of spinal electrical stimulation to suppress increased neuronal excitability, may reduce the severity of spasticity and its complications.

New functional electrical stimulation approaches to standing and walking

Spinal cord injury (SCI) is a devastating neurological trauma that is prevalent predominantly in young individuals. Several interventions in the areas of neuroregeneration, pharmacology and rehabilitation engineering/neuroscience are currently under investigation for restoring function after SCI. In this paper, we focus on the use of neuroprosthetic devices for restoring standing and ambulation as well as improving general health and wellness after SCI. Four neuroprosthetic approaches are discussed along with their demonstrated advantages and their future needs for improved clinical applicability. We first introduce surface functional electrical stimulation (FES) devices for restoring ambulation and highlight the importance of these devices for facilitating exercise activities and systemic physiological activation. Implanted muscle-based FES devices for restoring standing and walking that are currently undergoing clinical trials are then presented. The use of implanted peripheral nerve intraneural arrays of multi-site microelectrodes for providing fine and graded control of force during sit-to-stand maneuvers is subsequently demonstrated. Finally, intraspinal microstimulation (ISMS) of the lumbosacral spinal cord for restoring standing and walking is introduced and its results to date are presented. We conclude with a general discussion of the common needs of the neuroprosthetic devices presented in this paper and the improvements that may be incorporated in the future to advance their clinical utility and user satisfaction.

Simulation of Ca2+ persistent inward currents in spinal motoneurones : mode of activation and integration of synaptic inputs

The goal of this study was to investigate the nature of activation of the dendritic calcium persistent inward current (Ca2+ PIC) and its contribution to the enhancement and summation of synaptic inputs in spinal motoneurones. A compartmental cable model of a cat α‐motoneurone was developed comprising the realistic dendritic distribution of Ia‐afferent synapses and low‐voltage‐activated L‐type calcium (Cav1.3) channels distributed over the dendrites in a manner that was previously shown to match a wide set of experimental measurements. The level of synaptic activation was systematically increased and the resulting firing rate, somatic and dendritic membrane potentials, dendritic Cav1.3 channel conductance, and dendritic Ca2+ PIC were measured. Our simulation results suggest that during cell firing the dendritic Ca2+ PIC is not activated in an all‐or‐none manner. Instead, it is initially activated in a graded manner with increasing synaptic input until it reaches its full activation level, after which additional increases in synaptic input result in minimal changes in the Ca2+ PIC (PIC saturated). The range of graded activation of Ca2+ PIC occurs when the cell is recruited and causes a steep increase in the firing frequency as the synaptic current is increased, coinciding with the secondary range of the synaptic frequency–current (F–I) relationship. Once the Ca2+ PIC is saturated the slope of the F–I relationship is reduced, corresponding to the tertiary range of firing. When the post‐spike afterhyperpolarization (AHP) is blocked, either directly by blocking the calcium‐activated potassium channels, or indirectly by blocking the sodium spikes, the PIC is activated in an all‐or‐none manner with increasing synaptic input. Thus, the AHP serves to limit the depolarization of the cell during firing and enables graded, rather than all‐or‐none, activation of the Ca2+ PIC. The graded activation of the Ca2+ PIC with increasing synaptic input results in a graded (linear) enhancement and linear summation of synaptic inputs. In contrast, the saturated Ca2+ PIC enhances synaptic inputs by a constant amount (constant current), and leads to less‐than linear summation of multiple synaptic inputs. These model predictions improve our understanding of the mode of activation of the dendritic Ca2+ PIC and its role in the enhancement and integration of synaptic inputs.

Locomotor-Related Networks in the Lumbosacral Enlargement of the Adult Spinal Cat: Activation Through Intraspinal Microstimulation

It is commonly accepted that locomotor-related neuronal circuitry resides in the lumbosacral spinal cord. Pharmacological agents, epidural electrical stimulation, and sensory stimulation can be used to activate these intrinsic networks in in vitro neonatal rat and in vivo cat preparations. In this study, we investigated the use of low-level tonic intraspinal microstimulation (ISMS) as a means of activating spinal locomotor networks in adult cats with complete spinal transections. Trains of low-amplitude electrical pulses were delivered to the spinal cord via groups of fine microwires implanted in the ventral horns of the lumbosacral enlargement. In contrast to published reports, tonic ISMS applied through microwires in the caudal regions of the lumbosacral enlargement (L7-S1) was more effective in eliciting alternating movements in the hindlimbs than stimulation in the rostral regions. Possible mechanisms of action of tonic ISMS include depolarization of locally oscillating networks in the lumbosacral cord, backfiring of primary afferents, or activation of propriospinal neurons

Intraspinal microstimulation preferentially recruits fatigue‐resistant muscle fibres and generates gradual force in rat

Intraspinal microstimulation (ISMS), a novel rehabilitative therapy consisting of stimulation through fine, hair‐like microwires targeted at the ventral spinal cord, has been proposed for restoring standing and walking following spinal cord injury. This study compared muscle recruitment characteristics of ISMS with those produced by peripheral nerve cuff stimulation (NCS). Thirty‐three minutes of either ISMS or NCS at 1, 20 or 50 s−1 and 1.2 × threshold (T) amplitude depleted glycogen from muscle fibres of vastus lateralis and rectus femoris. ISMS and NCS were also carried out at 20 s−1 and 3.0T. Muscle serial sections were stained for glycogen and for myosin heavy chain (MHC)‐based fibre types using a panel of monoclonal antibodies. The results of this study show that ISMS recruited fatigue‐resistant (FR) fibres at 2.9, 1.9, 1.7 and 2.5 times their relative MHC content at 1, 20 and 50 s−1 1.2T and 20 s−1 3.0T, respectively. In contrast, NCS recruited FR fibres at 1.2, 1.0, 2.1 and 0.0 times their MHC content at 1, 20 and 50 s−1 1.2T and 20 s−1 3.0T, respectively. The proportion of FR fibres recruited by ISMS and NCS was significantly different in the 20 s−1 3.0T condition (P < 0.0001). We also report that force recruitment curves were 4.9‐fold less steep (P < 0.019) for ISMS than NCS. The findings of this study provide evidence for the efficacy of ISMS and further our understanding of muscle recruitment properties of this novel rehabilitative therapy.

Functional Electrical Stimulation and Spinal Cord Injury

Spinal cord injuries (SCI) can disrupt communications between the brain and the body, resulting in loss of control over otherwise intact neuromuscular systems. Functional electrical stimulation (FES) of the central and peripheral nervous system can use these intact neuromuscular systems to provide therapeutic exercise options to allow functional restoration and to manage medical complications following SCI. The use of FES for the restoration of muscular and organ functions may significantly decrease the morbidity and mortality following SCI. Many FES devices are commercially available and should be considered as part of the lifelong rehabilitation care plan for all eligible persons with SCI.

A Silicon Central Pattern Generator Controls Locomotion in Vivo

We present a neuromorphic silicon chip that emulates the activity of the biological spinal central pattern generator (CPG) and creates locomotor patterns to support walking. The chip implements ten integrate-and-fire silicon neurons and 190 programmable digital-to-analog converters that act as synapses. This architecture allows for each neuron to make synaptic connections to any of the other neurons as well as to any of eight external input signals and one tonic bias input. The chips functionality is confirmed by a series of experiments in which it controls the motor output of a paralyzed animal in real-time and enables it to walk along a three-meter platform. The walking is controlled under closed-loop conditions with the aide of sensory feedback that is recorded from the animals legs and fed into the silicon CPG. Although we and others have previously described biomimetic silicon locomotor control systems for robots, this is the first demonstration of a neuromorphic device that can replace some functions of the central nervous system in vivo.