Neuroregenerative Effects of Intraspinal Microstimulation (ISMS) Following Spinal Cord Injury (SCI)

Background Intraspinal microstimulation (ISMS) is a novel electrical stimulation technique that has demonstrated mobility restoration in animals with spinal cord injury (SCI). This project investigated: 1) the capacity of ISMS to restore functional walking in rats with SCI through 4 weeks of stimulation, and 2) the degree of walking deficit caused by ISMS surgery. Methods Thirteen Sprague Dawley rats were divided into three groups: 1) rats with hemi-section SCI (hSCI) and no implants (control group), 2) rats with hSCI and passive ISMS implants (ISMS sham group), and 3) rats with hSCI and implants with active electrical stimulation (ISMS group). All groups were trained to walk on a horizontal ladder and their performance was quantified pre- and post-surgery. Results We hypothesized that the rats with active ISMS implants would demonstrate the greatest improvement in functional walking compared to both control groups, and that the ISMS sham group would underperform the most. The preoperative functional walking scores of control, sham and ISMS rats were 5.7±0.2, 5.5±0.3 and 5.7±0.1, respectively (7-point scale; mean ± standard error). The post-surgery scores were 3.2±0.9, 2.6±0.6 and 3.3±0.8 for control, sham, and ISMS rats, respectively. Conclusions As the difference between the post-surgery functional walking scores of ISMS and control rats was not statistically significant, this may indicate that four weeks of ISMS stimulation is not enough to cause rehabilitative effects. Additionally, the ISMS sham group demonstrated impaired functional walking compared to the hSCI control group as predicted. Future studies will employ a larger sample size to fully elucidate this trend and utilize thinner microwires to mitigate cellular damage.

Effective Stimulation Type and Waveform for Force Control of the Motor Unit System: Implications for Intraspinal Microstimulation

The input–output properties of spinal motoneurons and muscle fibers comprising motor units are highly non-linear. The goal of this study was to investigate the stimulation type (continuous versus discrete) and waveform (linear versus non-linear) controlling force production at the motor unit level under intraspinal microstimulation. We constructed a physiological model of the motor unit with computer software enabling virtual experiments on single motor units under a wide range of input conditions, including intracellular and synaptic stimulation of the motoneuron and variation in the muscle length under neuromodulatory inputs originating from the brainstem. Continuous current intensity and impulse current frequency waveforms were inversely estimated such that the motor unit could linearly develop and relax the muscle force within a broad range of contraction speeds and levels during isometric contraction at various muscle lengths. Under both continuous and discrete stimulation, the stimulation waveform non-linearity increased with increasing speed and level of force production and with decreasing muscle length. Only discrete stimulation could control force relaxation at all muscle lengths. In contrast, continuous stimulation could not control force relaxation at high contraction levels in shorter-than-optimal muscles due to persistent inward current saturation on the motoneuron dendrites. These results indicate that non-linear adjustment of the stimulation waveform is more effective in regard to varying the force profile and muscle length and that the discrete stimulation protocol is a more robust approach for designing stimulation patterns aimed at neural interfaces for precise movement control under pathological conditions.

SPIKE-TRIGGERED INTRASPINAL MICROSTIMULATION IMPROVES MOTOR PERFORANCE IN AN AMBULATORY RAT MODEL OF SPINAL CORD INJURY

The purpose of this study was to determine if spike-triggered intraspinal microstimulation (ISMS) results in improved motor performance in an ambulatory rat model of spinal cord injury (SCI). Experiments were carried out in adult male Sprague Dawley rats with 175 kdyn moderate T8 contusion injury. Rats were randomly assigned to one of two groups: Control or Activity Dependent Stimulation (ADS) therapy. Four weeks post-SCI, all rats were implanted with a recording electrode in the left hindlimb motor cortex and a fine-wire, custom-made stimulating electrode in the contralateral lumbar spinal cord. Intracortical and intraspinal microstimulation were used to find sites of similar hip representation areas, which were paired together for ADS therapy. In the ADS therapy group, spike-stimulus conditioning was administered for 4 hours/day, 4 days/week, for 4 weeks via a tethered cable in a testing chamber. During therapy sessions, single-unit spikes were discriminated in real time in the hindlimb motor cortex and used to trigger stimulation in the spinal cord ventral horn. The optimal stimulus intensity (50% ISMS movement threshold) and spike-stimulus delay (10ms) determined in preliminary anesthetized preparations were used during ADS. Control rats were similarly implanted with electrodes but did not receive stimulation therapy. Motor performances of each rat were evaluated before SCI contusion, once a week post-SCI for four weeks (prior to electrode implantation), and once a week post-conditioning for four weeks. Behavioral testing included BBB scoring, Ledged Beam walking, Horizontal Ladder walking, treadmill kinematics via the DigiGait and TreadScan system, and open field walking using OptiTrack kinematic analysis. BBB scores were significantly improved in ADS rats compared to Control rats after 1 week of therapy. In the ADS therapy rats, BBB scores were significantly improved after two weeks of ADS therapy when compared to pre-therapy. Foot fault scores on the Horizontal Ladder were significantly lower in ADS rats compared to pre-therapy ADS and Control rats after 1 week of therapy and returned to pre-injury measures after three weeks of ADS therapy. The Ledged Beam test and kinematic analysis using the DigiGait and TreadScan system showed deficits after SCI in both ADS and Control rats but there were no significant differences between groups after 4 weeks of ADS therapy. These results show that activity dependent stimulation after spinal cord injury using spike-triggered ISMS enhances behavioral recovery of locomotor function as measured by the BBB score and the Horizontal Ladder task.

A general framework for automatic closed-loop control of bladder voiding induced by intraspinal microstimulation in rats

Individuals with spinal cord injury or neurological disorders have problems in voiding function due to the dyssynergic contraction of the urethral sphincter. Here, we introduce a closed-loop control of intraspinal microstimulation (ISMS) for efficient bladder voiding. The strategy is based on asynchronous two-electrode ISMS with combined pulse-amplitude and pulse-frequency modulation without requiring rhizotomy, neurotomy, or high-frequency blocking. Intermittent stimulation is alternately applied to the two electrodes that are implanted in the S2 lateral ventral horn and S1 dorsal gray commissure, to excite the bladder motoneurons and to inhibit the urethral sphincter motoneurons. Asynchronous stimulation would lead to reduce the net electric field and to maximize the selective stimulation. The proposed closed-loop system attains a highly voiding efficiency of 77.2–100%, with an average of 91.28 ± 8.4%. This work represents a promising approach to the development of a natural and robust motor neuroprosthesis device for restoring bladder functions.

Activity Dependent Stimulation Increases Synaptic Efficacy in Spared Pathways in an Anesthetized Rat Model of Spinal Cord Contusion Injury

ObjectiveThe purpose of this study was to assess the ability of intraspinal microstimulation, triggered by action potentials (spikes) recorded in motor cortex, to alter synaptic efficacy in descending motor pathways in an anesthetized rat model of spinal cord injury.ApproachExperiments were carried out in adult, male, Sprague Dawley rats with a moderate contusion injury at T8. Four weeks after SCI, and under ketamine/xylazine anesthesia, fine wire electromyographic (EMG) electrodes were implanted into four muscles of the right hindlimb. After exposure of the left motor cortex hindlimb area and laminectomy of the T13-L1 vertebrae, intracortical microstimulation (ICMS) and intraspinal microstimulation (ISMS) were used to determine the location of evoked hip movements in cortex and spinal cord, respectively. For activity-dependent stimulation sessions, a single shank, 16-channel, recording microelectrode was used to detect neuronal spikes in motor cortex that triggered ISMS in the spinal cord grey matter. Spinal cord injured rats were randomly assigned to one of four experimental groups differing by: a) cortical spike-ISMS stimulus delay (10 or 25 ms) and b) number of ISMS pulses (1 or 3). Activity-dependent stimulation sessions were conducted in three consecutive 1-hour conditioning bouts for a total of 3 hours. At the end of each conditioning bout, changes in synaptic efficacy were assessed using ICMS to examine the number of spikes evoked in spinal cord neurons during five minute test bouts. Evoked spikes were recorded, sorted, and displayed in post-stimulus spike histograms in 1-ms bins. Post-stimulus spike histograms and EMG recordings were characterized using stimulus triggered averaging techniques.Main resultsThe results showed that activity-dependent stimulation resulted in an increase in cortically-evoked spikes in spinal cord neurons at specific combinations of spike-ISMS delays and numbers of pulses. Efficacy in descending motor pathways was increased throughout all dorsoventral depths of the hindlimb spinal cord, including the ventral horn, in the vicinity of motor neurons. Changes were evident in some conditions as early as 1 hour after conditioning. EMG responses were never evoked with ICMS pre-or post-conditioning.SignificanceThese results show that after a spinal cord contusion injury, activity-dependent stimulation, consisting of cortical spike-driven ISMS, can increase synaptic efficacy in spared pathways between motor cortex and spinal cord. This suggests that activity-dependent stimulation may serve as an effective therapeutic approach for enhancing descending motor control after spinal cord injury.

Intelligent Control of a Spinal Prosthesis to Restore Walking After Neural Injury: Recent Work and Future Possibilities

This review focuses on the development of intelligent, intuitive control strategies for restoring walking using an innovative spinal neural prosthesis called intraspinal microstimulation (ISMS). These control strategies are inspired by the control of walking by the nervous system and are aimed at mimicking the natural functionality of locomotor-related sensorimotor systems. The work to date demonstrates how biologically inspired control strategies, some including machine learning methods, can be used to augment remaining function in models of complete and partial paralysis developed in anesthetized cats. This review highlights the advantages of learning predictions to produce automatically adaptive control of over-ground walking. This review also speculates on the possible future applications of similar machine learning algorithms for challenging walking tasks including navigating obstacles and traversing difficult terrain. Finally, this review explores the potential for plasticity and motor recovery with long-term use of such intelligent control systems and neural interfaces.

Intraspinal stimulation with silicon-based 3D microelectrode array for bladder voiding in cats before and after spinal cord injury

Bladder dysfunction is a significant and largely unaddressed problem for people living with spinal cord injury. Intermittent catheterization does not provide volitional control of micturition and has numerous side effects. Targeted electrical microstimulation of the spinal cord has been previously explored for restoring such volitional control in the animal model of experimental spinal cord injury. In this study, the development of the intraspinal microstimulation array technology was continued and evaluated in the feline animal model for its ability to provide more focused and reliable bladder control after a complete spinal cord transection. For the first time, the intraspinal multisite silicon array wad built using novel microfabrication processes to provide custom-designed tip geometry and 3D electrode distribution, better cost efficiency, reproducibility, scalability, and on-the-probe integration of active electronics. Long-term implantation was performed in 8 animals for a period up to 6 months, targeting the dorsal gray commissure area in the S1 sacral cord that is known to be involved in the coordination between the bladder detrusor and the external urethral sphincter. About one third of the electrode sites in the that area produced micturition-related responses. The effectiveness of stimulation increased starting from one month after spinal cord transection (as evaluated in one animal), likely due to supraspinal disinhibition of the spinal circuitry and/or hypertrophy and hyperexcitability of the spinal bladder afferents. Further studies are required to assess longer-term reliability of the developed intraspinal microstimulation array technology in preparation for eventual human translation.

Pavlovian Control of Intraspinal Microstimulation to Produce Over-Ground Walking

ABSTRACTObjectiveNeural interface technologies are more commonly used in people with neural injury. To achieve a symbiotic relationship between device and user, the control system of the device must augment remaining function and adapt to day-to-day changes. The goal of this study was to develop predictive control strategies to produce alternating, over-ground walking in a cat model of hemisection spinal cord injury (SCI) using intraspinal microstimulation (ISMS).ApproachEight cats were anaesthetized and placed in a sling over a walkway. The residual function of a hemisection SCI was mimicked by manually moving one hind-limb through the walking cycle over the walkway. ISMS targeted motor networks in the lumbosacral enlargement to activate muscles in the other limb using low levels of current (< 130 µA). Four different people took turns to move the “intact” limb. Two control strategies, which used ground reaction force and angular velocity information about the manually moved limb to control the timing of the transitions of the other limb, were compared. The first strategy, reaction-based control, used thresholds on the sensor values to initiate state transitions. The other strategy used a reinforcement learning strategy, Pavlovian control, to learn predictions about the sensor values. Thresholds on the predictions were used to initiate transitions.Main ResultsBoth control strategies were able to produce alternating, over-ground walking. Reaction-based control required manual tuning of the thresholds for each person to produce walking, whereas Pavlovian control did not. We demonstrate that learning occurs quickly during walking. Predictions of the sensor signals were learned quickly, initiating transitions in no more than 4 steps. Pavlovian control was resilient to transitions between people walking the limb, between cat experiments, and recovered from mistakes during walking.SignificanceThis work demonstrates that Pavlovian control can augment remaining function and allow for personalized walking with minimal tuning requirements.