Nikolaus Wenger

A Computational Model for Epidural Electrical Stimulation of Spinal Sensorimotor Circuits

Epidural electrical stimulation (EES) of lumbosacral segments can restore a range of movements after spinal cord injury. However, the mechanisms and neural structures through which EES facilitates movement execution remain unclear. Here, we designed a computational model and performed in vivo experiments to investigate the type of fibers, neurons, and circuits recruited in response to EES. We first developed a realistic finite element computer model of rat lumbosacral segments to identify the currents generated by EES. To evaluate the impact of these currents on sensorimotor circuits, we coupled this model with an anatomically realistic axon-cable model of motoneurons, interneurons, and myelinated afferent fibers for antagonistic ankle muscles. Comparisons between computer simulations and experiments revealed the ability of the model to predict EES-evoked motor responses over multiple intensities and locations. Analysis of the recruited neural structures revealed the lack of direct influence of EES on motoneurons and interneurons. Simulations and pharmacological experiments demonstrated that EES engages spinal circuits trans-synaptically through the recruitment of myelinated afferent fibers. The model also predicted the capacity of spatially distinct EES to modulate side-specific limb movements and, to a lesser extent, extension versus flexion. These predictions were confirmed during standing and walking enabled by EES in spinal rats. These combined results provide a mechanistic framework for the design of spinal neuroprosthetic systems to improve standing and walking after neurological disorders.

Closed-loop neuromodulation of spinal sensorimotor circuits controls refined locomotion after complete spinal cord injury.

Closed-loop neuromodulation of spinal sensorimotor circuits allows high-fidelity control over leg movements in paralyzed rats. Closing the Loop on Neuroprosthetic Control Patients with spinal cord injury (SCI) and paralysis may soon be outfitted with so-called neuromodulation devices, which electrically stimulate the brain or spinal cord, causing movement in the legs. Currently, tuning such modulation requires constant observation and patient-specific adjustments, which are not ideal for fluid movement or for broad translation of these technologies to injured patients. In response, Wenger et al. have created a closed-loop system that will essentially “auto-tune” the device, allowing the paralyzed patient—or, in their study, the paralyzed rat—to move freely, without worrying about adjusting electrical pulse width, amplitude, or frequency. The authors gave rats complete SCI epidural electrical stimulation and then mapped their leg movements and sensorimotor responses while in a body support system, walking upright (bipedal) on a treadmill, or climbing stairs. From this information, they devised a computational system that integrated feedback and feed-forward models for closed-loop, continuous control of leg movement and, in turn, a more natural locomotion. Closed-loop neuromodulation of spinal circuits could impart fluid motor control and prevent fatigue when rehabilitating patients with SCI. Neuromodulation of spinal sensorimotor circuits improves motor control in animal models and humans with spinal cord injury. With common neuromodulation devices, electrical stimulation parameters are tuned manually and remain constant during movement. We developed a mechanistic framework to optimize neuromodulation in real time to achieve high-fidelity control of leg kinematics during locomotion in rats. We first uncovered relationships between neuromodulation parameters and recruitment of distinct sensorimotor circuits, resulting in predictive adjustments of leg kinematics. Second, we established a technological platform with embedded control policies that integrated robust movement feedback and feed-forward control loops in real time. These developments allowed us to conceive a neuroprosthetic system that controlled a broad range of foot trajectories during continuous locomotion in paralyzed rats. Animals with complete spinal cord injury performed more than 1000 successive steps without failure, and were able to climb staircases of various heights and lengths with precision and fluidity. Beyond therapeutic potential, these findings provide a conceptual and technical framework to personalize neuromodulation treatments for other neurological disorders.

Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury

Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limited the therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here we developed stimulation protocols that reproduce the natural dynamics of motoneuron activation during locomotion. For this, we computed the spatiotemporal activation pattern of muscle synergies during locomotion in healthy rats. Computer simulations identified optimal electrode locations to target each synergy through the recruitment of proprioceptive feedback circuits. This framework steered the design of spatially selective spinal implants and real-time control software that modulate extensor and flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight-bearing capacity, endurance and skilled locomotion in several rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans.

Corticospinal neuroprostheses to restore locomotion after spinal cord injury

In this conceptual review, we highlight our strategy for, and progress in the development of corticospinal neuroprostheses for restoring locomotor functions and promoting neural repair after thoracic spinal cord injury in experimental animal models. We specifically focus on recent developments in recording and stimulating neural interfaces, decoding algorithms, extraction of real-time feedback information, and closed-loop control systems. Each of these complex neurotechnologies plays a significant role for the design of corticospinal neuroprostheses. Even more challenging is the coordinated integration of such multifaceted technologies into effective and practical neuroprosthetic systems to improve movement execution, and augment neural plasticity after injury. In this review we address our progress in rodent animal models to explore the viability of a technology-intensive strategy for recovery and repair of the damaged nervous system. The technical, practical, and regulatory hurdles that lie ahead along the path toward clinical applications are enormous - and their resolution is uncertain at this stage. However, it is imperative that the discoveries and technological developments being made across the field of neuroprosthetics do not stay in the lab, but instead reach clinical fruition at the fastest pace possible.

Mechanisms Underlying the Neuromodulation of Spinal Circuits for Correcting Gait and Balance Deficits after Spinal Cord Injury.

Epidural electrical stimulation of lumbar segments facilitates standing and walking in animal models and humans with spinal cord injury. However, the mechanisms through which this neuromodulation therapy engages spinal circuits remain enigmatic. Using computer simulations and behavioral experiments, we provide evidence that epidural electrical stimulation interacts with muscle spindle feedback circuits to modulate muscle activity during locomotion. Hypothesis-driven strategies emerging from simulations steered the design of stimulation protocols that adjust bilateral hindlimb kinematics throughout gait execution. These stimulation strategies corrected subject-specific gait and balance deficits in rats with incomplete and complete spinal cord injury. The conservation of muscle spindle feedback circuits across mammals suggests that the same mechanisms may facilitate motor control in humans. These results provide a conceptual framework to improve stimulation protocols for clinical applications.

Research Update: Platinum-elastomer mesocomposite as neural electrode coating

Platinum is electrochemically stable and biocompatible, and remains the preferred material for the fabrication of implantable neural electrodes. In a foil or film format, platinum is mechanically stiff compared to interfaced biological tissue. We report a soft, highly stable platinum-elastomer composite that offers both mechanical compliance and the electrochemical properties of platinum. We demonstrate the high-performance of the novel mesocomposite printed on stretchable microelectrodes both in vitro and in vivo. The platinum-elastomer composite is a new promising coating for chronic neural interfaces.

Configuration of electrical spinal cord stimulation through real-time processing of gait kinematics

Epidural electrical stimulation (EES) of the spinal cord and real-time processing of gait kinematics are powerful methods for the study of locomotion and the improvement of motor control after injury or in neurological disorders. Here, we describe equipment and surgical procedures that can be used to acquire chronic electromyographic (EMG) recordings from leg muscles and to implant targeted spinal cord stimulation systems that remain stable up to several months after implantation in rats and nonhuman primates. We also detail how to exploit these implants to configure electrical spinal cord stimulation policies that allow control over the degree of extension and flexion of each leg during locomotion. This protocol uses real-time processing of gait kinematics and locomotor performance, and can be configured within a few days. Once configured, stimulation bursts are delivered over specific spinal cord locations with precise timing that reproduces the natural spatiotemporal activation of motoneurons during locomotion. These protocols can also be easily adapted for the safe implantation of systems in the vicinity of the spinal cord and to conduct experiments involving real-time movement feedback and closed-loop controllers.This protocol describes how to configure targeted spinal cord stimulation using electromyographic recordings and real-time processing of gait kinematics to enable voluntary control of specific leg movements in rats and nonhuman primates.

Advantages of soft subdural implants for the delivery of electrochemical neuromodulation therapies to the spinal cord

OBJECTIVE We recently developed soft neural interfaces enabling the delivery of electrical and chemical stimulation to the spinal cord. These stimulations restored locomotion in animal models of paralysis. Soft interfaces can be placed either below or above the dura mater. Theoretically, the subdural location combines many advantages, including increased selectivity of electrical stimulation, lower stimulation thresholds, and targeted chemical stimulation through local drug delivery. However, these advantages have not been documented, nor have their functional impact been studied in silico or in a relevant animal model of neurological disorders using a multimodal neural interface. APPROACH We characterized the recruitment properties of subdural interfaces using a realistic computational model of the rat spinal cord that included explicit representation of the spinal roots. We then validated and complemented computer simulations with electrophysiological experiments in rats. We additionally performed behavioral experiments in rats that received a lateral spinal cord hemisection and were implanted with a soft interface. MAIN RESULTS In silico and in vivo experiments showed that the subdural location decreased stimulation thresholds compared to the epidural location while retaining high specificity. This feature reduces power consumption and risks of long-term damage in the tissues, thus increasing the clinical safety profile of this approach. The hemisection induced a transient paralysis of the leg ipsilateral to the injury. During this period, the delivery of electrical stimulation restricted to the injured side combined with local chemical modulation enabled coordinated locomotor movements of the paralyzed leg without affecting the non-impaired leg in all tested rats. Electrode properties remained stable over time, while anatomical examinations revealed excellent bio-integration properties. SIGNIFICANCE Soft neural interfaces inserted subdurally provide the opportunity to deliver electrical and chemical neuromodulation therapies using a single, bio-compatible and mechanically compliant device that effectively alleviates locomotor deficits after spinal cord injury.

A real-time platform for studying the modulatory capacity of epidural stimulation after spinal cord injury

Epidural electrical stimulation (EES) showed promises to improve standing and walking after neurological disorders. To date, EES has been delivered continuously, although time-dependent stimulations would likely be more efficient to activate specific subsets of sensorimotor circuits with the appropriate timing. To address this issue, we developed a real-time stimulation platform that allows to trigger EES during pre-defined phases of the gait cycle in freely walking rats. We leveraged this platform to demonstrate the ability of time-dependent EES to modulate key aspects of locomotor kinematics in rats with complete spinal cord transection. This platform will support the development of personalized stimulation strategies that can be tailored to the need of individual subjects.