Therapeutic Stimulation for Restoration of Function After Spinal Cord Injury.

Paralysis due to spinal cord injury can severely limit motor function and independence. This review summarizes different approaches to electrical stimulation of the spinal cord designed to restore motor function, with a brief discussion of their origins and the current understanding of their mechanisms of action. Spinal stimulation leads to impressive improvements in motor function along with some benefits to autonomic functions such as bladder control. Nonetheless, the precise mechanisms underlying these improvements and the optimal spinal stimulation approaches for restoration of motor function are largely unknown. Finally, spinal stimulation may augment other therapies that address the molecular and cellular environment of the injured spinal cord. The fact that several stimulation approaches are now leading to substantial and durable improvements in function following spinal cord injury provides a new perspectives on the previously "incurable" condition of paralysis.

Regenerative Rehabilitation: Combining Stem Cell Therapies and Activity-Dependent Stimulation.

The number of clinical trials in regenerative medicine is burgeoning, and stem cell/tissue engineering technologies hold the possibility of becoming the standard of care for a multitude of diseases and injuries. Advances in regenerative biology reveal novel molecular and cellular targets, with potential to optimize tissue healing and functional recovery, thereby refining rehabilitation clinical practice. The purpose of this review is to (1) highlight the potential for synergy between the fields of regenerative medicine and rehabilitation, a convergence of disciplines known as regenerative rehabilitation; (2) provide translational examples of regenerative rehabilitation within the context of neuromuscular injuries and diseases; and (3) offer recommendations for ways to leverage activity dependence via combined therapy and technology, with the goal of enhancing long-term recovery. The potential clinical benefits of regenerative rehabilitation will likely become a critical aspect in the standard of care for many neurological and musculoskeletal disorders.

Direct control of paralysed muscles by cortical neurons.

A potential treatment for paralysis resulting from spinal cord injury is to route control signals from the brain around the injury by artificial connections. Such signals could then control electrical stimulation of muscles, thereby restoring volitional movement to paralysed limbs. In previously separate experiments, activity of motor cortex neurons related to actual or imagined movements has been used to control computer cursors and robotic arms, and paralysed muscles have been activated by functional electrical stimulation. Here we show that Macaca nemestrina monkeys can directly control stimulation of muscles using the activity of neurons in the motor cortex, thereby restoring goal-directed movements to a transiently paralysed arm. Moreover, neurons could control functional stimulation equally well regardless of any previous association to movement, a finding that considerably expands the source of control signals for brain-machine interfaces. Monkeys learned to use these artificial connections from cortical cells to muscles to generate bidirectional wrist torques, and controlled multiple neuron-muscle pairs simultaneously. Such direct transforms from cortical activity to muscle stimulation could be implemented by autonomous electronic circuitry, creating a relatively natural neuroprosthesis. These results are the first demonstration that direct artificial connections between cortical cells and muscles can compensate for interrupted physiological pathways and restore volitional control of movement to paralysed limbs.

Preliminary investigation of an electromyography-controlled video game as a home program for persons in the chronic phase of stroke recovery.

OBJECTIVE: To investigate the preliminary effectiveness of surface electromyography (sEMG) biofeedback delivered via interaction with a commercial computer game to improve motor control in chronic stroke survivors. DESIGN: Single-blinded, 1-group, repeated-measures design: A1, A2, B, A3 (A, assessment; B, intervention). SETTING: Laboratory and participants' homes. PARTICIPANTS: A convenience sample of persons (N=9) between 40 and 75 years of age with moderate to severe upper extremity motor impairment and at least 6 months poststroke completed the study. INTERVENTION: The electromyography-controlled video game system targeted the wrist muscle activation with the goal of increasing selective muscle activation. Participants received several laboratory training sessions with the system and then were instructed to use the system at home for 45 minutes, 5 times per week for the following 4 weeks. MAIN OUTCOME MEASURES: Primary outcome measures included duration of system use, sEMG during home play, and pre/post sEMG measures during active wrist motion. Secondary outcomes included kinematic analysis of movement and functional outcomes, including the Wolf Motor Function Test and the Chedoke Arm and Hand Activity Inventory-9. RESULTS: One third of participants completed or exceeded the recommended amount of system use. Statistically significant changes were observed on both game play and pre/post sEMG outcomes. Limited carryover, however, was observed on kinematic or functional outcomes. CONCLUSIONS: This preliminary investigation indicates that use of the electromyography-controlled video game impacts muscle activation. Limited changes in kinematic and activity level outcomes, however, suggest that the intervention may benefit from the inclusion of a functional activity component.

REPORT-SCS: minimum reporting standards for spinal cord stimulation studies in spinal cord injury.

Objective.Electrical spinal cord stimulation (SCS) has emerged as a promising therapy for recovery of motor and autonomic dysfunctions following spinal cord injury (SCI). Despite the rise in studies using SCS for SCI complications, there are no standard guidelines for reporting SCS parameters in research publications, making it challenging to compare, interpret or reproduce reported effects across experimental studies.Approach.To develop guidelines for minimum reporting standards for SCS parameters in pre-clinical and clinical SCI research, we gathered an international panel of expert clinicians and scientists. Using a Delphi approach, we developed guideline items and surveyed the panel on their level of agreement for each item.Main results.There was strong agreement on 26 of the 29 items identified for establishing minimum reporting standards for SCS studies. The guidelines encompass three major SCS categories: hardware, configuration and current parameters, and the intervention.Significance.Standardized reporting of stimulation parameters will ensure that SCS studies can be easily analyzed, replicated, and interpreted by the scientific community, thereby expanding the SCS knowledge base and fostering transparency in reporting.

Mapping the Iceberg of Autonomic Recovery: Mechanistic Underpinnings of Neuromodulation following Spinal Cord Injury.

Spinal cord injury leads to disruption in autonomic control resulting in cardiovascular, bowel, and lower urinary tract dysfunctions, all of which significantly reduce health-related quality of life. Although spinal cord stimulation shows promise for promoting autonomic recovery, the underlying mechanisms are unclear. Based on current preclinical and clinical evidence, this narrative review provides the most plausible mechanisms underlying the effects of spinal cord stimulation for autonomic recovery, including activation of the somatoautonomic reflex and induction of neuroplastic changes in the spinal cord. Areas where evidence is limited are highlighted in an effort to guide the scientific community to further explore these mechanisms and advance the clinical translation of spinal cord stimulation for autonomic recovery.

Optogenetic spinal stimulation promotes new axonal growth and skilled forelimb recovery in rats with sub-chronic cervical spinal cord injury.

Objective.Spinal cord injury (SCI) leads to debilitating sensorimotor deficits that greatly limit quality of life. This work aims to develop a mechanistic understanding of how to best promote functional recovery following SCI. Electrical spinal stimulation is one promising approach that is effective in both animal models and humans with SCI. Optogenetic stimulation is an alternative method of stimulating the spinal cord that allows for cell-type-specific stimulation. The present work investigates the effects of preferentially stimulating neurons within the spinal cord and not glial cells, termed 'neuron-specific' optogenetic spinal stimulation. We examined forelimb recovery, axonal growth, and vasculature after optogenetic or sham stimulation in rats with cervical SCI.Approach.Adult female rats received a moderate cervical hemicontusion followed by the injection of a neuron-specific optogenetic viral vector ipsilateral and caudal to the lesion site. Animals then began rehabilitation on the skilled forelimb reaching task. At four weeks post-injury, rats received a micro-light emitting diode (µLED) implant to optogenetically stimulate the caudal spinal cord. Stimulation began at six weeks post-injury and occurred in conjunction with activities to promote use of the forelimbs. Following six weeks of stimulation, rats were perfused, and tissue stained for GAP-43, laminin, Nissl bodies and myelin. Location of viral transduction and transduced cell types were also assessed.Main Results.Our results demonstrate that neuron-specific optogenetic spinal stimulation significantly enhances recovery of skilled forelimb reaching. We also found significantly more GAP-43 and laminin labeling in the optogenetically stimulated groups indicating stimulation promotes axonal growth and angiogenesis.Significance.These findings indicate that optogenetic stimulation is a robust neuromodulator that could enable future therapies and investigations into the role of specific cell types, pathways, and neuronal populations in supporting recovery after SCI.

Activity-dependent plasticity and spinal cord stimulation for motor recovery following spinal cord injury.

Spinal cord injuries lead to permanent physical impairment despite most often being anatomically incomplete disruptions of the spinal cord. Remaining connections between the brain and spinal cord create the potential for inducing neural plasticity to improve sensorimotor function, even many years after injury. This narrative review provides an overview of the current evidence for spontaneous motor recovery, activity-dependent plasticity, and interventions for restoring motor control to residual brain and spinal cord networks via spinal cord stimulation. In addition to open-loop spinal cord stimulation to promote long-term neuroplasticity, we also review a more targeted approach: closed-loop stimulation. Lastly, we review mechanisms of spinal cord neuromodulation to promote sensorimotor recovery, with the goal of advancing the field of rehabilitation for physical impairments following spinal cord injury.

Automated lever task with minimum antigravity movement for rats with cervical spinal cord injury.

BACKGROUND: Although there is currently no cure for paralysis due to spinal cord injury (SCI), the highest treatment priority is restoring arm and hand function for people with cervical SCI. Preclinical animal models provide an opportunity to test innovative treatments, but severe cervical injury models require significant time and effort to assess responses to novel interventions. Moreover, there is no behavioral task that can assess forelimb movement in rats with severe cervical SCI unable to perform antigravity movements. NEW METHOD: We developed a novel lever pressing task for rats with severe cervical SCI. We employed an automated adaptive algorithm to train animals using open-source software and commercially available hardware. We found that using the adaptive training required only 13.3 ± 2.5 training days to achieve behavioral proficiency. The lever press task could quantify immediate and long-term improvements in severely impaired forelimb function effectively. This behavior platform has potential to facilitate rehabilitative training and assess effects of therapeutic modalities following SCI. COMPARISON WITH EXISTING METHODS: There is no existing assessment aiming to quantify forelimb extension movement in rodents without function against gravity. We found that the new lever press task in the antigravity position could assess the severity of cervical SCI as well as the compensatory movement in the proximal forelimb less affected by the injury. CONCLUSIONS: This study demonstrates that the new behavioral task is capable of tracking the functional changes with various therapies in rats with severe forelimb impairments in a cost- and time-efficient manner.

Glassy Carbon Neural Interface for Chronic Epidural Stimulation in Rats with Cervical Spinal Cord Injury.

There is growing evidence on the efficacy of electrical stimulation delivered via spinal neural interfaces to improve functional recovery following spinal cord injury. For such interfaces, carbon-based neural arrays are fast becoming recognized as a compelling material and platform due to biocompatibility and long-term electrochemical stability. Here, we introduce the design, fabrication, and in vivo characterization of a novel cervical epidural implant with carbon-based surface electrodes. Through finite element analysis and mechanical load tests, we demonstrated that the array could safely withstand loads applied to it during implantation and natural movement of the subject with minimal stress levels. Furthermore, the long-term in vivo performance of this neural array consisting of glassy carbon surface electrodes was investigated through acute and chronic spinal motor evoked potential recordings and electrode impedance tests in rats. We demonstrated stable stimulation performance for at least four weeks in a rat model of spinal cord injury. Lastly, we found that impedance measurements on all carbon-based spinal arrays were generally stable over time up to four weeks after implantation, with a slight increase in impedance in subsequent weeks when tested in spinally injured rats. Taken together, this study demonstrated the potential for carbon-based electrodes as a spinal neural interface to accelerate both mechanistic research and functional restoration in animal models of spinal cord injury.

Multisite Transcutaneous Spinal Stimulation for Walking and Autonomic Recovery in Motor-Incomplete Tetraplegia: A Single-Subject Design.

OBJECTIVE: This study investigated the effect of cervical and lumbar transcutaneous spinal cord stimulation (tSCS) combined with intensive training to improve walking and autonomic function after chronic spinal cord injury (SCI). METHODS: Two 64-year-old men with chronic motor incomplete cervical SCI participated in this single-subject design study. They each underwent 2 months of intensive locomotor training and 2 months of multisite cervical and lumbosacral tSCS paired with intensive locomotor training. RESULTS: The improvement in 6-Minute Walk Test distance after 2 months of tSCS with intensive training was threefold greater than after locomotor training alone. Both participants improved balance ability measured by the Berg Balance Scale and increased their ability to engage in daily home exercises. Gait analysis demonstrated increased step length for each individual. Both participants experienced improved sensation and bowel function, and 1 participant eliminated the need for intermittent catheterization after the stimulation phase of the study. CONCLUSION: These results suggest that noninvasive spinal cord stimulation might promote recovery of locomotor and autonomic functions beyond traditional gait training in people with chronic incomplete cervical SCI. IMPACT: Multisite transcutaneous spinal stimulation may induce neuroplasticity of the spinal networks and confer functional benefits following chronic cervical SCI.

Transcutaneous Spinal Cord Stimulation Restores Hand and Arm Function After Spinal Cord Injury.

Paralysis of the upper extremity severely restricts independence and quality of life after spinal cord injury. Regaining control of hand and arm movements is the highest treatment priority for people with paralysis, 6-fold higher than restoring walking ability. Nevertheless, current approaches to improve upper extremity function typically do not restore independence. Spinal cord stimulation is an emerging neuromodulation strategy to restore motor function. Recent studies using surgically implanted electrodes demonstrate impressive improvements in voluntary control of standing and stepping. Here we show that transcutaneous electrical stimulation of the spinal cord leads to rapid and sustained recovery of hand and arm function, even after complete paralysis. Notably, the magnitude of these improvements matched or exceeded previously reported results from surgically implanted stimulation. Additionally, muscle spasticity was reduced and autonomic functions including heart rate, thermoregulation, and bladder function improved. Perhaps most striking is that all six participants maintained their gains for at least three to six months beyond stimulation, indicating functional recovery mediated by long-term neuroplasticity. Several participants resumed their hobbies that require fine motor control, such as playing the guitar and oil painting, for the first time in up to 12 years since their injuries. Our findings demonstrate that non-invasive transcutaneous electrical stimulation of the spinal networks restores movement and function of the hands and arm for people with both complete paralysis and long-term spinal cord injury.

Brain-Computer-Spinal Interface Restores Upper Limb Function After Spinal Cord Injury.

Brain-computer interfaces (BCIs) are an emerging strategy for spinal cord injury (SCI) intervention that may be used to reanimate paralyzed limbs. This approach requires decoding movement intention from the brain to control movement-evoking stimulation. Common decoding methods use spike-sorting and require frequent calibration and high computational complexity. Furthermore, most applications of closed-loop stimulation act on peripheral nerves or muscles, resulting in rapid muscle fatigue. Here we show that a local field potential-based BCI can control spinal stimulation and improve forelimb function in rats with cervical SCI. We decoded forelimb movement via multi-channel local field potentials in the sensorimotor cortex using a canonical correlation analysis algorithm. We then used this decoded signal to trigger epidural spinal stimulation and restore forelimb movement. Finally, we implemented this closed-loop algorithm in a miniaturized onboard computing platform. This Brain-Computer-Spinal Interface (BCSI) utilized recording and stimulation approaches already used in separate human applications. Our goal was to demonstrate a potential neuroprosthetic intervention to improve function after upper extremity paralysis.

Respiratory resetting elicited by single pulse spinal stimulation.

Intraspinal microstimulation (ISMS) can effectively activate spinal motor circuits, but the impact on the endogenous respiratory pattern has not been systematically evaluated. Here we delivered ISMS in spontaneously breathing adult rats while simultaneously recording diaphragm and external intercostal electromyography activity. ISMS pulses were delivered from C2-T1 along two rostrocaudal tracts located 0.5 or 1 mm lateral to midline. A tungsten electrode was incrementally advanced from the dorsal spinal surface and 300µs biphasic pulses (10-90 µA) were delivered at depth increments of 600 µm. Dorsal ISMS often produced fractionated inspiratory bursting or caused early termination of the inspiratory effort. Conversely, ventral stimulation had no discernable impact on respiratory resetting. We conclude that ISMS targeting the ventral spinal cord is unlikely to directly alter the respiratory rhythm. Dorsal ISMS, however, may terminate the inspiratory burst through activation of spinobulbar pathways. We suggest that respiratory patterns should be included as an outcome variable in preclinical studies of ISMS.

Reconfiguring Motor Circuits for a Joint Manual and BCI Task.

Designing brain-computer interfaces (BCIs) that can be used in conjunction with ongoing motor behavior requires an understanding of how neural activity co-opted for brain control interacts with existing neural circuits. For example, BCIs may be used to regain lost motor function after stroke. This requires that neural activity controlling unaffected limbs is dissociated from activity controlling the BCI. In this study we investigated how primary motor cortex accomplishes simultaneous BCI control and motor control in a task that explicitly required both activities to be driven from the same brain region (i.e. a dual-control task). Single-unit activity was recorded from intracortical, multi-electrode arrays while a non-human primate performed this dual-control task. Compared to activity observed during naturalistic motor control, we found that both units used to drive the BCI directly (control units) and units that did not directly control the BCI (non-control units) significantly changed their tuning to wrist torque. Using a measure of effective connectivity, we observed that control units decrease their connectivity. Through an analysis of variance we found that the intrinsic variability of the control units has a significant effect on task proficiency. When this variance is accounted for, motor cortical activity is flexible enough to perform novel BCI tasks that require active decoupling of natural associations to wrist motion. This study provides insight into the neural activity that enables a dual-control brain-computer interface.

Robust passive dynamics of the musculoskeletal system compensate for unexpected surface changes during human hopping.

When human hoppers are surprised by a change in surface stiffness, they adapt almost instantly by changing leg stiffness, implying that neural feedback is not necessary. The goal of this simulation study was first to investigate whether leg stiffness can change without neural control adjustment when landing on an unexpected hard or unexpected compliant (soft) surface, and second to determine what underlying mechanisms are responsible for this change in leg stiffness. The muscle stimulation pattern of a forward dynamic musculoskeletal model was optimized to make the model match experimental hopping kinematics on hard and soft surfaces. Next, only surface stiffness was changed to determine how the mechanical interaction of the musculoskeletal model with the unexpected surface affected leg stiffness. It was found that leg stiffness adapted passively to both unexpected surfaces. On the unexpected hard surface, leg stiffness was lower than on the soft surface, resulting in close-to-normal center of mass displacement. This reduction in leg stiffness was a result of reduced joint stiffness caused by lower effective muscle stiffness. Faster flexion of the joints due to the interaction with the hard surface led to larger changes in muscle length, while the prescribed increase in active state and resulting muscle force remained nearly constant in time. Opposite effects were found on the unexpected soft surface, demonstrating the bidirectional stabilizing properties of passive dynamics. These passive adaptations to unexpected surfaces may be critical when negotiating disturbances during locomotion across variable terrain.

A Robust Encoding Scheme for Delivering Artificial Sensory Information via Direct Brain Stimulation.

Innovations for creating somatosensation via direct electrical stimulation of the brain will be required for the next generation of bi-directional cortical neuroprostheses. The current lack of tactile perception and proprioceptive input likely imposes a fundamental limit on speed and accuracy of brain-controlled prostheses or re-animated limbs. This study addresses the unique challenge of identifying a robust, high bandwidth sensory encoding scheme in a high-dimensional parameter space. Previous studies demonstrated single dimensional encoding schemes delivering low bandwidth sensory information, but no comparison has been performed across parameters, nor with update rates suitable for real-time operation of a neuroprosthesis. Here, we report the first comprehensive measurement of the resolution of key stimulation parameters such as pulse amplitude, pulse width, frequency, train interval and number of pulses. Surprisingly, modulation of stimulation frequency was largely undetectable. While we initially expected high frequency content to be an ideal candidate for passing high throughput sensory signals to the brain, we found only modulation of very low frequencies were detectable. Instead, the charge-per-phase of each pulse yields the highest resolution sensory signal, and is the key parameter modulating perceived intensity. The stimulation encoding patterns were designed for high-bandwidth information transfer that will be required for bi-directional brain interfaces. Our discovery of the stimulation features which best encode perceived intensity have significant implications for design of any neural interface seeking to convey information directly to the brain via electrical stimulation.

Neural engineering: the process, applications, and its role in the future of medicine.

OBJECTIVE: Recent advances in neural engineering have restored mobility to people with paralysis, relieved symptoms of movement disorders, reduced chronic pain, restored the sense of hearing, and provided sensory perception to individuals with sensory deficits. APPROACH: This progress was enabled by the team-based, interdisciplinary approaches used by neural engineers. Neural engineers have advanced clinical frontiers by leveraging tools and discoveries in quantitative and biological sciences and through collaborations between engineering, science, and medicine. The movement toward bioelectronic medicines, where neuromodulation aims to supplement or replace pharmaceuticals to treat chronic medical conditions such as high blood pressure, diabetes and psychiatric disorders is a prime example of a new frontier made possible by neural engineering. Although one of the major goals in neural engineering is to develop technology for clinical applications, this technology may also offer unique opportunities to gain insight into how biological systems operate. MAIN RESULTS: Despite significant technological progress, a number of ethical and strategic questions remain unexplored. Addressing these questions will accelerate technology development to address unmet needs. The future of these devices extends far beyond treatment of neurological impairments, including potential human augmentation applications. Our task, as neural engineers, is to push technology forward at the intersection of disciplines, while responsibly considering the readiness to transition this technology outside of the laboratory to consumer products. SIGNIFICANCE: This article aims to highlight the current state of the neural engineering field, its links with other engineering and science disciplines, and the challenges and opportunities ahead. The goal of this article is to foster new ideas for innovative applications in neurotechnology.

Now is the Critical Time for Engineered Neuroplasticity.

Recent advances in neuroscience and devices are ushering in a new generation of medical treatments. Engineered biodevices are demonstrating the potential to create long-term changes in neural circuits, termed neuroplasticity. Thus, the approach of engineering neuroplasticity is rapidly expanding, building on recent demonstrations of improved quality of life for people with movement disorders, epilepsy, and spinal cord injury. In addition, discovering the fundamental mechanisms of engineered neuroplasticity by leveraging anatomically well-documented systems like the spinal cord is likely to provide powerful insights into solutions for other neurotraumas, such as stroke and traumatic brain injury, as well as neurodegenerative disorders, such as Alzheimer's, Parkinson disease, and multiple sclerosis. Now is the time for advancing both the experimental neuroscience, device development, and pioneering human trials to reap the benefits of engineered neuroplasticity as a therapeutic approach for improving quality of life after spinal cord injury.

Intraspinal microstimulation for respiratory muscle activation.

A complex propriospinal network is synaptically coupled to phrenic and intercostal motoneurons, and this makes it difficult to predict how gray matter intraspinal microstimulation (ISMS) will recruit respiratory motor units. We therefore mapped the cervical and high thoracic gray matter at locations which ISMS activates diaphragm (DIA) and external intercostal (EIC) motor units. Respiratory muscle electromyography (EMG) was recorded in anesthetized female spinally intact adult rats while a stimulating electrode was advanced ventrally into the spinal cord in 600µm increments. At each depth, single biphasic stimuli were delivered at 10-90µA during both the inspiratory and expiratory phase independently. Twenty electrode tracks were made from C2-T1 at medial and lateral gray matter locations. During inspiration, ISMS evoked DIA and EIC activity throughout C2-T1 gray matter locations, with mutual activation occurring at 17±9% of sites. During inspiratory phase ISMS the average latency for DIA activation was 4.40±0.70ms. During the expiratory phase, ISMS-induced DIA activation required electrodes to be in close proximity to the phrenic motoneuron pool, and average activation latency was 3.30±0.50ms. We conclude that appropriately targeted ISMS can co-activate DIA and EIC motor units, and endogenous respiratory drive has a powerful impact on ISMS-induced respiratory motor unit activation. The long latency diaphragm motor unit activation suggests the presence of a complex propriospinal network that can modulate phrenic motor output.