To date, there is no effective therapy for spinal cord injury, and many patients could benefit dramatically from at least partial restoration of arm and hand function. Despite a substantial body of research investigating intraspinal microstimulation (ISMS) in frogs, rodents and cats, little is known about upper-limb responses to cervical stimulation in the primate. Here, we show for the first time that long trains of ISMS delivered to the macaque spinal cord can evoke functional arm and hand movements. Complex movements involving coordinated activation of multiple muscles could be elicited from a single electrode, while just two electrodes were required for independent control of reaching and grasping. We found that the motor responses to ISMS were described by a dual exponential model that depended only on stimulation history. We demonstrate that this model can be inverted to generate stimulus trains capable of eliciting arbitrary, graded motor responses, and could be used to restore volitional movements in a closed-loop brain–machine interface.
Intraspinal microstimulation (ISMS) involves the implantation of microwires into the spinal cord below the level of an injury to excite neural networks involved in the control of locomotion in the lower limbs. The goal of this study was to examine the potential spinal cord damage that might occur with chronic ISMS. We employed functional measures of force recruitment and immunohistochemical processing of serial spinal cord sections to evaluate any damage induced by spinal transection, implantation of ISMS arrays, and electrical stimulation of 4 hours/day for 30 days. Functional measurements showed no change in force recruitment following transection and chronic ISMS, indicating no changes to underlying neural networks. The implantation of sham intraspinal microwires produced a spatially-limited increase in the density of microglia/macrophages and GFAP+ astrocytes adjacent to the microwire tracks, indicating a persistent immune response. Most importantly, these results were not different from those around microwires that were chronically pulsed with charge levels up to 48 nC/phase. Likewise, measurements of neuronal density indicated no decrease in neuronal cell bodies in the ventral grey matter surrounding ISMS microwires (243.6/mm2 ± 35.3/mm2) compared to tissue surrounding sham microwires (207.8/mm2 ± 38.8/mm2). We conclude that the implantation of intraspinal microwires and chronic application of ISMS are well tolerated by spinal cord tissue.
This paper reports on a wireless stimulator device for use in animal experiments as part of an ongoing investigation into intraspinal stimulation (ISMS) for restoration of walking in humans with spinal cord injury. The principle behind using ISMS is the activation of residual motor-control neural networks within the spinal cord ventral horn below the level of lesion following a spinal cord injury. The attractiveness to this technique is that a small number of electrodes can be used to induce bilateral walking patterns in the lower limbs. In combination with advanced feedback algorithms, ISMS has the potential to restore walking for distances that exceed that produced by other types of functional electrical stimulation. Recent acute animal experiments have demonstrated the feasibility of using ISMS to produce the coordinated walking patterns. Here we described a wireless implantable stimulation system to be used in chronic animal experiments and for providing the basis for a system suitable for use in humans. Electrical operation of the wireless system is described, including a demonstration of reverse telemetry for monitoring the stimulating electrode voltages.
Complications of spinal cord injury in males include losing brainstem control of pudendal nerve–innervated perineal muscles involved in erection and ejaculation. We previously described, in adult male rats, a bulbospinal pathway originating in a discrete area within the medullary gigantocellularis (GiA/Gi), and lateral paragigantocellularis (LPGi) nuclei, which when electrically microstimulated unilaterally, produces a bilateral inhibition of pudendal motoneuron reflex circuitry after crossing to the contralateral spinal cord below T8. Microstimulation following a long-term lateral hemisection, however, revealed reflex inhibition from both sides of the medulla, suggesting the development or unmasking of an injury-induced bulbospinal pathway crossing the midline cranial to the spinal lesion. In the present study, we investigated this pathway anatomically using the transsynaptic neuronal tracer pseudorabies virus (PRV) injected unilaterally into the bulbospongiosus muscle in uninjured controls, and ipsilateral to a chronic (1–2 months) unilateral lesion of the lateral funiculus. At 4.75 days post-injection, PRV-labeled cells were found bilaterally in the GiA/Gi/LPGi with equal side-to-side labeling in uninjured controls, and with significantly greater labeling contralateral to the lesion/injection in lesioned animals. The finding of PRV-labeled neurons on both sides of the medulla after removing the mid-thoracic spinal pathway on one side provides anatomical evidence for the bilaterality in both the brainstem origin and the lumbosacral pudendal circuit termination of the spared lateral funicular bulbospinal pathway. This also suggests that this bilaterality may contribute to the quick functional recovery of bladder and sexual functions observed in animals and humans with lateral hemisection injury.
animal studies; electrophysiology; immunohistochemistry; in vivo studies; spinal cord injury
To summarize the changes that occur in the properties of bladder afferent neurons following spinal cord injury.
Literature review of anatomical, immunohistochemical, and pharmacologic studies of normal and dysfunctional bladder afferent pathways.
Studies in animals indicate that the micturition reflex is mediated by a spinobulbospinal pathway passing through coordination centers (periaqueductal gray and pontine micturition center) located in the rostral brain stem. This reflex pathway, which is activated by small myelinated (Aδ) bladder afferent nerves, is in turn modulated by higher centers in the cerebral cortex involved in the voluntary control of micturition. Spinal cord injury at cervical or thoracic levels disrupts voluntary voiding, as well as the normal reflex pathways that coordinate bladder and sphincter function. Following spinal cord injury, the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. The recovery of bladder function after spinal cord injury is dependent in part on the plasticity of bladder afferent pathways and the unmasking of reflexes triggered by unmyelinated, capsaicin-sensitive, C-fiber bladder afferent neurons. Plasticity is associated with morphologic, chemical, and electrical changes in bladder afferent neurons and appears to be mediated in part by neurotrophic factors released in the spinal cord and the peripheral target organs.
Spinal cord injury at sites remote from the lumbosacral spinal cord can indirectly influence properties of bladder afferent neurons by altering the function and chemical environment in the bladder or the spinal cord.
afferent neurons; micturition; neuropeptides; neuroplasticity; neurotrophic factors; urinary bladder; voltage-gated ion channels
The overall objective of this project is to develop a feedback-driven intraspinal microstimulation (ISMS) system. We hypothesize that ISMS will enhance the functionality of stepping by reducing muscle fatigue and producing synergistic movements by activating neural networks in the spinal cord. In the present pilot study, the controller was tested with ISMS and external sensors (force plates, gyroscopes, and accelerometers). Cats were partially supported in a sling and bi-laterally stepped overground on a 4-m instrumented walkway. The walkway had variable friction. Limb angle was controlled to within 10° even in the presence of variable friction. Peak ground reaction forces in each limb were approximately 12% of body weight (12.5% was full load bearing in this experimental setup); rarely, the total supportive force briefly decreased to as low as 4.1%. Magnetic resonance images were acquired of the excised spinal cord and the implanted array. The majority of electrodes (75%) were implanted successfully into their target regions. This represents the first successful application of ISMS for overground walking.
Spinal lesions substantially impair ambulation, occur generally in young and otherwise healthy individuals, and result in devastating effects on quality of life. Restoration of locomotion after damage to the spinal cord is challenging because axons of the damaged neurons do not regenerate spontaneously. Body-weight-supported treadmill training (BWSTT) is a therapeutic approach in which a person with a spinal cord injury (SCI) steps on a motorized treadmill while some body weight is removed through an upper body harness. BWSTT improves temporal gait parameters, muscle activation patterns, and clinical outcome measures in persons with SCI. These changes are likely the result of reorganization that occurs simultaneously in supraspinal and spinal cord neural circuits. This paper will focus on the cortical control of human locomotion and motor output, spinal reflex circuits, and spinal interneuronal circuits and how corticospinal control is reorganized after locomotor training in people with SCI. Based on neurophysiological studies, it is apparent that corticospinal plasticity is involved in restoration of locomotion after training. However, the neural mechanisms underlying restoration of lost voluntary motor function are not well understood and translational neuroscience research is needed so patient-orientated rehabilitation protocols to be developed.
Intraspinal microstimulation (ISMS) employs electrical stimulation of the ventral grey matter to reactivate paralyzed skeletal muscle. This work evaluated the transformations in the quadriceps muscle that occurred following complete transection and chronic stimulation with ISMS or a standard nerve cuff (NCS). Stimulation was applied for 30 days, 4 hours/day. Both methods induced significant increases in time-to-peak tension (ISMS 35%, NCS 25%) and ½ rise-time (ISMS 39%, NCS 25%) compared to intact controls (IC). Corresponding increases in type-IIA myosin heavy chain (MHC) and decreases in type-IID MHC were noted compared to IC. These results were unexpected because ISMS recruits motor units in a near-normal physiological order while NCS recruits motor units in a reversed order. Spinal cord transection and 30 days of stimulation did not alter either recruitment profile. The slope of the force recruitment curves obtained through ISMS following transection and 30 days of stimulation was similar to that obtained in intact animals, and 3.4-fold shallower than that obtained through NCS. The transformations observed in the current work are best explained by the near maximal level of motor unit recruitment, the total daily time of activity and the tonic nature of the stimulation paradigm.
Functional electrical stimulation; muscle plasticity; spinal motoneurons
This review highlights current tissue engineering and novel therapeutic approaches to axonal regeneration following spinal cord injury. The concept of developing 3-dimensional polymer scaffolds for placement into a spinal cord transection model has recently been more extensively explored as a solution for restoring neurologic function after injury. Given the patient morbidity associated with respiratory compromise, the discrete tracts in the spinal cord conveying innervation for breathing represent an important and achievable therapeutic target. The aim is to derive new neuronal tissue from the surrounding, healthy cord that will be guided by the polymer implant through the injured area to make functional reconnections. A variety of naturally derived and synthetic biomaterial polymers have been developed for placement in the injured spinal cord. Axonal growth is supported by inherent properties of the selected polymer, the architecture of the scaffold, permissive microstructures such as pores, grooves or polymer fibres, and surface modifications to provide improved adherence and growth directionality. Structural support of axonal regeneration is combined with integrated polymeric and cellular delivery systems for therapeutic drugs and for neurotrophic molecules to regionalize growth of specific nerve populations.
Spinal cord injury; Axonal regeneration; Polymer scaffold; Tissue engineering; Neurotrophins
One consequence of central nervous system injury or disease is the impairment of neural control of movement, resulting in spasticity and paralysis. To enhance recovery, restorative neurology procedures modify altered, yet preserved nervous system function. This review focuses on functional electrical stimulation (FES) and spinal cord stimulation (SCS) that utilize remaining capabilities of the distal apparatus of spinal cord, peripheral nerves and muscles in upper motor neuron dysfunctions. FES for the immediate generation of lower limb movement along with current rehabilitative techniques is reviewed. The potential of SCS for controlling spinal spasticity and enhancing lower limb function in multiple sclerosis and spinal cord injury is discussed. The necessity for precise electrode placement and appropriate stimulation parameter settings to achieve therapeutic specificity is elaborated. This will lead to our human work of epidural and transcutaneous stimulation targeting the lumbar spinal cord for enhancing motor functions in spinal cord injured people, supplemented by pertinent human research of other investigators. We conclude that the concept of restorative neurology recently received new appreciation by accumulated evidence for locomotor circuits residing in the human spinal cord. Technological and clinical advancements need to follow for a major impact on the functional recovery in individuals with severe damage to their motor system.
Functional electrical stimulation; Locomotion; Motor control; Multiple sclerosis; Neuromodulation; Restorative neurology; Spinal cord injury; Spinal cord stimulation
The purpose of this publication is to present our original work on a multi-muscle surface electromyographic approach to quantitatively characterize respiratory muscle activation patterns in individuals with chronic spinal cord injury using vector-based analysis.
During breathing, activation of respiratory muscles is coordinated by integrated input from the brain, brainstem, and spinal cord. When this coordination is disrupted by spinal cord injury (SCI), control of respiratory muscles innervated below the injury level is compromised1,2 leading to respiratory muscle dysfunction and pulmonary complications. These conditions are among the leading causes of death in patients with SCI3. Standard pulmonary function tests that assess respiratory motor function include spirometrical and maximum airway pressure outcomes: Forced Vital Capacity (FVC), Forced Expiratory Volume in one second (FEV1), Maximal Inspiratory Pressure (PImax) and Maximal Expiratory Pressure (PEmax)4,5. These values provide indirect measurements of respiratorymuscle performance6. In clinical practice and research, a surface electromyography (sEMG) recorded from respiratory muscles can be used to assess respiratory motor function and help to diagnose neuromuscular pathology. However, variability in the sEMG amplitude inhibits efforts to develop objective and direct measures of respiratory motor function6. Based on a multi-muscle sEMG approach to characterize motor control of limb muscles7, known as the voluntary response index (VRI)8, we developed an analytical tool to characterize respiratory motor control directly from sEMG data recorded from multiple respiratory muscles during the voluntary respiratory tasks. We have termed this the Respiratory Motor Control Assessment (RMCA)9. This vector analysis method quantifies the amount and distribution of activity across muscles and presents it in the form of an index that relates the degree to which sEMG output within a test-subject resembles that from a group of healthy (non-injured) controls. The resulting index value has been shown to have high face validity, sensitivity and specificity9–11. We showed previously9 that the RMCA outcomes significantly correlate with levels of SCI and pulmonary function measures. We are presenting here the method to quantitatively compare post-spinal cord injury respiratory multi-muscle activation patterns to those of healthy individuals.
Respiratory Muscles; Motor Control; Electromyography; Pulmonary Function Test; Spinal Cord Injury
Spinal cord injury disrupts the connections between the brain and spinal cord, often resulting in the loss of sensory and motor function below the lesion site. The most important reason for such permanent functional deficits is the failure of injured axons to regenerate after injury. In principle, the functional recovery could be achieved by two forms of axonal regrowth: the regeneration of lesioned axons which will reconnect with their original targets and the sprouting of spared axons that form new circuits and compensate for the lost function. Our recent studies reveal the activity of the mammalian target of rapamycin (mTOR) pathway, a major regulator of new protein synthesis, as a critical determinant of axon regrowth in the adult retinal ganglion neurons. In this review, I summarize current understanding of the cellular and molecular mechanisms that control the intrinsic regenerative ability of mature neurons.
This review presents a summary of the various types of cellular therapy used to treat spinal cord injury. The inhibitory environment and loss of axonal connections after spinal cord injury pose many obstacles to regenerating the lost tissue. Cellular therapy provides a means of restoring the cells lost to the injury and could potentially promote functional recovery after such injuries. A wide range of cell types have been investigated for such uses and the advantages and disadvantages of each cell type are discussed along with the research studying each cell type. Additionally, methods of delivering cells to the injury site are evaluated. Based on the current research, suggestions are given for future investigation of cellular therapies for spinal cord regeneration.
embryonic stem cells; neural stem cells; spinal cord injury; regenerative medicine; bone marrow stromal cells; biomaterials
Over the past 20 years, tremendous advances have been made in the field of spinal cord injury research. Yet, consumed with individual pieces of the puzzle, we have failed as a community to grasp the magnitude of the sum of our findings. Our current knowledge should allow us to improve the lives of patients suffering from spinal cord injury. Advances in multiple areas have provided tools for pursuing effective combination of strategies for recovering stepping and standing after a severe spinal cord injury. Muscle physiology research has provided insight into how to maintain functional muscle properties after a spinal cord injury.
Understanding the role of the spinal networks in processing sensory information that is important for the generation of motor functions has focused research on developing treatments that sharpen the sensitivity of the locomotor circuitry and that carefully manage the presentation of proprioceptive and cutaneous stimuli to favor recovery. Pharmacological facilitation or inhibition of neurotransmitter systems, spinal cord stimulation, and rehabilitative motor training, which all function by modulating the physiological state of the spinal circuitry, have emerged as promising approaches. Early technological developments, such as robotic training systems and high-density electrode arrays for stimulating the spinal cord, can significantly enhance the precision and minimize the invasiveness of treatment after an injury.
Strategies that seek out the complementary effects of combination treatments and that efficiently integrate relevant technical advances in bioengineering represent an untapped potential and are likely to have an immediate impact. Herein, we review key findings in each of these areas of research and present a unified vision for moving forward. Much work remains, but we already have the capability, and more importantly, the responsibility, to help spinal cord injury patients now.
spinal cord injury; rehabilitation; robotic motor training; pharmacological intervention; skeletal muscle adaptation; proprioception; epidural stimulation; locomotion
While axonal regeneration after CNS injury is limited, partial injury is frequently accompanied by extensive functional recovery. To investigate mechanisms underlying spontaneous recovery after incomplete spinal cord injury, adult rhesus monkeys underwent C7 spinal cord hemisections, with subsequent analysis of behavioral, electrophysiological and anatomical adaptations. We found remarkable spontaneous plasticity of corticospinal projections, with reconstitution of fully 60% of pre-lesion axon density arising from sprouting of spinal cord midline-crossing axons. This extensive anatomical recovery was associated with improvement in coordinated muscle recruitment, hand function and locomotion. These findings identify what may be the most extensive natural recovery of mammalian axonal projections after nervous system injury observed to date, highlighting an important role for primate models in translational disease research.
Electrical activation of an excitatory reflex between sensory fibers in the pudendal nerve and the bladder has been demonstrated in cats and is a potential means of restoring micturition function in persons with spinal cord injury. We investigated the clinical feasibility of activating this reflex to restore bladder function in persons with spinal cord injury by using intraurethral electrical stimulation to activate pudendal sensory fibers innervating the urethra. Excitatory bladder responses (contractions) were evoked by trains of electrical pulses applied to either the proximal (29.7 ± 11.6 cmH2O) or distal (30.2 ± 11.6 cmH2O) segment of the urethra. The results indicate that an excitatory reflex between pudendal nerve afferents and the bladder exists in humans with spinal injury and may provide a substrate for restoring micturition function.
Spinal cord injury (SCI) has been regarded clinically as an irreversible damage caused by tissue contusion due to a blunt external force. Past research had focused on the analysis of the pathogenesis of secondary injury that extends from the injury epicenter to the periphery, as well as tissue damage and neural cell death associated with secondary injury. Recent studies, however, have proven that neural stem (progenitor) cells are also present in the brain and spinal cord of adult mammals including humans. Analyses using spinal cord injury models have also demonstrated active dynamics of cells expressing several stem cell markers, and methods aiming at functional reconstruction by promoting the potential self-regeneration capacity of the spinal cord are being explored. Furthermore, reconstruction of the neural circuit requires not only replenishment or regeneration of neural cells but also regeneration of axons. Analysis of the tissue microenvironment after spinal cord injury and research aiming to remove axonal regeneration inhibitors have also made progress. SCI is one of the simplest central nervous injuries, but its pathogenesis is associated with diverse factors, and further studies are required to elucidate these complex interactions in order to achieve spinal cord regeneration and functional reconstruction.
glia; regeneration; spinal cord; injury; axon
Spinal cord trauma in the adult nervous system usually results in permanent loss of function below the injury level. The immature spinal cord has greater capacity for repair and can develop considerable functionality by adulthood. This study used the marsupial laboratory opossum Monodelphis domestica, which is born at a very early stage of neural development. Complete spinal cord transection was made in the lower-thoracic region of pups at postnatal-day 7 (P7) or P28, and the animals grew to adulthood. Injury at P7 resulted in a dense neuronal tissue bridge that connected the two ends of the cord; retrograde neuronal labelling indicated that supraspinal and propriospinal innervation spanned the injury site. This repair was associated with pronounced behavioural recovery, coordinated gait and an ability to use hindlimbs when swimming. Injury at P28 resulted in a cyst-like cavity encased in scar tissue forming at the injury site. Using retrograde labelling, no labelled brainstem or propriospinal neurons were found above the lesion, indicating that detectable neuronal connectivity had not spanned the injury site. However, these animals could use their hindlimbs to take weight-supporting steps but could not use their hindlimbs when swimming. White matter, demonstrated by Luxol Fast Blue staining, was present in the injury site of P7- but not P28-injured animals. Overall, these studies demonstrated that provided spinal injury occurs early in development, regrowth of supraspinal innervation is possible. This repair appears to lead to improved functional outcomes. At older ages, even without detectable axonal growth spanning the injury site, substantial development of locomotion was still possible. This outcome is discussed in conjunction with preliminary findings of differences in the local propriospinal circuits following spinal cord injury (demonstrated with fluororuby labelling), which may underlie the weight bearing locomotion observed in the apparent absence of axons bridging the lesion site in P28-injured Monodelphis.
Mesenchymal stem cells are widely used for transplantation into the injured spinal cord in vivo model and for safety, many human clinical trials are continuing to promote improvements of motor and sensory functions after spinal cord injury. Yet the exact mechanism for these improvements remains undefined. Neurogenic bladder following spinal cord injury is the main problem decreasing the quality of life for patients with spinal cord injury, but there are no clear data using stem cell transplantation for the improvement of neurogenic bladder for in vivo studies and the clinical setting.
The purpose of this study was to delineate the effect of human mesenchymal stem cell (hMSCs) transplantation on the restoration of neurogenic bladder and impaired hindlimb function after spinal cord contusion of rats and the relationship between neurotrophic factors such as brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) and bladder and hindlimb functions.
Modified moderate contusion injury were performed on the thoracic spinal cord of Sprague-Dawley rats using MASCIS impactor and hMSCs, human fibroblasts or phosphate-buffered saline were transplanted into injured spinal cord 9 days after injury for hMSC and two control groups respectively. Ladder test showed more rapid restoration of hindlimb function in hMSC group than in control group, but Basso, Beattie, and Bresnahan score and coupling score were not different significantly among hMSC and two control groups. Neurogenic bladder was not improved in either group. ED1 positive macrophages were significantly reduced in hMSC group than in two control groups, but ELISA and RT-PCR studies revealed BDNF and NT-3 levels in spinal cord and bladder were not different among hMSC and two control groups regardless the experimental duration.
hMSC transplantation was effective in reducing inflammatory reaction after spinal cord contusion of rats but not sufficient to recover locomotor and bladder dysfunction. BDNF and NT-3 levels in the spinal cord and bladder were not increased 28 and 56 days after hMSC transplantation.
Central cord syndrome (CCS) is extremely rare as a direct consequence of generalized epileptic seizure. CCS is associated with hyperextension of the spinal cord and has characteristic radiologic findings including posterior ligamentous injury and prevertebral hyperintensity following magnetic resonance imaging (MRI). We experienced the case of a 25-year-old man who suffered CCS after status epilepticus. Cervical spinal MRI revealed high signal intensity at the C1 level but with no signal or structural changes in other sites. After rehabilitation management, the patient significantly improved on the ASIA (American Spinal Injury Association) motor scale and bladder function. We proposed that epilepsy related CCS may be caused by muscle contractions during generalized seizure, which can induce traction injury of the spinal cord or relative narrowing of spinal canal via transient herniated nucleus pulposus or transient subluxation of vertebra. We also suggest CCS without radiologic findings of trauma has good prognosis compared with other CCS.
Central cord syndrome; Status epilepticus
Traumatic insults to the spinal cord induce both immediate mechanical damage and subsequent tissue degeneration leading to a substantial physiological, biochemical, and functional reorganization of the spinal cord. Various spinal cord injury (SCI) models have shown the adaptive potential of the spinal cord and its limitations in the case of total or partial absence of supraspinal influence. Meaningful recovery of function after SCI will most likely result from a combination of therapeutic strategies, including neural tissue transplants, exogenous neurotrophic factors, elimination of inhibitory molecules, functional sensorimotor training, and/or electrical stimulation of paralyzed muscles or spinal circuits. Peripheral nerve grafts provide a growth-permissive substratum and local neurotrophic factors to enhance the regenerative effort of axotomized neurons when grafted into the site of injury. Regenerating axons can be directed via the peripheral nerve graft toward an appropriate target, but they fail to extend beyond the distal graft–host interface because of the deposition of growth inhibitors at the site of SCI. One method to facilitate the emergence of axons from a graft into the spinal cord is to digest the chondroitin sulfate proteoglycans that are associated with a glial scar. Importantly, regenerating axons that do exit the graft are capable of forming functional synaptic contacts. These results have been demonstrated in acute injury models in rats and cats and after a chronic injury in rats and have important implications for our continuing efforts to promote structural and functional repair after SCI.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-011-0024-6) contains supplementary material, which is available to authorized users.
Spinal cord injury; peripheral nerve graft; axon regeneration; transplantation; neuroplasticity; chondroitinase
Functional loss of limb control in individuals with spinal cord injury or stroke can be caused by interruption of corticospinal pathways, although the neural circuits located above and below the lesion remain functional. An artificial neural connection that bridges the lost pathway and connects cortical to spinal circuits has potential to ameliorate the functional loss. We investigated the effects of introducing novel artificial neural connections in a paretic monkey that had a unilateral spinal cord lesion at the C2 level. The first application bridged the impaired spinal lesion. This allowed the monkey to drive the spinal stimulation through volitionally controlled power of high-gamma activity in either the premotor or motor cortex, and thereby to acquire a force-matching target. The second application created an artificial recurrent connection from a paretic agonist muscle to a spinal site, allowing muscle-controlled spinal stimulation to boost on-going activity in the muscle. These results suggest that artificial neural connections can compensate for interrupted descending pathways and promote volitional control of upper limb movement after damage of descending pathways such as spinal cord injury or stroke.
brain–computer interface; artificial neural connection; hand; spinal cord injury; local field potential; muscle; spinal cord; monkey
Structural discontinuity in the spinal cord after injury results in a disruption in the impulse conduction resulting in loss of various bodily functions depending upon the level of injury. This article presents a summary of the scientific research employing electrical stimulation as a means for anatomical or functional recovery for patients suffering from spinal cord injury. Electrical stimulation in the form of functional electrical stimulation (FES) can help facilitate and improve upper/lower limb mobility along with other body functions lost due to injury e.g. respiratory, sexual, bladder or bowel functions by applying a controlled electrical stimulus to generate contractions and functional movement in the paralysed muscles. The available rehabilitative techniques based on FES technology and various Food and Drug Administration, USA approved neuroprosthetic devices that are in use are discussed. The second part of the article summarises the experimental work done in the past 2 decades to study the effects of weakly applied direct current fields in promoting regeneration of neurites towards the cathode and the new emerging technique of oscillating field stimulation which has shown to promote bidirectional regeneration in the injured nerve fibres. The present article is not intended to be an exhaustive review but rather a summary aiming to highlight these two applications of electrical stimulation and the degree of anatomical/functional recovery associated with these in the field of spinal cord injury research.
Spinal cord injury; Oscillating field stimulation; Functional electrical stimulation; Axonal regeneration; Advances in spinal cord research
The loss of walking after human spinal cord injury has been attributed to the dominance of supraspinal over spinal mechanisms. The evidence for central pattern generation in humans is limited due to the inability to conclusively isolate the circuitry from descending and afferent input. However, studying individuals following spinal cord injury with no detectable influence on spinal networks from supraspinal centers can provide insight to their interaction with afferent input. The focus of this article is on the interaction of sensory input with human spinal networks in the generation of locomotor patterns. The functionally isolated human spinal cord has the capacity to generate locomotor patterns with appropriate afferent input. Locomotor Training is a rehabilitative strategy that has evolved from animal and humans studies focused on the neural plasticity of the spinal cord and has been successful for many people with acute and chronic incomplete spinal cord injury. However, even those individuals with clinically complete spinal cord injury that generate appropriate locomotor patterns during stepping with assistance on a treadmill with body weight support cannot sustain overground walking. This suggests that although a significant control of locomotion can occur at the level of spinal interneuronal networks the level of sustainable excitability of these circuits is still compromised. Future studies should focus on approaches to increase the central state of excitability and may include neural repair strategies, pharmacological interventions or epidural stimulation in combination with Locomotor Training.
Understanding how the vertebrate central nervous system develops and functions is a major goal of a large body of biological research. This research is driven both by intellectual curiosity about this amazing organ that coordinates our conscious and unconscious bodily processes, perceptions and actions and by the practical desire to develop effective treatments for people with spinal cord injuries or neurological diseases. In recent years, we have learnt an impressive amount about how the nerve cells that communicate with muscles, motoneurons, are made in a developing embryo and this knowledge has enabled researchers to grow motoneurons from stem cells. Building on the success of these studies, researchers have now started to unravel how most of the other nerve cells in the spinal cord are made and function. This review will describe what we currently know about spinal cord nerve cell development, concentrating on the largest category of nerve cells, which are called interneurons. I will then discuss how we can build and expand upon this knowledge base to elucidate the complete genetic programme that determines how different spinal cord nerve cells are made and connected up into neural circuits with particular functions.
interneuron; spinal cord; transcription factor; zebrafish; Shh; BMP