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Abstract

Spinal cord injury (SCI) has no cure and individuals with SCI become dependent on others for life. After injury, the signals below the lesion are disrupted, but the brain still produces motor commands. Researchers have bypassed this obstacle, which has given rise to the brain-machine interface (BMI). BMI devices are implanted in the brain or spinal cord, where they decode and send signals beyond the injured segment. Experiments were initially conducted on animals, with favorable results. BMIs are classified according to their type, function, signal generation, and so on. Because of invasiveness, their long-term use is questionable, because of infections and complications. The use of an implantable epidural array in patients with chronic SCI showed that participants were able to walk with the help of a stimulator, and after months of training, they were able to walk with the stimulator turned off. Another innovation is a robotic suit for paraplegics and tetraplegics that supports the movement of limbs. The research on stem cells has not shown favorable results. In future, one of these cutting-edge technologies will prevail over the other, but BMI seems to have the upper hand. The future of BMI with fusion of robotics and artificial intelligence is promising for patients with chronic SCI. These modern devices need to be less invasive, biocompatible, easily programmable, portable, and cost-effective. After these hurdles are overcome, the devices may become the mainstay of potential rehabilitation therapy for partial recovery. The time may come when all patients with severe SCI are told "You will walk again."

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Spinal cord injury disrupts the communication between the brain and the spinal circuits that orchestrate movement. To bypass the lesion, brain–computer interfaces1, 2, 3 have directly linked cortical activity to electrical stimulation of muscles, and have thus restored grasping abilities after hand paralysis1, 4. Theoretically, this strategy could also restore control over leg muscle activity for walking5. However, replicating the complex sequence of individual muscle activation patterns underlying natural and adaptive locomotor movements poses formidable conceptual and technological challenges6, 7. Recently, it was shown in rats that epidural electrical stimulation of the lumbar spinal cord can reproduce the natural activation of synergistic muscle groups producing locomotion8, 9, 10. Here we interface leg motor cortex activity with epidural electrical stimulation protocols to establish a brain–spine interface that alleviated gait deficits after a spinal cord injury in non-human primates. Rhesus monkeys (Macaca mulatta) were implanted with an intracortical microelectrode array in the leg area of the motor cortex and with a spinal cord stimulation system composed of a spatially selective epidural implant and a pulse generator with real-time triggering capabilities. We designed and implemented wireless control systems that linked online neural decoding of extension and flexion motor states with stimulation protocols promoting these movements. These systems allowed the monkeys to behave freely without any restrictions or constraining tethered electronics. After validation of the brain–spine interface in intact (uninjured) monkeys, we performed a unilateral corticospinal tract lesion at the thoracic level. As early as six days post-injury and without prior training of the monkeys, the brain–spine interface restored weight-bearing locomotion of the paralysed leg on a treadmill and overground. The implantable components integrated in the brain–spine interface have all been approved for investigational applications in similar human research, suggesting a practical translational pathway for proof-of-concept studies in people with spinal cord injury.
Article
Restoration of motor function is one of highest priorities in individuals afflicted with spinal cord injury (SCI). The application of brain-machine interfaces (BMIs) to neuroprostheses provides an innovative approach to treat patients with such sensorimotor impairments. A BMI decodes motor intent from cortical signals to control external devices such as a computer cursor or a robotic arm. Recent BMI systems can now use these motor intent signals to directly activate paretic muscles or to modulate the spinal cord in a way that reengage dormant neuromuscular systems below the level of injury. In this perspective, we review the progress made in the development of brain-machine-spinal-cord interfaces (BMSCIs) and highlight their potential for neurorehabilitation after SCI. The advancement and application of these neuroprostheses goes beyond improved motor control. The use of BMSCI may combine repetitive physical training along with intent-driven neuromodulation to promote neurorehabilitation by facilitating activity-dependent plasticity. Strong evidence suggests that proper timing of volitional neuromodulation facilitates long-term potentiation in the neuronal circuits that can promote permanent functional recovery in SCI subjects. However, the effectiveness of these implantable neuroprostheses must take into account the fact that there will be continuous changes in the interface between the signals of intent and the actual trigger to initiate the motor action.
Article
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.
Article
Nonhuman primate and human studies have suggested that populations of neurons in the posterior parietal cortex (PPC) may represent high-level aspects of action planning that can be used to control external devices as part of a brain-machine interface. However, there is no direct neuron-recording evidence that human PPC is involved in action planning, and the suitability of these signals for neuroprosthetic control has not been tested. We recorded neural population activity with arrays of microelectrodes implanted in the PPC of a tetraplegic subject. Motor imagery could be decoded from these neural populations, including imagined goals, trajectories, and types of movement. These findings indicate that the PPC of humans represents high-level, cognitive aspects of action and that the PPC can be a rich source for cognitive control signals for neural prosthetics that assist paralyzed patients. Copyright © 2015, American Association for the Advancement of Science.
Article
Brain-machine interfaces (BMIs) hold promise to treat neurological disabilities by linking intact brain circuitry to assistive devices, such as limb prostheses, wheelchairs, artificial sensors, and computers. BMIs have experienced very rapid development in recent years, facilitated by advances in neural recordings, computer technologies and robots. BMIs are commonly classified into three types: sensory, motor and bidirectional, which subserve motor, sensory and sensorimotor functions, respectively. Additionally, cognitive BMIs have emerged in the domain of higher brain functions. BMIs are also classified as noninvasive or invasive according to the degree of their interference with the biological tissue. Although noninvasive BMIs are safe and easy to implement, their information bandwidth is limited. Invasive BMIs hold promise to improve the bandwidth by utilizing multichannel recordings from ensembles of brain neurons. BMIs have a broad range of clinical goals, as well as the goal to enhance normal brain functions.
Article
Functional restoration of limb movement after traumatic spinal cord injury (SCI) remains the ultimate goal in SCI treatment and directs the focus of current research strategies. To date, most investigations in the treatment of SCI focus on repairing the injury site. Although offering some promise, these efforts have met with significant roadblocks because treatment measures that are successful in animal trials do not yield similar results in human trials. In contrast to biologic therapies, there are now emerging neural interface technologies, such as brain machine interface (BMI) and limb reanimation through electrical stimulators, to create a bypass around the site of the SCI. The BMI systems analyze brain signals to allow control of devices that are used to assist SCI patients. Such devices may include a computer, robotic arm, or exoskeleton. Limb reanimation technologies, which include functional electrical stimulation, epidural stimulation, and intraspinal microstimulation systems, activate neuronal pathways below the level of the SCI. We present a concise review of recent advances in the BMI and limb reanimation technologies that provides the foundation for the development of a bypass system to improve functional outcome after traumatic SCI. We also discuss challenges to the practical implementation of such a bypass system in both these developing fields.
Article
The objective of this work was to quantitatively investigate the mechanisms underlying the performance gains of the recently reported 'recalibrated feedback intention-trained Kalman Filter' (ReFIT-KF). This was accomplished by designing variants of the ReFIT-KF algorithm and evaluating training and online data to understand the neural basis of this improvement. We focused on assessing the contribution of two training set innovations of the ReFIT-KF algorithm: intention estimation and the two-stage training paradigm. Within the two-stage training paradigm, we found that intention estimation independently increased target acquisition rates by 37% and 59%, respectively, across two monkeys implanted with multiunit intracortical arrays. Intention estimation improved performance by enhancing the tuning properties and the mutual information between the kinematic and neural training data. Furthermore, intention estimation led to fewer shifts in channel tuning between the training set and online control, suggesting that less adaptation was required during online control. Retraining the decoder with online BMI training data also reduced shifts in tuning, suggesting a benefit of training a decoder in the same behavioral context; however, retraining also led to slower online decode velocities. Finally, we demonstrated that one- and two-stage training paradigms performed comparably when intention estimation is applied. These findings highlight the utility of intention estimation in reducing the need for adaptive strategies and improving the online performance of BMIs, helping to guide future BMI design decisions.
Article
Brain-machine and brain-computer interface technologies hold great promise for use in the recovery of sensory and motor functions lost as a result of nervous-system injuries or limb amputations. This Perspective describes the current state of noninvasive and invasive technologies with a view to potential applications. The scientific and technological challenges and barriers to translation are critically analyzed for a variety of approaches.
Article
Spinal cord injury (SCI) results in a loss of function and sensation below the level of the lesion. Neuroprosthetic technology has been developed to help restore motor and autonomic functions as well as to provide sensory feedback. This paper provides an overview of neuroprosthetic technology that aims to address the priorities for functional restoration as defined by individuals with SCI. We describe neuroprostheses that are in various stages of preclinical development, clinical testing, and commercialization including functional electrical stimulators, epidural and intraspinal microstimulation, bladder neuroprosthesis, and cortical stimulation for restoring sensation. We also discuss neural recording technologies that may provide command or feedback signals for neuroprosthetic devices. Conclusion/clinical relevance: Neuroprostheses have begun to address the priorities of individuals with SCI, although there remains room for improvement. In addition to continued technological improvements, closing the loop between the technology and the user may help provide intuitive device control with high levels of performance.
Twenty-six subjects were given baseline tests for electroencephalographic (EEG) alpha rhythm presence, and then a period of fifteen minutes to gain insight into mental activity associated with alpha presence and absence, while provided with an auditory feedback loop keyed to the presence of alpha. Sixteen of the subjects worked with eyes closed, and ten, with very high initial alpha baseline scores, worked with eyes open. After the fifteen minute practice period permitting control of alpha through feedback, the subjects were given a trial during which they attempted to produce as much alpha as possible and a trial in which they tried to produce as little as possible. The results indicated significant appropriate change for both the generation and suppression trials. Those who were able to control alpha spontaneously reported mental states reflecting relaxation, “letting go,” and pleasant affect associated with maintaining alpha.
Article
Since the original demonstration that electrical activity generated by ensembles of cortical neurons can be employed directly to control a robotic manipulator, research on brain-machine interfaces (BMIs) has experienced an impressive growth. Today BMIs designed for both experimental and clinical studies can translate raw neuronal signals into motor commands that reproduce arm reaching and hand grasping movements in artificial actuators. Clearly, these developments hold promise for the restoration of limb mobility in paralyzed subjects. However, as we review here, before this goal can be reached several bottlenecks have to be passed. These include designing a fully implantable biocompatible recording device, further developing real-time computational algorithms, introducing a method for providing the brain with sensory feedback from the actuators, and designing and building artificial prostheses that can be controlled directly by brain-derived signals. By reaching these milestones, future BMIs will be able to drive and control revolutionary prostheses that feel and act like the human arm.
Article
Repeated periods of stimulation of the spinal cord and training increased the ability to control movement in animal models of spinal cord injury. We hypothesised that tonic epidural spinal cord stimulation can modulate spinal circuitry in human beings into a physiological state that enables sensory input from standing and stepping movements to serve as a source of neural control to undertake these tasks. A 23-year-old man who had paraplegia from a C7-T1 subluxation as a result of a motor vehicle accident in July 2006, presented with complete loss of clinically detectable voluntary motor function and partial preservation of sensation below the T1 cord segment. After 170 locomotor training sessions over 26 months, a 16-electrode array was surgically placed on the dura (L1-S1 cord segments) in December 2009, to allow for chronic electrical stimulation. Spinal cord stimulation was done during sessions that lasted up to 250 min. We did 29 experiments and tested several stimulation combinations and parameters with the aim of the patient achieving standing and stepping. Epidural stimulation enabled the man to achieve full weight-bearing standing with assistance provided only for balance for 4·25 min. The patient achieved this standing during stimulation using parameters identified as specific for standing while providing bilateral load-bearing proprioceptive input. We also noted locomotor-like patterns when stimulation parameters were optimised for stepping. Additionally, 7 months after implantation, the patient recovered supraspinal control of some leg movements, but only during epidural stimulation. Task-specific training with epidural stimulation might reactivate previously silent spared neural circuits or promote plasticity. These interventions could be a viable clinical approach for functional recovery after severe paralysis. National Institutes of Health and Christopher and Dana Reeve Foundation.
Article
Literature review. To map traumatic spinal cord injury (TSCI) globally and provide a framework for an ongoing repository of data for prevention. An initiative of the ISCoS Prevention Committee. The results obtained from the search of Medline/Embase using search phrases: TSCI incidence, aetiology, prevalence and survival were analysed. Stratification of data into green/yellow/red quality 'zones' allowed comparison between data. Reported global prevalence of TSCI is insufficient (236-1009 per million). Incidence data was comparable only for regions in North America (39 per million), Western Europe (15 per million) and Australia (16 per million). The major cause of TSCI in these regions involves four-wheeled motor vehicles, in contrast to South-east Asia where two-wheeled (and non-standard) road transport predominates. Southern Asia and Oceania have falls from rooftops and trees as the primary cause. High-fall rates are also seen in developed regions with aged populations (Japan/Western Europe). Violence/self-harm (mainly firearm-related) was higher in North America (15%) than either Western Europe (6%) or Australia (2%). Sub-Saharan Africa has the highest reported violence-related TSCI in the world (38%). Rates are also high in north Africa/Middle East (24%) and Latin America (22%). Developed countries have significantly improved TSCI survival compared with developing countries, particularly for tetraplegia. Developing countries have the highest 1-year mortality rates and in some countries in sub-Saharan Africa the occurrence of a spinal injury is likely to be a fatal condition within a year. Missing prevalence and insufficient incidence data is a recurrent feature of this review. The piecemeal approach to epidemiological reporting of TSCI, particularly failing to include sound regional denominators has exhausted its utility. Minimum data collection standards are required.
Article
Stem cell therapy is a potential treatment for spinal cord injury (SCI), and a variety of different stem cell types have been evaluated in animal models and humans with SCI. No consensus exists regarding the type of stem cell, if any, that will prove to be effective therapeutically. Most data suggest that no single therapy will be sufficient to overcome all the biological complications caused by SCI. Rationales for therapeutic use of stem cells for SCI include replacement of damaged neurons and glial cells, secretion of trophic factors, regulation of gliosis and scar formation, prevention of cyst formation, and enhancement of axon elongation. Most therapeutic approaches that use stem cells involve implantation of these cells into the spinal cord. The attendant risks of stem cell therapy for SCI--including tumor formation, or abnormal circuit formation leading to dysfunction--must be weighed against the potential benefits of this approach. This Review will examine the biological effects of SCI, the opportunities for stem cell treatment, and the types of stem cells that might be used therapeutically. The limited information available on the possible benefits of stem cell therapy to humans will also be discussed.
Article
Canonically, 'mirror neurons' are cells in area F5 of the ventral premotor cortex that are active during both observation and execution of goal-directed movements. Recently, cells with similar properties have been observed in a number of other areas in the motor system, including the primary motor cortex. Mirror neurons are a part of a system whose function is thought to involve the prediction and interpretation of the sensory consequences of our own actions as well as the actions of others. Mirror-like responses are relevant to the development of brain-machine interfaces (BMIs) because they provide a robust way to map neural activity to behavior, and because they represent high-level information about goals and intentions that may have utility in future BMI applications.
Article
Single neurons were simultaneously recorded in the forepaw areas of the primary somatosensory (SI) cortex and ventroposterolateral (VPL) thalamus of awake rats during rest and running behaviors. Movement dependent changes in somatic sensory transmission were tested by generating post-stimulus histograms of these neurons' responses to stimulation through electrodes chronically implanted under the skin of the forepaw, while the animal ran on a timed treadmill. As viewed in post-paw-stimulus histograms, the evoked unit responses (EURs) could be differentiated into short (4.5 +/- 0.1-10.9 +/- 0.2 ms) and longer (12.9 +/- 0.4-31.3 +/- 0.9 ms) latency components ("SEURs" and "LEURs", respectively). The magnitudes of firing during these responses were measured and normalized as percent increases over background firing. By comparison with resting behavior, treadmill movement suppressed both SEURs and LEURs in the thalamus, as well as the cortex. The SEURs, however, were much more strongly suppressed in the SI cortex (-48.3 +/- 2.7%) than in the VPL thalamus (-28.1 +/- 6.7%). By contrast, similar magnitudes of suppression of LEURs were found in the SI (-25.8 +/- 8.6%) and VPL (-26.5 +/- 11.1%). These results suggest that the suppression of LEURs observed in the SI cortex may result from modulatory actions on subcortical circuits. Major suppression of SEURs, on the other hand, may occur intracortically, with a minor component occurring subcortically. Thus, VPL thalamus and SI cortex in the rat appear to be differentially subject to movement related modulation of sensory transmission.