Patients with spinal cord injury lack the connections between brain and spinal cord circuits that are essential for voluntary movement. Clinical systems that achieve muscle contraction through functional electrical stimulation (FES) have proven to be effective in allowing patients with tetraplegia to regain control of hand movements and to achieve a greater measure of independence in daily activities. In existing clinical systems, the patient uses residual proximal limb movements to trigger pre-programmed stimulation that causes the paralysed muscles to contract, allowing use of one or two basic grasps. Instead, we have developed an FES system in primates that is controlled by recordings made from microelectrodes permanently implanted in the brain. We simulated some of the effects of the paralysis caused by C5 or C6 spinal cord injury by injecting rhesus monkeys with a local anaesthetic to block the median and ulnar nerves at the elbow. Then, using recordings from approximately 100 neurons in the motor cortex, we predicted the intended activity of several of the paralysed muscles, and used these predictions to control the intensity of stimulation of the same muscles. This process essentially bypassed the spinal cord, restoring to the monkeys voluntary control of their paralysed muscles. This achievement is a major advance towards similar restoration of hand function in human patients through brain-controlled FES. We anticipate that in human patients, this neuroprosthesis would allow much more flexible and dexterous use of the hand than is possible with existing FES systems.
- Proceedings of the National Academy of Sciences of the United States of America
- Published over 1 year ago
The self-assembly of α-synuclein is closely associated with Parkinson’s disease and related syndromes. We show that squalamine, a natural product with known anticancer and antiviral activity, dramatically affects α-synuclein aggregation in vitro and in vivo. We elucidate the mechanism of action of squalamine by investigating its interaction with lipid vesicles, which are known to stimulate nucleation, and find that this compound displaces α-synuclein from the surfaces of such vesicles, thereby blocking the first steps in its aggregation process. We also show that squalamine almost completely suppresses the toxicity of α-synuclein oligomers in human neuroblastoma cells by inhibiting their interactions with lipid membranes. We further examine the effects of squalamine in a Caenorhabditis elegans strain overexpressing α-synuclein, observing a dramatic reduction of α-synuclein aggregation and an almost complete elimination of muscle paralysis. These findings suggest that squalamine could be a means of therapeutic intervention in Parkinson’s disease and related conditions.
Millions of people worldwide suffer from diseases that lead to paralysis through disruption of signal pathways between the brain and the muscles. Neuroprosthetic devices are designed to restore lost function and could be used to form an electronic ‘neural bypass’ to circumvent disconnected pathways in the nervous system. It has previously been shown that intracortically recorded signals can be decoded to extract information related to motion, allowing non-human primates and paralysed humans to control computers and robotic arms through imagined movements. In non-human primates, these types of signal have also been used to drive activation of chemically paralysed arm muscles. Here we show that intracortically recorded signals can be linked in real-time to muscle activation to restore movement in a paralysed human. We used a chronically implanted intracortical microelectrode array to record multiunit activity from the motor cortex in a study participant with quadriplegia from cervical spinal cord injury. We applied machine-learning algorithms to decode the neuronal activity and control activation of the participant’s forearm muscles through a custom-built high-resolution neuromuscular electrical stimulation system. The system provided isolated finger movements and the participant achieved continuous cortical control of six different wrist and hand motions. Furthermore, he was able to use the system to complete functional tasks relevant to daily living. Clinical assessment showed that, when using the system, his motor impairment improved from the fifth to the sixth cervical (C5-C6) to the seventh cervical to first thoracic (C7-T1) level unilaterally, conferring on him the critical abilities to grasp, manipulate, and release objects. This is the first demonstration to our knowledge of successful control of muscle activation using intracortically recorded signals in a paralysed human. These results have significant implications in advancing neuroprosthetic technology for people worldwide living with the effects of paralysis.
Spinal cord injury disrupts the communication between the brain and the spinal circuits that orchestrate movement. To bypass the lesion, brain-computer interfaces have directly linked cortical activity to electrical stimulation of muscles, and have thus restored grasping abilities after hand paralysis. Theoretically, this strategy could also restore control over leg muscle activity for walking. However, replicating the complex sequence of individual muscle activation patterns underlying natural and adaptive locomotor movements poses formidable conceptual and technological challenges. 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 locomotion. 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.
The prognosis for recovery of motor function in motor complete spinal cord injured (SCI) individuals is poor. Our research team has demonstrated that lumbosacral spinal cord epidural stimulation (scES) and activity-based training can progressively promote the recovery of volitional leg movements and standing in individuals with chronic clinically complete SCI. However, scES was required to perform these motor tasks. Herein, we show the progressive recovery of voluntary leg movement and standing without scES in an individual with chronic, motor complete SCI throughout 3.7 years of activity-based interventions utilizing scES configurations customized for the different motor tasks that were specifically trained (standing, stepping, volitional leg movement). In particular, this report details the ongoing neural adaptations that allowed a functional progression from no volitional muscle activation to a refined, task-specific activation pattern and movement generation during volitional attempts without scES. Similarly, we observed the re-emergence of muscle activation patterns sufficient for standing with independent knee and hip extension. These findings highlight the recovery potential of the human nervous system after chronic clinically motor complete SCI.
Previously, we reported that one individual who had a motor complete, but sensory incomplete spinal cord injury regained voluntary movement after 7 months of epidural stimulation and stand training. We presumed that the residual sensory pathways were critical in this recovery. However, we now report in three more individuals voluntary movement occurred with epidural stimulation immediately after implant even in two who were diagnosed with a motor and sensory complete lesion. We demonstrate that neuromodulating the spinal circuitry with epidural stimulation, enables completely paralysed individuals to process conceptual, auditory and visual input to regain relatively fine voluntary control of paralysed muscles. We show that neuromodulation of the sub-threshold motor state of excitability of the lumbosacral spinal networks was the key to recovery of intentional movement in four of four individuals diagnosed as having complete paralysis of the legs. We have uncovered a fundamentally new intervention strategy that can dramatically affect recovery of voluntary movement in individuals with complete paralysis even years after injury.
Half of human spinal cord injuries lead to chronic paralysis. Here, we introduce an electrochemical neuroprosthesis and a robotic postural interface designed to encourage supraspinally mediated movements in rats with paralyzing lesions. Despite the interruption of direct supraspinal pathways, the cortex regained the capacity to transform contextual information into task-specific commands to execute refined locomotion. This recovery relied on the extensive remodeling of cortical projections, including the formation of brainstem and intraspinal relays that restored qualitative control over electrochemically enabled lumbosacral circuitries. Automated treadmill-restricted training, which did not engage cortical neurons, failed to promote translesional plasticity and recovery. By encouraging active participation under functional states, our training paradigm triggered a cortex-dependent recovery that may improve function after similar injuries in humans.
Paresis acquired in the intensive care unit (ICU) is common in patients who are critically ill and independently predicts mortality and morbidity. Manual muscle testing (MMT) and handgrip dynamometry assessments have been used to evaluate muscle weakness in patients in a medical ICU, but similar data for patients in a surgical ICU (SICU) are limited.
Paralysis following spinal cord injury, brainstem stroke, amyotrophic lateral sclerosis and other disorders can disconnect the brain from the body, eliminating the ability to perform volitional movements. A neural interface system could restore mobility and independence for people with paralysis by translating neuronal activity directly into control signals for assistive devices. We have previously shown that people with long-standing tetraplegia can use a neural interface system to move and click a computer cursor and to control physical devices. Able-bodied monkeys have used a neural interface system to control a robotic arm, but it is unknown whether people with profound upper extremity paralysis or limb loss could use cortical neuronal ensemble signals to direct useful arm actions. Here we demonstrate the ability of two people with long-standing tetraplegia to use neural interface system-based control of a robotic arm to perform three-dimensional reach and grasp movements. Participants controlled the arm and hand over a broad space without explicit training, using signals decoded from a small, local population of motor cortex (MI) neurons recorded from a 96-channel microelectrode array. One of the study participants, implanted with the sensor 5 years earlier, also used a robotic arm to drink coffee from a bottle. Although robotic reach and grasp actions were not as fast or accurate as those of an able-bodied person, our results demonstrate the feasibility for people with tetraplegia, years after injury to the central nervous system, to recreate useful multidimensional control of complex devices directly from a small sample of neural signals.
Background: Electric stimulation (ES) has been recognized as an effective method to improve motor function to paralysed patients with stroke. It is important for ES to synchronize with voluntary movement. To enhance this co-ordination, the finger-equipped electrode (FEE) was developed. The purpose of this study was to evaluate FEE in improving motor function of upper extremities (UEs) in patients with chronic stroke. Methods and subjects: The study participants included four patients with chronic stroke who received FEE electronic stimulation (FEE-ES) plus passive and active training and three control patients who underwent training without FEE-ES. The patients were treated five times weekly for 4 weeks. UE motor function was evaluated before and after treatment using Fugl-Meyer Assessment (FMA) and Brunnstrom recovery staging. Results: The mean age of patients in each group was 60-years and there was a mean of 49 months since the onset of symptoms. All patients had severe UE weakness. The patients receiving FEE-ES had greater improvement in UE function than control patients (total, proximal and distal FMA, p < 0.05; Brunnstrom staging of UE, p < 0.05). Discussion: The results indicate that FEE-ES may be an effective treatment for patients with chronic stroke.