Targeted neurotechnology restores walking in humans with spinal cord injury.

Spinal cord injury leads to severe locomotor deficits or even complete leg paralysis. Here we introduce targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation. Using an implanted pulse generator with real-time triggering capabilities, we delivered trains of spatially selective stimulation to the lumbosacral spinal cord with timing that coincided with the intended movement. Within one week, this spatiotemporal stimulation had re-established adaptive control of paralysed muscles during overground walking. Locomotor performance improved during rehabilitation. After a few months, participants regained voluntary control over previously paralysed muscles without stimulation and could walk or cycle in ecological settings during spatiotemporal stimulation. These results establish a technological framework for improving neurological recovery and supporting the activities of daily living after spinal cord injury.

A brain-spine interface alleviating gait deficits after spinal cord injury in primates.

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.

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

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

Neuroprosthetic technologies to augment the impact of neurorehabilitation after spinal cord injury.

Spinal cord injury leads to a range of disabilities, including limitations in locomotor activity, that seriously diminish the patients' autonomy and quality of life. Electrochemical neuromodulation therapies, robot-assisted rehabilitation and willpower-based training paradigms restored supraspinal control of locomotion in rodent models of severe spinal cord injury. This treatment promoted extensive and ubiquitous remodeling of spared circuits and residual neural pathways. In four chronic paraplegic individuals, electrical neuromodulation of the spinal cord resulted in the immediate recovery of voluntary leg movements, suggesting that the therapeutic concepts developed in rodent models may also apply to humans. Here, we briefly review previous work, summarize current developments, and highlight impediments to translate these interventions into medical practice to improve functional recovery of spinal-cord-injured individuals.

A Computational Framework for Electrical Stimulation of Vestibular Nerve.

The vestibular organs are very important to generate reflexes critical for stabilizing gaze and body posture. Vestibular diseases significantly reduce the quality of life of people who are affected by them. Some research groups have recently started developing vestibular neuroprostheses to mitigate these symptoms. However, many scientific and technological issues need to be addressed to optimise their use in clinical trials. We developed a computational model able to mimic the response of human vestibular nerves and which can be exploited for "in-silico" testing of new strategies to design implantable vestibular prostheses. First, a digital model of the vestibular system was reconstructed from anatomical data. Monopolar stimulation was delivered at different positions and distances from ampullary nerves. The electrical potential induced by the injected current was computed through finite-element methods and drove extra-cellular stimulation of fibers in the vestibular, facial, and cochlear nerves. The electrical activity of vestibular nerves and the resulting eye movements elicited by different stimulation protocols were investigated. A set of electrode configurations was analyzed in terms of selectivity at increasing injected current. Electrode position along the nerve plays a major role in producing undesired activity in other nontargeted nerves, whereas distance from the fiber does not significantly affect selectivity. Indications are provided to minimize misalignment in nonoptimal electrode locations. Eye movements elicited by the different stimulation protocols are calculated and compared to experimental values, for the purpose of model validation.

Biomaterials. Electronic dura mater for long-term multimodal neural interfaces.

The mechanical mismatch between soft neural tissues and stiff neural implants hinders the long-term performance of implantable neuroprostheses. Here, we designed and fabricated soft neural implants with the shape and elasticity of dura mater, the protective membrane of the brain and spinal cord. The electronic dura mater, which we call e-dura, embeds interconnects, electrodes, and chemotrodes that sustain millions of mechanical stretch cycles, electrical stimulation pulses, and chemical injections. These integrated modalities enable multiple neuroprosthetic applications. The soft implants extracted cortical states in freely behaving animals for brain-machine interface and delivered electrochemical spinal neuromodulation that restored locomotion after paralyzing spinal cord injury.