Abstract:We introduce a new class of neural implants with the topology and compliance of dura mater, the protective membrane of the brain and spinal cord. These neural interfaces, which we called e-dura, achieve chronic bio-integration within the subdural space where they conform to the statics and dynamics of neural tissue. 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. e-dura extracted cortical states in freely behaving animals for brain machine interface, and delivered electrochemical spinal neuromodulation that restored locomotion after paralyzing spinal cord injury. e-dura offers a novel platform for chronic multimodal neural interfaces in basic research and neuroprosthetics.3 Neuroprosthetic medicine is improving the lives of countless individuals. Cochlear implants restore hearing in deaf children, deep brain stimulation alleviates Parkinsonian symptoms, and spinal cord neuromodulation attenuates chronic neuropathic pain (1). These interventions rely on implants developed in the 1980s (2, 3). Since then, advances in electroceutical, pharmaceutical, and more recently optogenetic treatments triggered development of myriad neural interfaces that combine multiple modalities (4-9). However, the conversion of these sophisticated technologies into chronic implants mediating long-lasting functional benefits has yet to be achieved. A recurring challenge restricting chronic bio-integration is the substantial biomechanical mismatch between implants and neural tissues (10-13). Here, we introduce a new class of soft multimodal neural interfaces that achieve chronic bio-integration, and we demonstrate their long-term efficacy in clinically relevant applications. e-dura fabrication. We designed and engineered soft interfaces that mimic the topology and mechanical behavior of the dura mater (Fig. 1A-B). The implant, which we called electronic dura mater or e-dura, integrates a transparent silicone substrate (120µm in thickness), stretchable gold interconnects (35nm in thickness), soft electrodes coated with a novel platinum-silicone composite (300µm in diameter), and a compliant fluidic microchannel (100µm x 50µm in crosssection) (Fig. 1C-D, fig. S1-S2-S3). The interconnects and electrodes transmit electrical excitation and transfer electrophysiological signals.The microfluidic channel, termed chemotrode (14), delivers drugs locally (Fig. 1C, fig. S3). Microcracks in the gold interconnects (15) and the newly developed soft platinum-silicone composite electrodes confer exceptional stretchability to the entire implant (Fig. 1B, Movie S1). The patterning techniques of metallization and microfluidics support rapid manufacturing of customized neuroprostheses.4 e-dura implantation. Most implants used experimentally or clinically to assess and treat neurological disorders are placed above the dura mater (3,(16)(17)(18). The compliance of e-...

After complete spinal cord transections that removed all supraspinal inputs in adult rats, combinations of serotonergic agonists and epidural electrical stimulation were able to acutely transform spinal networks from nonfunctional to highly functional and adaptive states as early as 1 week after injury. Using kinematics, physiological and anatomical analyses, we found that these interventions could recruit specific populations of spinal circuits, refine their control via sensory input and functionally remodel these locomotor pathways when combined with training. The emergence of these new functional states enabled full weight-bearing treadmill locomotion in paralyzed rats that was almost indistinguishable from voluntary stepping. We propose that, in the absence of supraspinal input, spinal locomotion can emerge from a combination of central pattern-generating capability and the ability of these spinal circuits to use sensory afferent input to control stepping. These findings provide a strategy by which individuals with spinal cord injuries could regain substantial levels of motor control.Severe spinal cord injuries that remove all supraspinal input to lumbosacral spinal circuits lead to permanent paralysis of the legs in adult rodents 1-3 and humans. Nevertheless, networks of neurons in the lumbosacral spinal cord retain an intrinsic capability to oscillate and generate coordinated rhythmic motor outputs. Circuits underlying such rhythmic and oscillatory outputs are commonly referred to as central pattern generators (CPGs) and are found in all invertebrate and vertebrate animals 4,5 . Although the anatomical architecture of locomotor CPGs remains poorly understood, especially in mammals 5 , the functional phenomenon, central pattern generation, has been documented extensively. Indirect evidence suggests that CPGs are present in human spinal cord 6,7 . These observations offer the possibility of directly accessing and activating spinal cord CPGs to facilitate locomotor recovery after a severe spinal cord injury (SCI).Correspondence should be addressed to G.C. (gregoire.courtine@bli.uzh.ch). Note: Supplementary information is available on the Nature Neuroscience website.Author Contributions: G.C., Y.P.G., I.L., M.V.S. and V.R.E. designed the study. G.C., R.R.R., H.Z. and P.M. performed the surgeries. G.C., Y.P.G., R.v.d.B., P.M. and A.Y. carried out the experiments. G.C., A.Y., B.S., Y.A., R.I. and M.V.S. conducted the anatomical assessments. G.C. analyzed the data. G.C., R.R.R., M.V.S. and V.R.E. wrote the manuscript. G.C. supervised the study. 16,20,21 that lead to specific improvements of stepping patterns. These interventions, however, have shown limited potential for promoting weight-bearing capacities and there have been few attempts to correlate the specific functional states induced pharmacologically 9,10 , electrically [11][12][13]19,22 or by locomotor training 2,20 with distinct characteristics of stepping motor patterns. When studied in sufficient statistical detail, analyses of kinematics and...

Regaining Limb Movement Despite many years of intensive research, there is still an urgent need for novel treatments to help patients restore motor function after spinal cord injuries. van den Brand et al. (p. 1182 ) produced left and right hemisections at different levels of the rat thoracic spinal cord to cause complete hind limb paralysis mimicking the situation in humans with spinal cord injury. Systemic application of pharmacological agents, combined with a multisystem rehabilitation program including a robotic postural neuroprosthesis, restored voluntary movements of both hind limbs.

Epidural electrical stimulation (EES) of lumbosacral segments can restore a range of movements after spinal cord injury. However, the mechanisms and neural structures through which EES facilitates movement execution remain unclear. Here, we designed a computational model and performed in vivo experiments to investigate the type of fibers, neurons, and circuits recruited in response to EES. We first developed a realistic finite element computer model of rat lumbosacral segments to identify the currents generated by EES. To evaluate the impact of these currents on sensorimotor circuits, we coupled this model with an anatomically realistic axon-cable model of motoneurons, interneurons, and myelinated afferent fibers for antagonistic ankle muscles. Comparisons between computer simulations and experiments revealed the ability of the model to predict EES-evoked motor responses over multiple intensities and locations. Analysis of the recruited neural structures revealed the lack of direct influence of EES on motoneurons and interneurons. Simulations and pharmacological experiments demonstrated that EES engages spinal circuits trans-synaptically through the recruitment of myelinated afferent fibers. The model also predicted the capacity of spatially distinct EES to modulate side-specific limb movements and, to a lesser extent, extension versus flexion. These predictions were confirmed during standing and walking enabled by EES in spinal rats. These combined results provide a mechanistic framework for the design of spinal neuroprosthetic systems to improve standing and walking after neurological disorders.

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 this therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here, we developed novel 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 versus flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight–bearing capacities, endurance and skilled locomotion in multiple rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans.

Neuromodulation of spinal sensorimotor circuits improves motor control in animal models and humans with spinal cord injury. With common neuromodulation devices, electrical stimulation parameters are tuned manually and remain constant during movement. We developed a mechanistic framework to optimize neuromodulation in real time to achieve high-fidelity control of leg kinematics during locomotion in rats. We first uncovered relationships between neuromodulation parameters and recruitment of distinct sensorimotor circuits, resulting in predictive adjustments of leg kinematics. Second, we established a technological platform with embedded control policies that integrated robust movement feedback and feed-forward control loops in real time. These developments allowed us to conceive a neuroprosthetic system that controlled a broad range of foot trajectories during continuous locomotion in paralyzed rats. Animals with complete spinal cord injury performed more than 1000 successive steps without failure, and were able to climb staircases of various heights and lengths with precision and fluidity. Beyond therapeutic potential, these findings provide a conceptual and technical framework to personalize neuromodulation treatments for other neurological disorders.

Experimental and clinical studies suggest that primate species exhibit greater recovery after lateralized compared to symmetrical spinal cord injuries. Although this observation has major implications for designing clinical trials and translational therapies, advantages in recovery of nonhuman primates over other species has not been shown statistically to date, nor have the associated repair mechanisms been identified. We monitored recovery in more than 400 quadriplegic patients and found that that functional gains increased with the laterality of spinal cord damage. Electrophysiological analyses suggested that corticospinal tract reorganization contributes to the greater recovery after lateralized compared with symmetrical injuries. To investigate underlying mechanisms, we modeled lateralized injuries in rats and monkeys using a lateral hemisection, and compared anatomical and functional outcomes with patients who suffered similar lesions. Standardized assessments revealed that monkeys and humans showed greater recovery of locomotion and hand function than rats. Recovery correlated with the formation of corticospinal detour circuits below the injury, which were extensive in monkeys, but nearly absent in rats. Our results uncover pronounced inter-species differences in the nature and extent of spinal cord repair mechanisms, likely resulting from fundamental differences in the anatomical and functional characteristics of the motor systems in primates versus rodents. Although rodents remain essential for advancing regenerative therapies, the unique response of the primate corticospinal tract after injury re-emphasizes the importance of primate models for designing clinically relevant treatments.

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