Long-Term Training with a Brain-Machine Interface-Based Gait Protocol Induces Partial Neurological Recovery in Paraplegic Patients

Brain-machine interfaces (BMIs) provide a new assistive strategy aimed at restoring mobility in severely paralyzed patients. Yet, no study in animals or in human subjects has indicated that long-term BMI training could induce any type of clinical recovery. Eight chronic (3-13 years) spinal cord injury (SCI) paraplegics were subjected to long-term training (12 months) with a multi-stage BMI-based gait neurorehabilitation paradigm aimed at restoring locomotion. This paradigm combined intense immersive virtual reality training, enriched visual-tactile feedback, and walking with two EEG-controlled robotic actuators, including a custom-designed lower limb exoskeleton capable of delivering tactile feedback to subjects. Following 12 months of training with this paradigm, all eight patients experienced neurological improvements in somatic sensation (pain localization, fine/crude touch, and proprioceptive sensing) in multiple dermatomes. Patients also regained voluntary motor control in key muscles below the SCI level, as measured by EMGs, resulting in marked improvement in their walking index. As a result, 50% of these patients were upgraded to an incomplete paraplegia classification. Neurological recovery was paralleled by the reemergence of lower limb motor imagery at cortical level. We hypothesize that this unprecedented neurological recovery results from both cortical and spinal cord plasticity triggered by long-term BMI usage.

Non-invasive, Brain-controlled Functional Electrical Stimulation for Locomotion Rehabilitation in Individuals with Paraplegia

Mohamed Bouri, Miguel Nicolelis, Solaiman Shokur

Spinal cord injury (SCI) impairs the flow of sensory and motor signals between the brain and the areas of the body located below the lesion level. Here, we describe a neurorehabilitation setup combining several approaches that were shown to have a positive effect in patients with SCI: gait training by means of non-invasive, surface functional electrical stimulation (sFES) of the lower-limbs, proprioceptive and tactile feedback, balance control through overground walking and cue-based decoding of cortical motor commands using a brain-machine interface (BMI). The central component of this new approach was the development of a novel muscle stimulation paradigm for step generation using 16 sFES channels taking all sub-phases of physiological gait into account. We also developed a new BMI protocol to identify left and right leg motor imagery that was used to trigger an sFES-generated step movement. Our system was tested and validated with two patients with chronic paraplegia. These patients were able to walk safely with 65-70% body weight support, accumulating a total of 4,580 steps with this setup. We observed cardiovascular improvements and less dependency on walking assistance, but also partial neurological recovery in both patients, with substantial rates of motor improvement for one of them.

2019

Neurorehabilitation and neuroprosthetic technologies to regain motor function following spinal cord injury

Rubia van den Brand

Spinal cord injury (SCI) leads to a range of disabilities, including locomotor impairments that seriously diminish the patients’ quality of life. Strategies to promote functional recovery after severe SCI will undoubtedly include approaches to regenerate injured pathways. The present work pursues a less ambitious, but potentially more rapidly applicable approach to improve function after SCI by applying neurorehabilitation augmented with neuroprosthetic technologies. In an intact situation, the production of standing and walking results from the integration of information within spinal neuronal networks that receive signals from supraspinal centers and afferent pathways. In the majority of cases, the spinal neuronal networks that coordinate leg movements are located below the injury. Due to the interruption of supraspinal signals, these networks are in a non-functional state. Over the past decades multiple research groups have developed interventions to access dormant spinal networks in order to enable functional states during rehabilitation. The underlying objective is to promote activity-dependent plasticity in the trained sensorimotor pathways. During my thesis, I contributed to the development of neuroprosthetic technologies that provide a powerful means to reanimate non-functional networks. The aim of these paradigms is to mimic the supraspinal signals that are normally delivered to spinal locomotor circuits to generate hindlimb motor function. These technologies include: (i) An electrical spinal neuroprosthesis that replaces the supraspinal excitatory drive to augment the central state of excitability, and thus increase the susceptibility of spinal circuits to respond to afferent input. (ii) A chemical spinal neuroprosthesis mimicking the supraspinal source of monoaminergic neuromodulation that promotes locomotor permissive states of spinal circuits. (iii) A robotic postural neuroprosthesis that provides optimal conditions of posture and balance, which enable sensory feedback to become a source of motor control after severe SCI. Multifactorial statistical analyses revealed that each sub-system of the developed neuroprosthetic technologies mediates distinct influences on the production of gait performance, suggesting targeting of selective spinal circuits. Optimal combinations of neuroprosthetic technologies transformed lumbosacral locomotor circuits from dormant to highly functional states, which enabled paralyzed rats with complete SCI to perform weight-bearing stepping with plantar placement for extended periods of time. After 8-weeks of locomotor training enabled by an electrochemical neuroprosthesis, rats with complete SCI exhibited significantly improved gait performance, which was associated with activity-dependent plasticity in lumbosacral circuits. Trained rats were able to instantaneously adapt hindlimb locomotor patterns to changes in speed, load and direction of stepping in the complete absence of brain input. Under these conditions, ‘the smart spinal brain’ interprets multifaceted afferent information to generate motor outputs that meet both internal and external requirements for maintaining successful locomotor states despite dramatic changes in environmental conditions. Non-ambulatory individuals with severe SCI typically exhibit progressive neuronal dysfunction in the chronic stage of injury. To investigate the underlying mechanisms, we developed a new model of severe SCI that consists of 7 two opposite side, staggered lateral hemisections. This SCI completely interrupts direct supraspinal input to spinal locomotor circuits, but spares a bridge of intact neural tissue through which intraspinal remodeling could occur. This SCI not only led to permanent paralysis but also triggered various functional alterations that resembled the signature characteristics of neuronal dysfunction seen in human individuals. Anatomical analyses revealed that undirected compensatory plasticity of sub-lesional spinal circuits was in part responsible for neuronal dysfunction in the chronic stage of severe SCI. This aberrant sprouting led to a chaotic recruitment of sensorimotor circuits that contributed to the emergence of abnormal reflex properties and deterioration of gait performance. We next investigated whether neurorehabilitation augmented with neuroprosthetic technologies was able to prevent the development of neuronal dysfunction, and instead improve functional recovery, in rats with two opposite side, staggered lateral hemisections. For this aim, we developed a rehabilitation program combining (i) automated treadmill-based training to induce beneficial activity-dependent plasticity of sub-lesional spinal circuits and (ii) overground active training encouraging the rat to engage its paralyzed hindlimbs in order to promote remodeling of descending neuronal pathways. After eight weeks of active training, paralyzed rats recovered the capacity to initiate and sustain full-weight bearing bipedal locomotion overground, and even to climb staircases and avoid obstacles. Combinations of anatomical and complementary experiments demonstrated that training promoted multi-level plasticity of spared neuronal pathways above and across the lesion, which restored supraspinal control of lumbosacral locomotor circuits. Rats that were exclusively trained on the treadmill showed improved stepping capacities, but plasticity was restricted to the trained spinal circuits. They failed to initiate or sustain locomotion overground. These results demonstrate the importance of active training under highly functional states to promote reorganization of spared neuronal systems through activity-dependent mechanisms after a severe SCI. Activity-based approaches have become common medical practices to improve functional recovery following incomplete SCI in humans. However, after more severe SCI these interventions show limited efficacy, possibly due to the non-functional state of the spinal cord during training. A recent case study tested this hypothesis in a paraplegic man who suffered chronic motor paralysis. Epidural electrical spinal cord stimulation was applied during stand training to enable functional states of spinal circuits. After several months of rehabilitation, the chronically paralyzed individual regained supraspinal control over specific leg joint movements in a supine position. However, this capacity was only present when stimulation was applied. These results suggest that the therapeutic paradigms that we developed and demonstrated in rats may also apply to human patients. While challenges lie ahead, neurorehabilitation augmented with neuroprosthetic technologies may progressively become a new treatment option to improve functional recovery of spinal-cord-injured human patients. The present work emphasizes the importance of fostering bridges between neuroscience, technology and medicine to develop neurotechnologies and rehabilitation paradigms that have the potential to translate into clinical practices.

ETH Zurich2014

Neuroprosthetic rehabilitation and translational mechanism after severe spinal cord injury

Lucia Florinda Friedli Wittler

Traumatic SCIs have long-term health, economic and social consequences, stressing the urgency to develop interventions to improve recovery after such injuries. Today, the only proven effective interventions to enhance recovery after SCI are activity-based rehabilitation therapies, such as locomotor training. However, locomotor training shows no or very limited efficacy to improve function after a severe SCI that induces paralysis of the limbs. To mimic the outcome of severe but incomplete SCI in rodents, we developed a model of double opposite-side lateral hemisections termed staggered hemisection in adult rats. This model induced permanent paralysis below the level of injury but leaves an intervening gap of intact neural tissue that provides a substrate for recovery. We showed that this SCI leads to degradation of motor functions, which correlates with the formation of aberrant neuronal connections below the lesion. Robotic devices with a rehabilitative purpose should act as propulsive or postural neuroprosthesis allowing training under natural conditions. Our versatile robotic interface provides multidirectional bodyweight support during overground locomotion in rats. We next evaluated the effects of robot-assisted gait training enabled by electrochemical stimulation of spinal circuits to restore locomotion after staggered hemisection SCI. We found that after two months of daily training, paralyzed rats recovered the ability to initiate, sustain and adjust bipedal locomotion while supported in the robot under electrochemical stimulation. This recovery correlated with ubiquitous reorganization of corticospinal, brainstem, and intraspinal fibers. We next evaluated whether this treatment was capable of restoring supraspinal control of locomotion after a clinically relevant SCI. Rats received a severe contusion of the spinal cord that spared less than 10% of intact tissue. Robot-assisted rehabilitation restored weight-bearing locomotion in all the trained rats when stimulated electrochemicallay and in a subset of rats in the absence of any enabling factors which paralelled with the reorganization of axonal projections of reticulospinal fibers below the contusion. Virus-mediated silencing of reticulospinal neurons projecting to lumbar segments demonstrated that these inputs were necessary to initiate and sustain walking after training. When delaying the onset of training by two months, in the chronic stage, all the rats regained voluntary locomotor movements but the extent of the recovery was reduced compared to rats trained early after SCI. The results provide a strong rationale to evaluate the impact of neuroprosthetic training to improve motor functions in human patients with incomplete SCI. Translation of treatment paradigms developed in rodent models into effective clinical applications remains a major challenge in biomedical research. Here, we studied recovery of motor functions in more than 400 quadriplegic patients who presented various degree of spinal cord damage laterality. We found that recovery increases with the asymmetry of early motor deficits. We conclude that emergence of spinal cord decussating corticospinal fibers and bilateral motor cortex projections during mammalian evolution supports greater recovery after lateralized SCI primates compared to rodents. Novel experimental models and dedicated therapeutic strategies are necessary to take advantage of this powerful neuronal substrate for recovery after SCI.