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
