A new age for rehabilitation.
ABSTRACT In this review we will describe newly developed techniques that are being used to recover levels of motor function after a severe spinal cord injury that have not been observed previously. These new approaches include pharmacological neuromodulation and/or epidural stimulation of the spinal cord circuitries in combination with motor training. By combining the increased levels of excitability of the interneuronal spinal circuitries using these interventions and the ability of the spinal circuitries to interpret and respond appropriately to ongoing complex ensembles of sensory input, the peripheral sensory system can become an effective source for the control of motor function. Similar types of neuromodulation have been shown to enable the brain to regain functional connectivity with the spinal cord circuitries below a clinically complete spinal cord lesion. In fact, some level of voluntary control of movement has been observed in subjects with complete paralysis in the presence of epidural stimulation. The biological mechanisms thought to underlie the recovery of motor function after a severe spinal cord injury are based on decades of research on a wide range of animal models. Fortunately the extensive conservation of neural mechanisms of motor control has provided a window for gaining considerable insight into the mechanisms of recovery of motor function in humans.
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ABSTRACT: Spinal cord injury results from an insult inflicted on the spinal cord that usually encompasses its 4 major functions (motor, sensory, autonomic, and reflex). The type of deficits resulting from spinal cord injury arise from primary insult, but their long-term severity is due to a multitude of pathophysiological processes during the secondary phase of injury. The failure of the mammalian spinal cord to regenerate and repair is often attributed to the very feature that makes the central nervous system special-it becomes so highly specialized to perform higher functions that it cannot effectively reactivate developmental programs to re-build novel circuitry to restore function after injury. Added to this is an extensive gliotic and immune response that is essential for clearance of cellular debris, but also lays down many obstacles that are detrimental to regeneration. Here, we discuss how the mature chromatin state of different central nervous system cells (neural, glial, and immune) may contribute to secondary pathophysiology, and how restoring silenced developmental gene expression by altering histone acetylation could stall secondary damage and contribute to novel approaches to stimulate endogenous repair.Journal of the American Society for Experimental NeuroTherapeutics 10/2013; · 5.38 Impact Factor
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ABSTRACT: Traumatic spinal cord injury (SCI) often leads to debilitating loss of locomotor function. Neuroplasticity of spinal circuitry underlies some functional recovery and therefore represents a therapeutic target to improve locomotor function following SCI. However, the cellular and molecular mechanisms mediating neuroplasticity below the lesion level are not fully understood. The present study performed a gene expression profiling in the rat lumbar spinal cord at 1 and 3 weeks after contusive SCI at T9. Another group of rats received treadmill locomotor training (TMT) until 3 weeks, and gene expression profiles were compared between animals with and without TMT. Microarray analysis showed that many inflammation-related genes were robustly upregulated in the lumbar spinal cord at both 1 and 3 weeks after thoracic injury. Notably, several components involved in an early complement activation pathway were concurrently upregulated. In line with the microarray finding, the number of microglia substantially increased not only in the white matter but also in the gray matter. C3 and complement receptor 3 were intensely expressed in the ventral horn after injury. Furthermore, synaptic puncta near ventral motor neurons were frequently colocalized with microglia after injury, implicating complement activation and microglial cells in synaptic remodeling in the lumbar locomotor circuitry after SCI. Interestingly, TMT did not influence the injury-induced upregulation of inflammation-related genes. Instead, TMT restored pre-injury expression patterns of several genes that were downregulated by injury. Notably, TMT increased the expression of genes involved in neuroplasticity (Arc, Nrcam) and angiogenesis (Adam8, Tie1), suggesting that TMT may improve locomotor function in part by promoting neurovascular remodeling in the lumbar motor circuitry.PLoS ONE 01/2014; 9(2):e88215. · 3.53 Impact Factor
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ABSTRACT: Electrical stimulation of the spinal cord has potential applications following spinal cord injury for reanimating paralysed limbs and promoting neuroplastic changes that may facilitate motor rehabilitation. Here we systematically compare the efficacy, selectivity and frequency-dependence of different stimulation methods in the cervical enlargement of anaesthetized monkeys. Stimulating electrodes were positioned at multiple epidural and subdural sites on both dorsal and ventral surfaces, as well as at different depths within the spinal cord. Motor responses were recorded from arm, forearm and hand muscles. Stimulation efficacy increased from dorsal to ventral stimulation sites, with the exception of ventral epidural electrodes which had the highest recruitment thresholds. Compared to epidural and intraspinal methods, responses to subdural stimulation were more selective but also more similar between adjacent sites. Trains of stimuli delivered to ventral sites elicited consistent responses at all frequencies whereas from dorsal sites we observed a mixture of short-latency facilitation and long-latency suppression. Finally, paired stimuli delivered to dorsal surface and intraspinal sites exhibited symmetric facilitatory interactions at interstimulus intervals between 2–5 ms whereas on the ventral side interactions tended to be suppressive for near-simultaneous stimuli. We interpret these results in the context of differential activation of afferent and efferent roots and intraspinal circuit elements. In particular, we propose that distinct direct and indirect actions of spinal cord stimulation on motoneurons may be advantageous for different applications, and this should be taken into consideration when designing neuroprostheses for upper-limb function.Journal of Neural Engineering 02/2014; 11(1):016005. · 3.28 Impact Factor