Cortical reorganization in training.

Plasticity within the human central motor system occurs and has been studied with transcranial magnetic stimulation in patients with amputations, spinal cord injuries, and ischemic nerve block. These studies have identified a pattern of motor system reorganization that results in enlarged muscle representation areas and large motor evoked potentials (MEPs) for muscles immediately proximal to the lesion. Some of these changes are apparent minutes after ischemic nerve block, weeks after spinal cord injury, and as early as six months after amputation.These studies motivated us to study the cortical motor reorganization after finger movement training in normals and after anastomosis of intercostal nerves to the musculocutaneous nerve in young patients with cervical root avulsions due to a traumatic motorcycle injury.     

犬脊髓损伤治疗动物模型

目的　建立犬脊髓损伤治疗动物模型 ,为实验研究提供直接的病例材料。方法　人工损伤犬脊髓 ,使用直流电场刺激使脊髓损伤恢复。结果　人工犬脊髓损伤模型建立 ,直流电场刺激治疗可恢复神经功能。结论直流电场刺激在不同时期对犬脊髓再生及功能恢复均有明显促进作用 ,能促进脊髓再生 ,使脊髓通路更快更完善的建立     

Tracking extranigral degeneration in animal models of Parkinson's disease: quest for effective therapeutic strategies

Sporadic Parkinson's disease (PD) is now interpreted as a complex nervous system disorder in which the projection neurons are predominantly damaged. Such an interpretation is based on mapping of Lewy body and Lewy neurite pathology. Symptoms of the human disease are much widespread, which span from pre-clinical non-motor symptoms and clinical motor symptoms to cognitive discrepancies often seen in advanced stages. Existing symptomatic treatments further complicate with overt drug-irresponsive symptoms. PD is better understood by assimilation of extranigral degenerative pathways with nigrostriatal degenerative mechanisms. The term 'extranigral' appeared first in the 1990s to more rigorously define the nigral pathology by process of elimination. However, as clinicians progressively identified PD symptoms unresponsive to the gold standard drug l-DOPA, definitions of PD symptoms were redefined. Non-motor symptoms prodromal to motor symptoms just as pre-clinical to clinical, and conjointly emerged the concept of nigral versus extranigral degeneration in PD. While nigrostriatal degeneration is responsible for the neurobiological substrates of extrapyramydal motor features, extranigral degeneration corroborates a vast majority of other changes in discrete central, peripheral, and enteric nervous system nuclei, which together account for global symptoms of the human disease. As an extranigral site, spinal cord degeneration has also been implicated in PD progression. Interconnected to the upper CNS structures with descending and ascending pathways, spinal neurons participate in movement and sensory circuits, controlling movement and reflexes. Several clinical and in vivo studies have demonstrated signs of parkinsonism-related degenerative processes in spinal cord, which led to recent consideration of spinal cord as an area of potential therapeutic target. In a nutshell, this review explores how the existing animal models can actually reflect the human disease in order to facilitate PD research. Evolution of extranigral degeneration studies has been succinctly revisited, followed by a survey on animal models in light of recent findings in clinical PD. Together, it may help to develop effective therapeutic strategies for PD.     

Infantile spinale Muskelatrophie: mehr als eine Motoneuronerkrankung?

Infantile spinal muscular atrophy (SMA) is characterized by loss of motor neurons in the ventral horn of the spinal cord leading to weakness and muscle atrophy and occurs as a result of homozygous deletions or mutations in the survival motor neuron (SMN 1) gene. Loss of SMN 1 leads to a dramatic reduction in survival motor neuron (SMN) protein in the motor neurons of the spinal cord and of the brain stem. The SMA disease severity ranges from extremely severe to a relatively mild adult onset form of proximal muscle atrophy. More recently, clinical case reports in patients and studies in animal models provided evidence that severe SMN protein deficiency not only results in loss of motor neurons but also to additional organ manifestations. These include the peripheral, central and autonomic nervous system, development and function of the heart and the digestive tract and metabolic deficiencies. Therefore, to develop the most efficient therapeutic approach and also prevent further complications in patients that may arise with extended survival following therapeutic interventions, it is necessary to investigate in detail the specific damage to every system independently. The comparison of the defects in SMA mouse models will provide valuable insights; however, phenotypic differences between mice and men still remain.     

Sensorimotor regulation of movements: Novel strategies for the recovery of mobility

A series of observations have provided important insight into properties of the spinal as well as supraspinal circuitries that control posture and movement. We have demonstrated that spinal rats can regain full weight-bearing standing and stepping over a range of speeds and directions with the aid of electrically enabling motor control (eEmc), pharmacological modulation (fEmc), and training [1, 2]. Also, we have reported that voluntary control movements of individual joints and limbs can be regained after complete paralysis in humans [3, 4]. However, the ability to generate significant levels of voluntary weight-bearing stepping with or without epidural spinal cord stimulation remains limited. Herein we introduce a novel method of painless transcutaneous electrical enabling motor control (pcEmc) and sensory enabling motor control (sEmc) strategy to neuromodulate the physiological state of the spinal cord. We have found that a combination of a novel non-invasive transcutaneous spinal cord stimulation and sensory-motor stimulation of leg mechanoreceptors can modulate the spinal locomotor circuitry to state that enables voluntary rhythmic locomotor movements.     

Cholinergic receptor alterations in the cerebral cortex of spinal cord injured rat

Many areas of the cerebral cortex process sensory information or coordinate motor output necessary for control of movement. Disturbances in cortical cholinergic system can affect locomotor coordination. Spinal cord injury causes severe motor impairment and disturbances in cholinergic signalling can aggravate the situation. Considering the impact of cortical cholinergic firing in locomotion, we focussed the study in understanding the cholinergic alterations in cerebral cortex during spinal cord injury. The gene expression of key enzymes in cholinergic pathway - acetylcholine esterase and choline acetyl transferase showed significant upregulation in the cerebral cortex of spinal cord injured group compared to control with the fold increase in expression of acetylcholine esterase prominently higher than cholineacetyl transferase. The decreased muscarinic receptor density and reduced immunostaining of muscarinic receptor subtypes along with down regulated gene expression of muscarinic M1 and M3 receptor subtypes accounts for dysfunction of metabotropic acetylcholine receptors in spinal cord injury group. Ionotropic acetylcholine receptor alterations were evident from the decreased gene expression of alpha 7 nicotinic receptors and reduced immunostaining of alpha 7 nicotinic receptors in confocal imaging. Our data pin points the disturbances in cortical cholinergic function due to spinal cord injury; which can augment the locomotor deficits. This can be taken into account while devising a proper therapeutic approach to manage spinal cord injury.     

Effects of sustained stimulation on the excitability of motoneurons innervating paralyzed and control muscles.

The excitability of thenar motoneurons (reflected by F-wave persistence and amplitude) and thenar muscle force were measured during a stimulation protocol (90 s of 18-Hz supramaximal electrical stimulation of the median nerve) designed to induce muscle fatigue (force decline). Data from muscles (n = 15) paralyzed by chronic cervical spinal cord injury were compared with those obtained from control muscles (n = 6). The persistence of F waves in both paralyzed and control muscles increased from approximately 60 to approximately 76% during the first 10 s of the fatigue protocol. Persistence then declined progressively to approximately 33% at 90 s. These changes in F-wave persistence suggest that similar reductions occur in the excitability of the motoneurons to paralyzed and control motor units after sustained antidromic activation. Despite this, significantly larger force declines occurred in the paralyzed muscles of spinal cord-injured subjects (approximately 60%) than in the muscles of control subjects (approximately 15%). These data suggest that the decreases in motoneuron excitability for both the spinal cord-injured and control subjects are a result of activity-dependent changes in motoneuron properties that are independent of fatigue-related processes in the muscles.     

Treatments for spinal cord injury: is there hope in neurosteroids?

In this review, we describe the current therapeutic strategies to find a cure for paralysis. We use the example of DHEA, a neurosteroid normally produced in the developing neural tube, to raise the hypothesis that such a class of molecules, capable of modulating proliferation of committed neural precursors, could serve as an environmental cue in the adult injured spinal cord to promote re-population of CNS lesion with endogenous dormant precursor cells. Such mechanism may be a part of the natural response to heal the injured CNS and promote recovery of function, suggesting that neurosteroid-treatment could be a promising and novel therapeutic avenue for SCI. We will review pertinent biological activities of DHEA supporting this hypothesis, demonstrate that such activities, dependent on an intact sonic-hedgehog pathway, are responsible for the motor and bladder functional recovery observed after DHEA-treatment in the adult injured spinal cord. We will also raise the current limitations to further development of DHEA- or other neurosteroid-treatments as drug candidates, including the urgent need to further document DHEA long-term safety in CNS indications.     

Optimal stimulation of paralyzed muscle after human spinal cord injury.

Muscle properties change profoundly as a result of disuse after spinal cord injury. To study the extent to which these changes can be reversed by electrical stimulation, tibialis anterior muscles in complete spinal cord-injured subjects were stimulated for progressively longer times (15 min, 45 min, 2 h, and 8 h/day) in 6-wk intervals. An index of muscle endurance to repetitive stimulation doubled (from 0.4 to 0.8), contraction and half-relaxation times increased markedly (from 70 to approximately 100 ms), but little or no change was measured in twitch or tetanic tension with increasing amounts of stimulation. The changes observed with 2 h/day of stimulation brought the physiological values close to those for normal (control) subjects. A decrease in the stimulation period produced a reversal of the changes. No effects were observed in the contralateral (unstimulated) muscle at any time, nor was there evidence of decreased numbers of motor units in these subjects secondary to spinal cord injury. Motor unit properties changed in parallel with those of the whole muscle. The occasional spasms occurring in these subjects are not sufficient to maintain normal muscle properties, but these properties can largely be restored by 1-2 h/day of electrical stimulation.     

Animal models of spinal cord contusion injuries.

BACKGROUND AND PURPOSE: Traumatic spinal cord injury causes initial mechanical disruption of tissue, leading to a complex secondary sequence of pathophysiologic changes and neurologic impairment. These sequelae depend on the impact force delivered to the spinal cord at the time of injury. Successful clinical evaluation of the efficacy of any therapeutic regimen depends on the reliability and reproducibility of an experimental animal model. We describe a trauma device and the biomechanical parameters required to induce severe or moderate spinal cord contusion injury in cats and rats. METHODS: Recovery after injury was determined by behavioral, electrophysiologic, and histologic evaluations. RESULTS: Behavioral and electrophysiologic tests after injury clearly identified the experimental groups. A stable severe paraplegic state (defined as 6 months for cats and 8 weeks for rats), without evidence of behavioral or electrophysiologic recovery, was induced by a 65-Newton (N) load for cats and a 35-N load for rats. Moderate spinal cord contusion injury, from which cats and rats partially recovered after approximately 3 months and 4 weeks, respectively, was induced by a 45- and 25-N load, respectively. CONCLUSION: Use of these injury conditions provides reliable animal models for studies designed to evaluate potential therapeutic regimens for spinal cord injury.     

Effects of vibrotactile stimulation on the control of muscle tone and movement facilitation in children with cerebral injury

Afferent signals from the muscle's proprioceptors play important role in the control of muscle tone and in the facilitation of movements. Peripheral afferent pathway enables the restoration of connections with supraspinal structures and so includes mechanism of synaptic inhibition in the performance of normal movement. Different sensory stimuli, as vibrotactile stimulation, excite muscle's proprioceptors which then send sensorimotor information via spinal cord. In this way afferent signals promote cortical control and modulation of movements. The goal of this study is to evaluate the effects of vibrotactile stimulation on the spasticity and motor performance in children with cerebral injury. Subjects included in this study were 13 children who were developing the classification of spastic cerebral palsy. For all children perinatal brain damage was documented by medical reports and neonatal brain ultrasound scan. At the mean age of 3 years and 6 months subject underwent the assessment of motor development by Gross Motor Function Measurement (GMFM-88). Gross Motor Classification System (GMFCS) has been used to classify functions of lower extremities. Therapeutic intervention was conducted once a week during 3 months. All subjects were stimulated with vibrotactile stimuli of 40Hz in duration of 20 minutes in order to reduce spasticity. After the ending of the treatment subjects underwent second assessment of motor performance and the classification of lower extremities functions. The results have shown that there was a significant improvement in motor performance, what has been seen in the facilitation of rotations, better postural trunk stability and head control and in greater selectivity of movements. Further randomized, control trial investigations with bigger sample and included spasm scale are needed to gain better insight in the role of vibrotactile stimulation in the facilitation of normal movements.     

Clonus is explained from increased reflex gain and enlarged tissue viscoelasticity

Upper motor neuron diseases (UMND), such as stroke and spinal cord injury (SCI), are assumed to produce alterations in muscle tissue in association with neural damage. Distinguishing between these two factors is of clinical importance in choosing appropriate therapy. We studied the effect of changes in the gain of the Ia reflex pathway and tissue viscoelasticity on the emergence, frequency, and persistence of ankle clonus: a clinically significant, involuntary oscillatory movement disorder. Monte Carlo simulations were performed to explain our experimental observations in patients with stroke (n = 3) and SCI (n = 4) using a nonlinear antagonistic muscle model of the human ankle joint. Ia reflex gain was varied by changing motor unit pool threshold and gain, and passive tissue viscosity and elasticity were varied by changing optimal muscle length. Tissue viscoelasticity appeared to have a strong effect on the emergence and persistence of clonus. Observed frequencies of ankle movement, prior to and after the experimental intervention of a sudden damper, was predicted by the model. The simulations revealed that reflex gains were largest in patients with the largest tissue viscoelasticity. We conclude that ankle clonus in stroke and SCI is the result of a combination of, and suggests a relation between, (i) a decrease in threshold and an increase in gain of the motor unit pool and (ii) a decrease in optimal muscle length.     

The effects of long-standing limb loss on anatomical reorganization of the somatosensory afferents in the brainstem and spinal cord

We examined the terminations of sensory afferents in the brainstem and spinal cord of squirrel monkeys and prosimian galagos 4-8 years after a therapeutic forelimb or hindlimb amputation within 2 months of birth. In each animal, the distributions of labeled sensory afferent terminations from remaining body parts proximal to the limb stump were much more extensive than in normal animals. These sprouted afferents extended into the portions of the dorsal horn of the spinal cord as well as the cuneate and external cuneate nuclei of the brainstem (forelimb amputees) or spinal Clarke's column (hindlimb amputee) related to the amputated limb. Such reorganization in sensory afferents along with reorganization of the motor efferents to muscles (Wu and Kaas, J Neurosci 19: 7679-7697, 1999, Neuron 28: 967-978, 2000) may provide a basis for mislocated phantom sensations of missing forelimb movements accompanying actual shoulder movements during cortical stimulation or movement imagery in patients with amputations.     

The effects of long-standing limb loss on anatomical reorganization of the somatosensory afferents in the brainstem and spinal cord

We examined the terminations of sensory afferents in the brainstem and spinal cord of squirrel monkeys and prosimian galagos 4-8 years after a therapeutic forelimb or hindlimb amputation within 2 months of birth. In each animal, the distributions of labeled sensory afferent terminations from remaining body parts proximal to the limb stump were much more extensive than in normal animals. These sprouted afferents extended into the portions of the dorsal horn of the spinal cord as well as the cuneate and external cuneate nuclei of the brainstem (forelimb amputees) or spinal Clarke's column (hindlimb amputee) related to the amputated limb. Such reorganization in sensory afferents along with reorganization of the motor efferents to muscles (Wu and Kaas, J Neurosci 19 : 7679-7697, 1999, Neuron 28 : 967-978, 2000) may provide a basis for mislocated phantom sensations of missing forelimb movements accompanying actual shoulder movements during cortical stimulation or movement imagery in patients with amputations.     

Cadence control system for paediatric functional electrical stimulation cycling

Functional electrical stimulation can be used to enable spinal cord injured children to participate in cycling training as part of a fitness programme or exercise testing procedure. Exercise can reduce the impact of secondary health conditions due to the injury. Functional electrical stimulation has shown promising results in adults with a spinal cord injury, but additional considerations are needed to realise the method for the child with spinal cord injury, partly owing to their limited force producing capacity. An electric motor provides a practical means of performing cycling at controlled cadences, exercising for longer durations and can also be used for recreational outdoor cycling. Here, a novel real-time control technique is developed for cadence regulation during cycling. A feedback control structure is developed based on an empirical model derived from separate identification tests and pole placement and then verified in a series of reference-tracking tests. The system produced cadence responses in close agreement with reference values in all cases and demonstrated satisfactory robustness of stability characteristics. This approach moves towards the practical application of the technology as a training tool for paediatric spinal cord injured subjects.     

In memoriam: Dr. Gary A. Dudley (1952-2006) a modern pioneer in the study of muscle and resistance training

Dr. Gary Alton Dudley was a modern pioneer in the study of muscle. His work encompassed almost 30 years of study with dramatic discoveries in the areas of muscle physiology, resistance training, and spinal cord injury and therapy. The greater understanding of muscle fiber changes with training, as well as novel experiments using magnetic resonance imaging and single fiber analyses, allowed for many discoveries in the areas of resistance training and detraining, the roles of electrical stimulation in training muscle, the compatibility of different exercise modes, and the characteristics of and treatment interventions for spinal cord injury. His work and insights will provide future investigators a knowledge base from which to work for both basic and applied research in muscle and exercise physiology.     

Neuroprosthetics of the upper extremity--clinical application in spinal cord injury and future perspectives.

Within the last couple of years, partial restoration of lost motor functions in a larger number of spinal cord injured patients has become possible by the introduction of neuroprostheses into the clinical environment. The Freehand system in particular is the first implantable neuroprosthesis from which a certain group of tetraplegic patients with stable shoulder function, but missing or weak grasp and hold function of the hand do benefit. The system is based on the combination of electrical stimulation and operative tendon transfers and thus represents a multicomponent concept for long-term restoration of the grasp function. The crucial prerequisites for successful use of an implantable neuroprosthesis are the right indication, careful preoperative muscle stimulation, differentiated planning of the surgery and functional training adopted to the individual residual functions. After successful completion of an extensive rehabilitation program, patients are able to use the system for activities of daily living without the need for special additional aids, which enhances their quality of life and independency. In order to extend the group of potential users of neuroprostheses in the future, new technological developments will have to take into account that nowadays the majority of spinal cord injured patients suffer from an incomplete lesion of the spinal cord. For these particular patients who still possess residual functions, modular, "naturally" controllable systems for supporting these functions are needed rather than complex systems to substitute them.     

Safety and possible outcome assessment of autologous Schwann cell and bone marrow mesenchymal stromal cell co-transplantation for treatment of patients with chronic spinal cord injury

Background aimsCell replacement therapy has become a promising issue that has raised much hope in the regeneration of central nervous system injury. Evidence indicates that successful functional recovery in patients with spinal cord injury will not simply emphasize a single therapeutic strategy. Therefore, many recent studies have used combination strategies for spinal cord regeneration.MethodsWe assessed the safety and feasibility of a bone marrow mesenchymal stromal cell and Schwann cell combination for the treatment of patients with chronic spinal cord injury. Eight subjects who received a complete traumatic spinal cord injury (American Spinal Injury Association [ASIA] classification A) enrolled in this study. The patients received this autologous combination of cells directly into the injury site. The mean duration of follow-up was approximately 24 months.ResultsNo magnetic resonance imaging evidence of neoplastic tissue overgrowth, syringomyelia or psuedomeningocele in any of the patients was seen during the study. There was no deterioration in sensory or motor function in any of the patients during the course of the study. Three patients had negligible improvement in ASIA sensory scale. No motor score improvement and no change in ASIA classification was seen. The patients had widely subjective changes in the course of the study such as urination and defecation sensation and more stability and trunk equilibrium in the sitting position.ConclusionsThere were no adverse findings at least 2 years after autologous transplantation of Schwann cell and mesenchymal stromal cell combination into the injured spinal cord. It appears that the use of this combination of cells is safe for clinical application to spinal cord regeneration.     

Glial tumor necrosis factor alpha (TNFα) generates metaplastic inhibition of spinal learning

Injury-induced overexpression of tumor necrosis factor alpha (TNFα) in the spinal cord can induce chronic neuroinflammation and excitotoxicity that ultimately undermines functional recovery. Here we investigate how TNFα might also act to upset spinal function by modulating spinal plasticity. Using a model of instrumental learning in the injured spinal cord, we have previously shown that peripheral intermittent stimulation can produce a plastic change in spinal plasticity (metaplasticity), resulting in the prolonged inhibition of spinal learning. We hypothesized that spinal metaplasticity may be mediated by TNFα. We found that intermittent stimulation increased protein levels in the spinal cord. Using intrathecal pharmacological manipulations, we showed TNFα to be both necessary and sufficient for the long-term inhibition of a spinal instrumental learning task. These effects were found to be dependent on glial production of TNFα and involved downstream alterations in calcium-permeable AMPA receptors. These findings suggest a crucial role for glial TNFα in undermining spinal learning, and demonstrate the therapeutic potential of inhibiting TNFα activity to rescue and restore adaptive spinal plasticity to the injured spinal cord. TNFα modulation represents a novel therapeutic target for improving rehabilitation after spinal cord injury.