Zinc deficiency impairs axonal regeneration and functional recovery after spinal cord injury by modulating macrophage polarization via NF-κB pathway.

Background: Spinal cord injury (SCI) is a devastating disease that results in permanent paralysis. Currently, there is no effective treatment for SCI, and it is important to identify factors that can provide therapeutic intervention during the course of the disease. Zinc, an essential trace element, has attracted attention as a regulator of inflammatory responses. In this study, we investigated the effect of zinc status on the SCI pathology and whether or not zinc could be a potential therapeutic target. Methods: We created experimental mouse models with three different serum zinc concentration by changing the zinc content of the diet. After inducing contusion injury to the spinal cord of three mouse models, we assessed inflammation, apoptosis, demyelination, axonal regeneration, and the number of nuclear translocations of NF-κB in macrophages by using qPCR and immunostaining. In addition, macrophages in the injured spinal cord of these mouse models were isolated by flow cytometry, and their intracellular zinc concentration level and gene expression were examined. Functional recovery was assessed using the open field motor score, a foot print analysis, and a grid walk test. Statistical analysis was performed using Wilcoxon rank-sum test and ANOVA with the Tukey-Kramer test. Results: In macrophages after SCI, zinc deficiency promoted nuclear translocation of NF-κB, polarization to pro-inflammatory like phenotype and expression of pro-inflammatory cytokines. The inflammatory response exacerbated by zinc deficiency led to worsening motor function by inducing more apoptosis of oligodendrocytes and demyelination and inhibiting axonal regeneration in the lesion site compared to the normal zinc condition. Furthermore, zinc supplementation after SCI attenuated these zinc-deficiency-induced series of responses and improved motor function. Conclusion: We demonstrated that zinc affected axonal regeneration and motor functional recovery after SCI by negatively regulating NF-κB activity and the subsequent inflammatory response in macrophages. Our findings suggest that zinc supplementation after SCI may be a novel therapeutic strategy for SCI.

Engaging Spinal Networks to Mitigate Supraspinal Dysfunction After CP.

Although children with cerebral palsy seem to have the neural networks necessary to generate most movements, they are markedly dysfunctional, largely attributable to abnormal patterns of muscle activation, often characterized as spasticity, largely reflecting a functionally abnormal spinal-supraspinal connectivity. While it is generally assumed that the etiologies of the disruptive functions associated with cerebral palsy can be attributed primarily to supraspinal networks, we propose that the more normal connectivity that persists between peripheral proprioception-cutaneous input to the spinal networks can be used to guide the reorganization of a more normal spinal-supraspinal connectivity. The level of plasticity necessary to achieve the required reorganization within and among different neural networks can be achieved with a combination of spinal neuromodulation and specific activity-dependent mechanisms. By engaging these two concepts, we hypothesize that bidirectional reorganization of proprioception-spinal cord-brain connectivity to higher levels of functionality can be achieved without invasive surgery.

Redundancy and multifunctionality among spinal locomotor networks.

c-Fos is used to identify system-wide neural activation with cellular resolution in vivo. However, c-Fos can only capture neural activation of one event. Targeted recombination in active populations (TRAP) allows the capture of two different c-Fos activation patterns in the same animal. So far, TRAP has only been used to examine brain circuits. This study uses TRAP to investigate spinal circuit activation during resting and stepping, giving novel insights of network activation during these events. The level of colabeled (c-Fos+ and TRAP+) neurons observed after performing two bouts of stepping suggests that there is a probabilistic-like phenomenon that can recruit many combinations of neural populations (synapses) when repetitively generating many step cycles. Between two 30-min bouts of stepping, each consisting of thousands of steps, only ∼20% of the neurons activated from the first bout of stepping were also activated by the second bout. We also show colabeling of interneurons that have been active during stepping and resting. The use of the FosTRAP methodology in the spinal cord provides a new tool to compare the engagement of different populations of spinal interneurons in vivo under different motor tasks or under different conditions.NEW & NOTEWORTHY The results are consistent with there being an extensive amount of redundancy among spinal locomotor circuits. Using the newly developed FosTRAP mouse model, only ∼20% of neurons that were active (labeled by Fos-linked tdTomato expression) during a first bout of 30-min stepping were also labeled for c-Fos during a second bout of stepping. This finding suggests variability of neural networks that enables selection of many combinations of neurons (synapses) when generating each step cycle.

Noninvasive spinal neuromodulation to map and augment lower urinary tract function in rhesus macaques.

Dysfunction of the lower urinary tract (LUT) is prevalent in neurological disorders, including multiple sclerosis, stroke, spinal cord injury and neurodegenerative conditions. Common symptoms include urgency, incontinence, and urinary retention. Recent advances in neuromodulation have resulted in improved treatments for overactive bladder symptoms of urgency, frequency, and nocturia. However, there are presently no treatments available for the induction of voiding to overcome urinary retention. We demonstrate that transcutaneous spinal cord stimulation (TSCS), a non-invasive intervention, applied over the thoracolumbar spine in neurologically intact rhesus macaques can activate the LUT, including activation of the bladder detrusor muscle, the urethral sphincter and pelvic floor muscles. Urodynamic studies show improved voiding efficiency and decreased post-voiding residual volumes in the bladder, while maintaining coordinated activity in the detrusor and sphincter with physiologic detrusor peak pressure, contraction duration, and urine flow rate remaining unchanged. We conclude that TSCS may represent a novel approach to activate the LUT and enable voiding in select neurological conditions.

Macrophage centripetal migration drives spontaneous healing process after spinal cord injury.

Traumatic spinal cord injury (SCI) brings numerous inflammatory cells, including macrophages, from the circulating blood to lesions, but pathophysiological impact resulting from spatiotemporal dynamics of macrophages is unknown. Here, we show that macrophages centripetally migrate toward the lesion epicenter after infiltrating into the wide range of spinal cord, depending on the gradient of chemoattractant C5a. However, macrophages lacking interferon regulatory factor 8 (IRF8) cannot migrate toward the epicenter and remain widely scattered in the injured cord with profound axonal loss and little remyelination, resulting in a poor functional outcome after SCI. Time-lapse imaging and P2X/YRs blockade revealed that macrophage migration via IRF8 was caused by purinergic receptors involved in the C5a-directed migration. Conversely, pharmacological promotion of IRF8 activation facilitated macrophage centripetal movement, thereby improving the SCI recovery. Our findings reveal the importance of macrophage centripetal migration via IRF8, providing a novel therapeutic target for central nervous system injury.

Noninvasive neurophysiological mapping of the lower urinary tract in adult and aging rhesus macaques.

The lower urinary tract (LUT) may be activated by spinal cord stimulation, but the physiological mapping characteristics of LUT activation with noninvasive transcutaneous spinal cord stimulation (TSCS) are not known. The effects of aging on the contractile properties of the detrusor are also not well understood. Therefore, TSCS was applied over the T10/T11 to L6/L7 spinous processes in adult ( n = 6) and aged ( n = 9) female rhesus macaques. A combination of urodynamic studies and electromyography recordings of the external urethral sphincter (EUS), external anal sphincter (EAS), and pelvic floor muscles was performed. Distinct functional maps were demonstrated for TSCS-evoked detrusor and urethral pressures and for the activation of the EUS, EAS, and pelvic floor muscles. The magnitude of responses for each peripheral target organ was dependent on TSCS location and strength. The strongest detrusor contraction was observed with TSCS at the L1/L2 site in adults and the L3/L4 site in aged subjects. TSCS-evoked bladder pressure at the L1/L2 site was significantly higher for the adults compared with the aged subjects ( P < 0.05). Cumulative normalized TSCS-evoked pressures, calculated for five consecutive sites between the T11/T12 and L3/L4 levels, were significantly lower for aged compared with adult subjects ( P < 0.05). The aged animals also showed a caudal shift for the TSCS site that generated the strongest detrusor contraction. We conclude that natural aging in rhesus macaques is associated with decreased detrusor contractility, a finding of significant translational research relevance as detrusor underactivity is a common occurrence with aging in humans. NEW & NOTEWORTHY Transcutaneous spinal cord stimulation (TSCS) was used to map lower urinary tract function in adult and aged rhesus macaques. Aging was associated with decreased peak pressure responses to TSCS, reduced cumulative normalized evoked bladder pressure responses, and a caudal shift for the site generating the strongest TSCS-induced detrusor contraction. We demonstrate the utility of TSCS as a new diagnostic tool for detrusor contractility assessments and conclude that aging is associated with decreased detrusor contractility in primates.

Generalized convulsive seizures are associated with ketamine anesthesia in a rhesus macaque (Macaca mulatta) undergoing urodynamic studies and transcutaneous spinal cord stimulation.

A female rhesus macaque developed two episodes of generalized convulsions during transcutaneous spinal cord stimulation (TSCS) and urodynamic studies under ketamine anesthesia. The seizures took place in the absence of active TSCS and bladder pressure elevation. Ketamine anesthesia remains the primary risk factor for the convulsions during these experimental procedures.

Iron 'ElectriRx' man: Overground stepping in an exoskeleton combined with noninvasive spinal cord stimulation after paralysis.

We asked whether coordinated voluntary movement of the lower limbs could be regained in an individual having been completely paralyzed (>4 yr) and completely absent of vision (>15 yr) using a novel strategy - transcutaneous spinal cord stimulation at selected sites over the spinal vertebrae with just one week of training. We also asked whether this stimulation strategy could facilitate stepping assisted by an exoskeleton (EKSO, EKSO Bionics) that is designed so that the subject can voluntarily complement the work being performed by the exoskeleton. We found that spinal cord stimulation enhanced the level of effort that the subject could generate while stepping in the exoskeleton. In addition, stimulation improved the coordination patterns of the lower limb muscles resulting in a more continuous, smooth stepping motion in the exoskeleton. These stepping sessions in the presence of stimulation were accompanied by greater cardiac responses and sweating than could be attained without the stimulation. Based on the data from this case study it appears that there is considerable potential for positive synergistic effects after complete paralysis by combining the overground stepping in an exoskeleton, a novel transcutaneous spinal cord stimulation paradigm, and daily training.

Identification of interneurons activated at different inclines during treadmill locomotion in adult rats.

By using c-fos as an activity-dependent marker, we identified the cholinergic interneurons around the central canal and lumbar interneurons throughout the gray matter that were activated after a 30-min bout of quadrupedal treadmill stepping at a 0° or 25° incline in adult rats. Increased loading (elevated treadmill incline) imposed during treadmill stepping activated more cholinergic interneurons in the proximity of the central canal, i.e., central canal cluster cells and partition neurons. Since cholinergic central canal cells are thought to modulate motoneuron excitability, these data suggest that increased load during stepping may increase motoneuronal activity through activating more cholinergic central canal cells. We identified the muscle-specific motoneurons and afferent terminals in the spinal cord by injecting cholera toxin subunit B in the soleus and tibialis anterior muscles. The number of interneurons in lumbar segments L4 (tibialis anterior) and L5 (soleus) was higher in both groups that stepped on the treadmill compared with control and was highest in rats that stepped at a 25° incline. In a majority of laminae, the distribution of total and muscle-specific activated interneurons was highest in the 25° incline group and lowest in the control group for both muscles. These data could reflect increased peripheral (proprioceptive) input as well as supraspinal drive associated with stepping and demonstrate the differences in 1) the activation of cholinergic interneurons near the central canal and 2) the laminar and segmental location of interneurons throughout the gray matter that play a role in generating stepping under different loading conditions in adult rats.

Neuromodulation of evoked muscle potentials induced by epidural spinal-cord stimulation in paralyzed individuals.

Epidural stimulation (ES) of the lumbosacral spinal cord has been used to facilitate standing and voluntary movement after clinically motor-complete spinal-cord injury. It seems of importance to examine how the epidurally evoked potentials are modulated in the spinal circuitry and projected to various motor pools. We hypothesized that chronically implanted electrode arrays over the lumbosacral spinal cord can be used to assess functionally spinal circuitry linked to specific motor pools. The purpose of this study was to investigate the functional and topographic organization of compound evoked potentials induced by the stimulation. Three individuals with complete motor paralysis of the lower limbs participated in the study. The evoked potentials to epidural spinal stimulation were investigated after surgery in a supine position and in one participant, during both supine and standing, with body weight load of 60%. The stimulation was delivered with intensity from 0.5 to 10 V at a frequency of 2 Hz. Recruitment curves of evoked potentials in knee and ankle muscles were collected at three localized and two wide-field stimulation configurations. Epidural electrical stimulation of rostral and caudal areas of lumbar spinal cord resulted in a selective topographical recruitment of proximal and distal leg muscles, as revealed by both magnitude and thresholds of the evoked potentials. ES activated both afferent and efferent pathways. The components of neural pathways that can mediate motor-evoked potentials were highly dependent on the stimulation parameters and sensory conditions, suggesting a weight-bearing-induced reorganization of the spinal circuitries.

Improvement of gait patterns in step-trained, complete spinal cord-transected rats treated with a peripheral nerve graft and acidic fibroblast growth factor.

The effects of peripheral nerve grafts (PNG) and acidic fibroblast growth factor (alpha FGF) combined with step training on the locomotor performance of complete spinal cord-transected (ST, T8) adult rats were studied. Rats were assigned randomly to five groups (N=10 per group): sham control (laminectomy only), ST only, ST-step-trained, repaired (ST with PNG and alpha FGF treatment), or repaired-step-trained. Step-trained rats were stepped bipedally on a treadmill 20 min/day, 5 days/week for 6 months. Bipolar intramuscular EMG electrodes were implanted in the soleus and tibialis anterior (TA) muscles of ST-step-trained (n=3) and repaired-step-trained (n=2) rats. Gait analysis was conducted at 3 and 6 months after surgery. Stepping analysis was completed on the best continuous 10-s period of stepping performed in a 2-min trial. Significantly better stepping (number of steps, stance duration, swing duration, maximum step length, and maximum step height) was observed in the repaired and repaired-step-trained than in the ST and ST-step-trained rats. Mean EMG amplitudes in both the soleus and TA were significantly higher and the patterns of activation of flexors and extensors more reciprocal in the repaired-step-trained than ST-step-trained rats. 5-HT fibers were present in the lumbar area of repaired but not ST rats. Thus, PNG plus alpha FGF treatment resulted in a clear improvement in locomotor performance with or without step training. Furthermore, the number of 5-HT fibers observed below the lesion was related directly to stepping performance. These observations indicate that the improved stepping performance in Repaired rats may be due to newly formed supraspinal control via regeneration.

Enhanced motor function by training in spinal cord contused rats following radiation therapy.

Weight-bearing stepping, without supraspinal re-connectivity, can be attained by treadmill training in an animal whose spinal cord has been completely transected at the lower thoracic level. Repair of damaged tissue and of supraspinal connectivity/circuitry following spinal cord injury in rat can be achieved by specific cell elimination with radiation therapy of the lesion site delivered within a critical time window, 2-3 weeks postinjury. Here we examined the effects of training in the repaired spinal cord following clinical radiation therapy. Studies were performed in a severe rat spinal cord contusion injury model, one similar to fracture/crush injuries in humans; the injury was at the lower thoracic level and the training was a combined hindlimb standing and stepping protocol. Radiotherapy, in a similar manner to that reported previously, resulted in a significant level of tissue repair/preservation at the lesion site. Training in the irradiated group, as determined by limb kinematics tests, resulted in functional improvements that were significant for standing and stepping capacity, and yielded a significant direct correlation between standing and stepping performance. In contrast, the training in the unirradiated group resulted in no apparent beneficial effects, and yielded an inverse correlation between standing and stepping performance, e.g., subject with good standing showed poor stepping capacity. Further, without any training, a differential functional change was observed in the irradiated group; standing capacity was significantly inhibited while stepping showed a slight trend of improvement compared with the unirradiated group. These data suggest that following repair by radiation therapy the spinal circuitries which control posture and locomotor were modified, and that the beneficial functional modulation of these circuitries is use dependent. Further, for restoring beneficial motor function following radiotherapy, training seems to be crucial.

Transformation of nonfunctional spinal circuits into functional states after the loss of brain input.

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.

Facilitation of stepping with epidural stimulation in spinal rats: role of sensory input.

We investigated the role of afferent information during recovery of coordinated rhythmic activity of the hindlimbs in rats with a complete spinal cord section (approximately T8) and unilateral deafferentation (T12-S2) to answer the following questions: (1) Can bilateral stepping be generated with only afferent projections intact on one side? (2) Can the sensory input from the non-deafferented side compensate for the loss of the afferent input from the deafferented side through the crossed connections within the lumbosacral spinal cord? (3) Which afferent projections to the spinal cord from the non-deafferented side predominantly mediate the effect of epidural stimulation to facilitate stepping? Recovery of stepping ability was tested under the facilitating influence of epidural stimulation at the S1 spinal segment, or epidural stimulation plus quipazine, a 5-HT agonist. All chronic spinal rats were able to generate stepping-like patterns on a moving treadmill on the non-deafferented, but not deafferented, side from 3 to 7 weeks after surgery when facilitated by epidural stimulation. Adaptation to the loss of unilateral afferent input was evident at 7 weeks after surgery, when some movements occurred on the deafferented side. Spinal-cord-evoked potentials were observed on both sides, although middle (monosynaptic) and late (long latency) responses were more prominent on the non-deafferented side. The afferent information arising from the non-deafferented side, however, eventually could mediate limited restoration of hindlimb movements on the deafferented side. These data suggest that facilitation of stepping with epidural stimulation is mediated primarily through ipsilateral afferents that project to the locomotor networks.

Persistence of motor unit and muscle fiber types in the presence of inactivity.

The clarity of categorizing skeletal muscle fibers in individual motor units into phenotypes based on quantitative single fiber enzyme activities and as a function of neuromuscular activity level was examined. Neuromuscular activity was eliminated in adult cat hindlimb muscles by spinal cord isolation (SI), i.e. complete spinal cord transection at a low thoracic and a high sacral level with bilateral dorsal rhizotomy between the transection sites. One motor unit was isolated via ventral root teasing procedures from the tibialis anterior (TA) muscle of each hindlimb in control and SI cats, and physiologically tested and glycogen depleted through repetitive stimulation; fibers comprising each motor unit were visualized through glycogen staining. Each motor unit was composed of fibers of the same myosin immunohistochemical type. Myofibrillar adenosine triphosphatase, succinate dehydrogenase and alpha-glycerophosphate dehydrogenase activities were determined for a sample of motor unit and non-motor unit fibers, providing a measure of three enzyme activities often used to characterize fiber phenotype within a single unit. Although normal enzyme activities were altered after 6 months of inactivity, the relationships among the three enzymes were largely maintained. These data demonstrate that it is not the diversity in any single enzyme property but the profile of several metabolic pathways that underlies the significance of fiber phenotypes. These profiles must reflect a high level of coordination of expression of selected combinations of genes. Although neuromuscular activity level influences fiber phenotype, the present results demonstrate that activity-independent mechanisms remain important sources of the control of phenotype establishment in the near absence of activity.

Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases.

We previously identified a common set of genes, termed atrogenes, whose expression is coordinately induced or suppressed in muscle during systemic wasting states (fasting, cancer cachexia, renal failure, diabetes). To determine whether this transcriptional program also functions during atrophy resulting from loss of contractile activity and whether atrogene expression correlates with the rate of muscle weight loss, we used cDNA microarrays and RT-polymerase chain reaction to analyze changes in mRNA from rat gastrocnemius during disuse atrophy induced by denervation or spinal cord isolation. Three days after Den or SI, the rate of muscle weight loss was greatest, and 78% of the atrogenes identified during systemic catabolic states were induced or repressed. Of particular interest were the large inductions of key ubiquitin ligases, atrogin-1 (35- to 44-fold) and MuRF1 (12- to 22-fold), and the suppression of PGC-1alpha and PGC-1beta coactivators (15-fold). When atrophy slowed (day 14), the expression of 92% of these atrogenes returned toward basal levels. At 28 days, the atrophy-inducing transcription factor, FoxO1, was still induced and may be important in maintaining the "atrophied" state. Thus, 1) the atrophy associated with systemic catabolic states and following disuse involves similar transcriptional adaptations; and 2) disuse atrophy proceeds through multiple phases corresponding to rapidly atrophying and atrophied muscles that involve distinct transcriptional patterns.

Neurobiology of exercise.

Voluntary physical activity and exercise training can favorably influence brain plasticity by facilitating neurogenerative, neuroadaptive, and neuroprotective processes. At least some of the processes are mediated by neurotrophic factors. Motor skill training and regular exercise enhance executive functions of cognition and some types of learning, including motor learning in the spinal cord. These adaptations in the central nervous system have implications for the prevention and treatment of obesity, cancer, depression, the decline in cognition associated with aging, and neurological disorders such as Parkinson's disease, Alzheimer's dementia, ischemic stroke, and head and spinal cord injury. Chronic voluntary physical activity also attenuates neural responses to stress in brain circuits responsible for regulating peripheral sympathetic activity, suggesting constraint on sympathetic responses to stress that could plausibly contribute to reductions in clinical disorders such as hypertension, heart failure, oxidative stress, and suppression of immunity. Mechanisms explaining these adaptations are not as yet known, but metabolic and neurochemical pathways among skeletal muscle, the spinal cord, and the brain offer plausible, testable mechanisms that might help explain effects of physical activity and exercise on the central nervous system.

Performance of locomotion and foot grasping following a unilateral thoracic corticospinal tract lesion in monkeys (Macaca mulatta).

Six adult monkeys (Macaca mulatta) received a unilateral lesion of the lateral corticospinal tract (CST) in the thoracic spinal cord. Prior to surgery, the animals were trained to perform quadrupedal stepping on a treadmill, and item retrieval with the foot. Whole body kinematics and electromyogram (EMG) recordings were made prior to, and at regular intervals over a period of 12 weeks after the CST lesion. After 1 week of recovery, all monkeys were able to walk unaided quadrupedally on the treadmill. The animals, however, dragged the hindpaw ipsilateral to the lesion along the treadmill belt during the swing phase and showed a significant reorganization of the spatiotemporal pattern of hindlimb (HL) and forelimb (FL) displacements. The inability to appropriately trigger the swing phase resulted in an increase in the cycle duration and stride length of both HLs. The stance duration decreased in the ipsilateral HL, and increased in the contralateral HL and both FLs. Consequently, there was a dramatic disruption of interlimb and intralimb coupling that was reflected in the limb kinematic and EMG patterns. The CST lesion completely abolished the ability of the monkeys to retrieve items with the foot ipsilateral to the lesion and significantly disrupted the level of performance of the contralateral HL during the first 2 weeks post-lesion. Interestingly, selected HL muscles remained almost quiescent when the monkeys attempted to retrieve items, but were unsuccessful with the affected foot at 1 week post-lesion, whereas the capacity to activate the same muscles was preserved, although reduced, during stepping. Spatial and temporal parameters of gait, kinematics, and EMG patterns recorded during locomotion generally converged toward control values over time, but significant differences persisted up to 12 weeks post-lesion. Although some control was recovered over the distal foot musculature, fine foot grasping remained significantly impaired at the end of the testing period. These findings demonstrate that the CST pathway from the brain normally makes an important contribution to interlimb and intralimb coordination during basic locomotion, and to muscle activation to produce dexterous foot digit movements in the monkey. Furthermore, the present study indicates that the primate has the ability to rapidly accommodate locomotor performance, and to a lesser degree fine foot motor skills, to a reduction in supraspinal control. Identification of the neural substrates mediating the rapid recovery of motor function following injury to the primate spinal cord could provide insight into developing repair strategies to augment functional recovery from neuromotor impairments.

Exercise restores levels of neurotrophins and synaptic plasticity following spinal cord injury.

We have conducted studies to determine the potential of exercise to benefit the injured spinal cord using neurotrophins. Adult rats were randomly assigned to one of three groups: (1) intact control (Con); (2) sedentary, hemisected at a mid-thoracic level (Sed-Hx), or (3) exercised, hemisected (Ex-Hx). One week after surgery, the Ex-Hx rats were exposed to voluntary running wheels for 3, 7, or 28 days. BDNF mRNA levels on the lesioned side of the spinal cord lumbar region of Sed-Hx rats were approximately 80% of Con values at all time points and BDNF protein levels were approximately 40% of Con at 28 days. Exercise compensated for the reductions in BDNF after hemisection, such that BDNF mRNA levels in the Ex-Hx rats were similar to Con after 3 days and higher than Con after 7 (17%) and 28 (27%) days of exercise. After 28 days of exercise, BDNF protein levels were 33% higher in Ex-Hx than Con rats and were highly correlated (r=0.86) to running distance. The levels of the downstream effectors for the action of BDNF on synaptic plasticity synapsin I and CREB were lower in Sed-Hx than Con rats at all time points. Synapsin I mRNA and protein levels were higher in Ex-Hx rats than Sed-Hx rats and similar to Con rats at 28 days. CREB mRNA values were higher in Ex-Hx than Sed-Hx rats at all time points. Hemisection had no significant effects on the levels of NT-3 mRNA or protein; however, voluntary exercise resulted in an increase in NT-3 mRNA levels after 28 days (145%). These results are consistent with the concept that synaptic pathways under the regulatory role of BDNF induced by exercise can play a role in facilitating recovery of locomotion following spinal cord injury.

Paralysis recovery in humans and model systems.

Considerable evidence now demonstrates that extensive functional and anatomical reorganization following spinal cord injury occurs in centers of the brain that have some input into spinal motor pools. This is very encouraging, given the accumulating evidence that new connections formed across spinal lesions may not be initially functionally useful. The second area of advancement in the field of paralysis recovery is in the development of effective interventions to counter axonal growth inhibition. A third area of significant progress is the development of robotic devices to quantify the performance level of motor tasks following spinal cord injury and to 'teach' the spinal cord to step and stand. Advances are being made with robotic devices for mice, rats and humans.