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1.  Wireless control of intraspinal microstimulation in a rodent model of paralysis 
Journal of neurosurgery  2014;123(1):232-242.
OBJECT
Despite a promising outlook, existing intraspinal microstimulation (ISMS) techniques for restoring functional motor control after spinal cord injury are not yet suitable for use outside a controlled laboratory environment. Thus, successful application of ISMS therapy in humans will require the use of versatile chronic neurostimulation systems. The objective of this study was to establish proof of principle for wireless control of ISMS to evoke controlled motor function in a rodent model of complete spinal cord injury.
METHODS
The lumbar spinal cord in each of 17 fully anesthetized Sprague-Dawley rats was stimulated via ISMS electrodes to evoke hindlimb function. Nine subjects underwent complete surgical transection of the spinal cord at the T-4 level 7 days before stimulation. Targeting for both groups (spinalized and control) was performed under visual inspection via dorsal spinal cord landmarks such as the dorsal root entry zone and the dorsal median fissure. Teflon-insulated stimulating platinum-iridium microwire electrodes (50 μm in diameter, with a 30- to 60-μm exposed tip) were implanted within the ventral gray matter to an approximate depth of 1.8 mm. Electrode implantation was performed using a free-hand delivery technique (n = 12) or a Kopf spinal frame system (n = 5) to compare the efficacy of these 2 commonly used targeting techniques. Stimulation was controlled remotely using a wireless neurostimulation control system. Hindlimb movements evoked by stimulation were tracked via kinematic markers placed on the hips, knees, ankles, and paws. Postmortem fixation and staining of the spinal cord tissue were conducted to determine the final positions of the stimulating electrodes within the spinal cord tissue.
RESULTS
The results show that wireless ISMS was capable of evoking controlled and sustained activation of ankle, knee, and hip muscles in 90% of the spinalized rats (n = 9) and 100% of the healthy control rats (n = 8). No functional differences between movements evoked by either of the 2 targeting techniques were revealed. However, frame-based targeting required fewer electrode penetrations to evoke target movements.
CONCLUSIONS
Clinical restoration of functional movement via ISMS remains a distant goal. However, the technology presented herein represents the first step toward restoring functional independence for individuals with chronic spinal cord injury.
http://thejns.org/doi/abs/10.3171/2014.10.JNS132370
doi:10.3171/2014.10.JNS132370
PMCID: PMC4457704  PMID: 25479124
intraspinal microstimulation; functional electrical stimulation; spinal cord injury; diagnostic and operative techniques
2.  Cervical intraspinal microstimulation evokes robust forelimb movements before and after injury 
Journal of neural engineering  2013;10(3):036001.
Objective
Intraspinal microstimulation (ISMS) is a promising method for reanimating paralyzed limbs following neurological injury. ISMS within the cervical and lumbar spinal cord is capable of evoking a variety of highly-functional movements prior to injury, but the ability of ISMS to evoke forelimb movements after cervical spinal cord injury is unknown. Here we examine the forelimb movements and muscles activated by cervical ISMS both before and after contusion injury.
Approach
We documented the forelimb muscles activated and movements evoked via systematic stimulation of the rodent cervical spinal cord both before injury and three, six and nine weeks following a moderate C4/C5 lateralized contusion injury. Animals were anesthetized with isoflurane to permit construction of somatotopic maps of evoked movements, and quantify evoked muscle synergies between cervical segments C3 and T1.
Main results
When ISMS was delivered to the cervical spinal cord, a variety of responses were observed at 68% of locations tested, with a spatial distribution that generally corresponded to the location of motor neuron pools. Stimulus currents required to achieve movement and the number of sites where movements could be evoked were unchanged by spinal cord injury. A transient shift toward extension-dominated movements and restricted muscle synergies were observed at three and six weeks following injury, respectively. By nine weeks after injury, however, ISMS-evoked patterns were similar to spinally-intact animals.
Significance
The results demonstrate the potential for cervical ISMS to reanimate hand and arm function following spinal cord injury. Robust forelimb movements can be evoked both before and during the chronic stages of recovery from a clinically-relevant and sustained cervical contusion injury.
doi:10.1088/1741-2560/10/3/036001
PMCID: PMC3732065  PMID: 23548462
neuroprosthesis; spinal stimulation; spinal cord injury; reanimation
3.  Therapeutic intraspinal microstimulation improves forelimb function after cervical contusion injury 
Journal of neural engineering  2013;10(4):044001.
Objective
Intraspinal microstimulation (ISMS) is a promising method for activating the spinal cord distal to an injury. The objectives of this study were to examine the ability of chronically implanted stimulating wires within the cervical spinal cord to (1) directly produce forelimb movements, and (2) assess whether ISMS stimulation improved subsequent volitional control of paretic extremities following injury.
Approach
We developed a technique for implanting intraspinal stimulating electrodes within the cervical spinal cord segments C6-T1 of Long-Evans rats. Beginning 4 weeks after a severe cervical contusion injury at C4–C5, animals in the treatment condition received therapeutic ISMS 7 hours/day, 5 days/week for the following 12 weeks.
Main Results
Over 12 weeks of therapeutic ISMS, stimulus-evoked forelimb movements were relatively stable. We also explored whether therapeutic ISMS promotes recovery of forelimb reaching movements. Animals receiving daily therapeutic ISMS performed significantly better than unstimulated animals during behavioral tests conducted without stimulation. Quantitative video analysis of forelimb movements showed that stimulated animals performed better in the movements reinforced by stimulation, including extending the elbow to advance the forelimb and opening the digits. While threshold current to elicit forelimb movement gradually increased over time, no differences were observed between chronically stimulated and unstimulated electrodes suggesting that no additional tissue damage was produced by the electrical stimulation.
Significance
The results indicate that therapeutic intraspinal stimulation delivered via chronic microwire implants within the cervical spinal cord confers benefits extending beyond the period of stimulation, suggesting future strategies for neural devices to promote sustained recovery after injury.
doi:10.1088/1741-2560/10/4/044001
PMCID: PMC3748939  PMID: 23715242
spinal cord injury; ISMS; regenerative stimulation; neuroprosthesis
4.  The Effects of Intraspinal Microstimulation on Spinal Cord Tissue in the Rat 
Biomaterials  2010;31(21):5552-5563.
Intraspinal microstimulation (ISMS) involves the implantation of microwires into the spinal cord below the level of an injury to excite neural networks involved in the control of locomotion in the lower limbs. The goal of this study was to examine the potential spinal cord damage that might occur with chronic ISMS. We employed functional measures of force recruitment and immunohistochemical processing of serial spinal cord sections to evaluate any damage induced by spinal transection, implantation of ISMS arrays, and electrical stimulation of 4 hours/day for 30 days. Functional measurements showed no change in force recruitment following transection and chronic ISMS, indicating no changes to underlying neural networks. The implantation of sham intraspinal microwires produced a spatially-limited increase in the density of microglia/macrophages and GFAP+ astrocytes adjacent to the microwire tracks, indicating a persistent immune response. Most importantly, these results were not different from those around microwires that were chronically pulsed with charge levels up to 48 nC/phase. Likewise, measurements of neuronal density indicated no decrease in neuronal cell bodies in the ventral grey matter surrounding ISMS microwires (243.6/mm2 ± 35.3/mm2) compared to tissue surrounding sham microwires (207.8/mm2 ± 38.8/mm2). We conclude that the implantation of intraspinal microwires and chronic application of ISMS are well tolerated by spinal cord tissue.
doi:10.1016/j.biomaterials.2010.03.051
PMCID: PMC2875271  PMID: 20430436
5.  Extensive Neuronal Differentiation of Human Neural Stem Cell Grafts in Adult Rat Spinal Cord 
PLoS Medicine  2007;4(2):e39.
Background
Effective treatments for degenerative and traumatic diseases of the nervous system are not currently available. The support or replacement of injured neurons with neural grafts, already an established approach in experimental therapeutics, has been recently invigorated with the addition of neural and embryonic stem-derived precursors as inexhaustible, self-propagating alternatives to fetal tissues. The adult spinal cord, i.e., the site of common devastating injuries and motor neuron disease, has been an especially challenging target for stem cell therapies. In most cases, neural stem cell (NSC) transplants have shown either poor differentiation or a preferential choice of glial lineages.
Methods and Findings
In the present investigation, we grafted NSCs from human fetal spinal cord grown in monolayer into the lumbar cord of normal or injured adult nude rats and observed large-scale differentiation of these cells into neurons that formed axons and synapses and established extensive contacts with host motor neurons. Spinal cord microenvironment appeared to influence fate choice, with centrally located cells taking on a predominant neuronal path, and cells located under the pia membrane persisting as NSCs or presenting with astrocytic phenotypes. Slightly fewer than one-tenth of grafted neurons differentiated into oligodendrocytes. The presence of lesions increased the frequency of astrocytic phenotypes in the white matter.
Conclusions
NSC grafts can show substantial neuronal differentiation in the normal and injured adult spinal cord with good potential of integration into host neural circuits. In view of recent similar findings from other laboratories, the extent of neuronal differentiation observed here disputes the notion of a spinal cord that is constitutively unfavorable to neuronal repair. Restoration of spinal cord circuitry in traumatic and degenerative diseases may be more realistic than previously thought, although major challenges remain, especially with respect to the establishment of neuromuscular connections.
When neural stem cells from human fetal spinal cord were grafted into the lumbar cord of normal or injured adult nude rats, substantial neuronal differentiation was found.
Editors' Summary
Background.
Every year, spinal cord injuries, many caused by road traffic accidents, paralyze about 11,000 people in the US. This paralysis occurs because the spinal cord is the main communication highway between the body and the brain. Information from the skin and other sensory organs is transmitted to the brain along the spinal cord by bundles of neurons, nervous system cells that transmit and receive messages. The brain then sends information back down the spinal cord to control movement, breathing, and other bodily functions. The bones of the spine normally protect the spinal cord but, if these are broken or dislocated, the spinal cord can be cut or compressed, which interrupts the information flow. Damage near the top of the spinal cord can paralyze the arms and legs (tetraplegia); damage lower down paralyzes the legs only (paraplegia). Spinal cord injuries also cause many other medical problems, including the loss of bowel and bladder control. Although the deleterious effects of spinal cord injuries can be minimized by quickly immobilizing the patient and using drugs to reduce inflammation, the damaged nerve fibers never regrow. Consequently, spinal cord injury is permanent.
Why Was This Study Done?
Scientists are currently searching for ways to reverse spinal cord damage. One potential approach is to replace the damaged neurons using neural stem cells (NSCs). These cells, which can be isolated from embryos and from some areas of the adult nervous system, are able to develop into all the specialized cells types of the nervous system. However, because most attempts to repair spinal cord damage with NSC transplants have been unsuccessful, many scientists believe that the environment of the spinal cord is unsuitable for nerve regeneration. In this study, the researchers have investigated what happens to NSCs derived from the spinal cord of a human fetus after transplantation into the spinal cord of adult rats.
What Did the Researchers Do and Find?
The researchers injected human NSCs that they had grown in dishes into the spinal cord of intact nude rats (animals that lack a functioning immune system and so do not destroy human cells) and into nude rats whose spinal cord had been damaged at the transplantation site. The survival and fate of the transplanted cells was assessed by staining thin slices of spinal cord with an antibody that binds to a human-specific protein and with antibodies that recognize proteins specific to NSCs, neurons, or other nervous system cells. The researchers report that the human cells survived well in the adult spinal cord of the injured and normal rats and migrated into the gray matter of the spinal cord (which contains neuronal cell bodies) and into the white matter (which contains the long extensions of nerve cells that carry nerve impulses). 75% and 60% of the human cells in the gray and white matter, respectively, contained a neuron-specific protein six months after transplantation but only 10% of those in the membrane surrounding the spinal cord became neurons; the rest developed into astrocytes (another nervous system cell type) or remained as stem cells. Finally, many of the human-derived neurons made the neurotransmitter GABA (one of the chemicals that transfers messages between neurons) and made contacts with host spinal cord neurons.
What Do These Findings Mean?
These findings suggest that human NSC grafts can, after all, develop into neurons (predominantly GABA-producing neurons) in normal and injured adult spinal cord and integrate into the existing spinal cord if the conditions are right. Although these animal experiments suggest that NSC transplants might help people with spinal injuries, they have some important limitations. For example, the spinal cord lesions used here are mild and unlike those seen in human patients. This and the use of nude rats might have reduced the scarring in the damaged spinal cord that is often a major barrier to nerve regeneration. Furthermore, the researchers did not test whether NSC transplants provide functional improvements after spinal cord injury. However, since other researchers have also recently reported that NSCs can grow and develop into neurons in injured adult spinal cord, these new results further strengthen hopes it might eventually be possible to use human NSCs to repair damaged spinal cords.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/doi:10.1371/journal.pmed.0040039.
The US National Institute of Neurological Disorders and Stroke provides information on spinal cord injury and current spinal cord research
Spinal Research (a UK charity) offers information on spinal cord injury and repair
The US National Spinal Cord Injury Association Web site contains factsheets on spinal cord injuries
MedlinePlus encyclopedia has pages on spinal cord trauma and interactive tutorials on spinal cord injury
The International Society for Stem Cell Research offers information on all sorts of stem cells including NSCs
The US National Human Neural Stem Cell Resource provides information on human NSCs, including the current US government's stance on stem cell research
doi:10.1371/journal.pmed.0040039
PMCID: PMC1796906  PMID: 17298165
6.  An Implantable Neural Stimulator for Intraspinal MicroStimulation 
This paper reports on a wireless stimulator device for use in animal experiments as part of an ongoing investigation into intraspinal stimulation (ISMS) for restoration of walking in humans with spinal cord injury. The principle behind using ISMS is the activation of residual motor-control neural networks within the spinal cord ventral horn below the level of lesion following a spinal cord injury. The attractiveness to this technique is that a small number of electrodes can be used to induce bilateral walking patterns in the lower limbs. In combination with advanced feedback algorithms, ISMS has the potential to restore walking for distances that exceed that produced by other types of functional electrical stimulation. Recent acute animal experiments have demonstrated the feasibility of using ISMS to produce the coordinated walking patterns. Here we described a wireless implantable stimulation system to be used in chronic animal experiments and for providing the basis for a system suitable for use in humans. Electrical operation of the wireless system is described, including a demonstration of reverse telemetry for monitoring the stimulating electrode voltages.
doi:10.1109/EMBC.2012.6346077
PMCID: PMC3795508  PMID: 23366038
7.  Reanimating the arm and hand with intraspinal microstimulation 
Journal of neural engineering  2011;8(5):054001.
To date, there is no effective therapy for spinal cord injury, and many patients could benefit dramatically from at least partial restoration of arm and hand function. Despite a substantial body of research investigating intraspinal microstimulation (ISMS) in frogs, rodents and cats, little is known about upper-limb responses to cervical stimulation in the primate. Here, we show for the first time that long trains of ISMS delivered to the macaque spinal cord can evoke functional arm and hand movements. Complex movements involving coordinated activation of multiple muscles could be elicited from a single electrode, while just two electrodes were required for independent control of reaching and grasping. We found that the motor responses to ISMS were described by a dual exponential model that depended only on stimulation history. We demonstrate that this model can be inverted to generate stimulus trains capable of eliciting arbitrary, graded motor responses, and could be used to restore volitional movements in a closed-loop brain–machine interface.
doi:10.1088/1741-2560/8/5/054001
PMCID: PMC3306897  PMID: 21828907
8.  Generation of Locomotor-Like Activity in the Isolated Rat Spinal Cord Using Intraspinal Electrical Microstimulation Driven by a Digital Neuromorphic CPG 
Neural prostheses based on electrical microstimulation offer promising perspectives to restore functions following lesions of the central nervous system (CNS). They require the identification of appropriate stimulation sites and the coordination of their activation to achieve the restoration of functional activity. On the long term, a challenging perspective is to control microstimulation by artificial neural networks hybridized to the living tissue. Regarding the use of this strategy to restore locomotor activity in the spinal cord, to date, there has been no proof of principle of such hybrid approach driving intraspinal microstimulation (ISMS). Here, we address a first step toward this goal in the neonatal rat spinal cord isolated ex vivo, which can display locomotor-like activity while offering an easy access to intraspinal circuitry. Microelectrode arrays were inserted in the lumbar region to determine appropriate stimulation sites to elicit elementary bursting patterns on bilateral L2/L5 ventral roots. Two intraspinal sites were identified at L1 level, one on each side of the spinal cord laterally from the midline and approximately at a median position dorso-ventrally. An artificial CPG implemented on digital integrated circuit (FPGA) was built to generate alternating activity and was hybridized to the living spinal cord to drive electrical microstimulation on these two identified sites. Using this strategy, sustained left-right and flexor-extensor alternating activity on bilateral L2/L5 ventral roots could be generated in either whole or thoracically transected spinal cords. These results are a first step toward hybrid artificial/biological solutions based on electrical microstimulation for the restoration of lost function in the injured CNS.
doi:10.3389/fnins.2016.00067
PMCID: PMC4779903  PMID: 27013936
hybrid neural networks; neural prostheses; neuromorphic hardware; rehabilitation
9.  Spinal Commissural Connections to Motoneurons Controlling the Primate Hand and Wrist 
The Journal of Neuroscience  2013;33(23):9614-9625.
Left–right coordination is essential for locomotor movements and is partly mediated by spinal commissural systems. Such coordination is also essential for reaching and manipulation in primates, but the role of spinal commissural systems here has not been studied. We investigated commissural connectivity to motoneurons innervating forelimb muscles using intracellular recordings in acutely anesthetized macaque monkeys. In 57 of 81 motoneurons, synaptic responses (52 of 57 excitatory) were evoked after contralateral intraspinal microstimulation in the gray matter (cISMS; 300 μA maximum current intensity). Some responses (15 of 57) occurred at latencies compatible with a monosynaptic linkage, including in motoneurons projecting to intrinsic hand muscles (9 cells). Three pieces of evidence suggest that these effects reflected the action of commissural interneurons. In two cells, preceding cISMS with stimulation of the contralateral medial brainstem descending pathways facilitated the motoneuron responses, suggesting that cISMS acted on cell bodies whose excitability was increased by descending inputs. Pairing cISMS with stimulation of the contralateral corticospinal tract yielded no evidence of response occlusion in 16 cells tested, suggesting that the effects were not merely axon reflexes generated by stimulation of corticospinal axon branches, which cross the midline. Finally, stimulation of contralateral peripheral nerves evoked responses in 28 of 52 motoneurons (7 of 9 projecting to the hand). Our results demonstrate the existence of commissural neurons with access to spinal motoneurons in primate cervical spinal cord that receive inputs from the periphery as well as descending pathways. Most importantly, commissural neurons also innervate motoneurons of intrinsic hand muscles.
doi:10.1523/JNEUROSCI.0269-13.2013
PMCID: PMC3951829  PMID: 23739958
10.  Therapeutic intraspinal stimulation to generate activity and promote long-term recovery 
Neuroprosthetic approaches have tremendous potential for the treatment of injuries to the brain and spinal cord by inducing appropriate neural activity in otherwise disordered circuits. Substantial work has demonstrated that stimulation applied to both the central and peripheral nervous system leads to immediate and in some cases sustained benefits after injury. Here we focus on cervical intraspinal microstimulation (ISMS) as a promising method of activating the spinal cord distal to an injury site, either to directly produce movements or more intriguingly to improve subsequent volitional control of the paretic extremities. Incomplete injuries to the spinal cord are the most commonly observed in human patients, and these injuries spare neural tissue bypassing the lesion that could be influenced by neural devices to promote recovery of function. In fact, recent results have demonstrated that therapeutic ISMS leads to modest but sustained improvements in forelimb function after an incomplete spinal cord injury (SCI). This therapeutic spinal stimulation may promote long-term recovery of function by providing the necessary electrical activity needed for neuron survival, axon growth, and synaptic stability.
doi:10.3389/fnins.2014.00021
PMCID: PMC3936503  PMID: 24578680
spinal cord injury; electrical activity; regenerative stimulation; neuroprosthesis; ISMS
11.  Infiltrating Blood-Derived Macrophages Are Vital Cells Playing an Anti-inflammatory Role in Recovery from Spinal Cord Injury in Mice 
PLoS Medicine  2009;6(7):e1000113.
Using a mouse model of spinal injury, Michal Schwartz and colleagues tested the effect of macrophages on the recovery process and demonstrate an important anti-inflammatory role for a subset of infiltrating monocyte-derived macrophages that is dependent upon their expression of interleukin 10.
Background
Although macrophages (MΦ) are known as essential players in wound healing, their contribution to recovery from spinal cord injury (SCI) is a subject of debate. The difficulties in distinguishing between different MΦ subpopulations at the lesion site have further contributed to the controversy and led to the common view of MΦ as functionally homogenous. Given the massive accumulation in the injured spinal cord of activated resident microglia, which are the native immune occupants of the central nervous system (CNS), the recruitment of additional infiltrating monocytes from the peripheral blood seems puzzling. A key question that remains is whether the infiltrating monocyte-derived MΦ contribute to repair, or represent an unavoidable detrimental response. The hypothesis of the current study is that a specific population of infiltrating monocyte-derived MΦ is functionally distinct from the inflammatory resident microglia and is essential for recovery from SCI.
Methods and Findings
We inflicted SCI in adult mice, and tested the effect of infiltrating monocyte-derived MΦ on the recovery process. Adoptive transfer experiments and bone marrow chimeras were used to functionally distinguish between the resident microglia and the infiltrating monocyte-derived MΦ. We followed the infiltration of the monocyte-derived MΦ to the injured site and characterized their spatial distribution and phenotype. Increasing the naïve monocyte pool by either adoptive transfer or CNS-specific vaccination resulted in a higher number of spontaneously recruited cells and improved recovery. Selective ablation of infiltrating monocyte-derived MΦ following SCI while sparing the resident microglia, using either antibody-mediated depletion or conditional ablation by diphtheria toxin, impaired recovery. Reconstitution of the peripheral blood with monocytes resistant to ablation restored the lost motor functions. Importantly, the infiltrating monocyte-derived MΦ displayed a local anti-inflammatory beneficial role, which was critically dependent upon their expression of interleukin 10.
Conclusions
The results of this study attribute a novel anti-inflammatory role to a unique subset of infiltrating monocyte-derived MΦ in SCI recovery, which cannot be provided by the activated resident microglia. According to our results, limited recovery following SCI can be attributed in part to the inadequate, untimely, spontaneous recruitment of monocytes. This process is amenable to boosting either by active vaccination with a myelin-derived altered peptide ligand, which indicates involvement of adaptive immunity in monocyte recruitment, or by augmenting the naïve monocyte pool in the peripheral blood. Thus, our study sheds new light on the long-held debate regarding the contribution of MΦ to recovery from CNS injuries, and has potentially far-reaching therapeutic implications.
Please see later in the article for Editors' Summary
Editors' Summary
Background
Every year, spinal cord injuries paralyze about 11,000 people in the US. The spinal cord, which contains bundles of nervous system cells called neurons, is the communication highway between the brain and the body. Messages from the brain travel down the spinal cord to control movement, breathing and other bodily functions; messages from the skin and other sensory organs travel up the spinal cord to keep the brain informed about the body. The bones of the spine normally protect the spinal cord but, if these are broken or displaced, the spinal cord can be cut or compressed, which interrupts the information flow. Damage near the top of the spinal cord paralyzes the arms and legs (tetraplegia); damage lower down paralyzes the legs only (paraplegia). Spinal cord injuries also cause other medical problems, including the loss of bladder and bowel control. Currently, there is no effective treatment for spinal cord injuries, which usually cause permanent disability because the damaged nerve fibers rarely regrow.
Why Was This Study Done?
After a spinal cord injury, immune system cells called macrophages accumulate at the injury site. Some of these macrophages—so-called monocyte-derived macrophages—come into (infiltrate) the spinal cord from the blood in response to the injury, whereas others—microglia—are always in the nervous system. Although macrophages are essential for wound healing in other parts of the body, it is unclear whether they have good or bad effects in the spinal cord. Many experts believe that immune system cells hinder healing in the spinal cord and should be suppressed or eliminated, but other scientists claim that macrophages secrete factors that stimulate nerve regrowth. Furthermore, although some macrophages elsewhere in the body have proinflammatory (potentially deleterious) effects, others have anti-inflammatory (beneficial) effects. So do the infiltrating monocyte-derived macrophages and the resident microglia (which are proinflammatory) have different functions at spinal cord injury sites? In this study, the researchers try to answer this important question.
What Did the Researchers Do and Find?
The researchers bruised a small section of the spinal cord of adult mice and then investigated the effect of infiltrating monocyte-derived macrophages on the recovery process. Monocyte-derived macrophages and microglia cannot be distinguished using standard staining techniques so to study their behavior after spinal cord injury the researchers introduced labeled monocyte-derived macrophages into their experimental animals by using adoptive transfer (injection of genetically labeled monocytes into the animals) or by making bone marrow chimeras. In this second technique, the animals' monocyte-derived macrophages (but not their microglia) were killed by irradiating the animals before injection of genetically labeled bone marrow, the source of monocytes. Using these approaches, the researchers found that monocyte-derived macrophages collected at the margins of spinal cord injury sites whereas microglia accumulated throughout the sites. When the pool of monocyte-derived macrophages in the mice was increased by adoptive transfer or by using a technique called “CNS-specific vaccination,” more monocyte-derived macrophages infiltrated the injury site and the animals' physical recovery from injury improved. Conversely, removal of the infiltrating monocyte-derived macrophages from the injury site reduced the animals' physical recovery. Other experiments indicated that the infiltrating monocyte-derived macrophages have a beneficial, local anti-inflammatory effect that is dependent on their expression of interleukin-10 (an anti-inflammatory signaling molecule).
What Do These Findings Mean?
These findings provide new information about the contribution of monocyte-derived macrophages to spontaneous recovery from spinal cord injury, a contribution that has long been debated. In particular, the findings suggest that this subset of macrophages (but not the resident microglia) has a beneficial effect on spinal cord injuries that is mediated by their production of the anti-inflammatory molecule interleukin-10. The findings also show that the effect of these monocyte-derived macrophages can be boosted, at least in mice. Although results obtained in experiments done in animals do not always accurately reflect what happens in people, this new understanding of the different functions of microglia and infiltrating monocyte-derived macrophages after injury to the spinal cord may eventually lead to the development of better treatments for spinal cord injuries.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000113.
The MedlinePlus encyclopedia provides information about spinal cord injuries (in English and Spanish)
The US National Institute of Neurological Disorders and Stroke provides detailed information about spinal cord injury, including information on current research into the problem (in English and Spanish)
MedlinePlus provides an interactive tutorial on spinal cord injury and a list of links to additional information (in English and Spanish)
doi:10.1371/journal.pmed.1000113
PMCID: PMC2707628  PMID: 19636355
12.  Restoring Stepping After Spinal Cord Injury Using Intraspinal Microstimulation and Novel Control Strategies 
Conference Proceedings  2011;2011:5798-5801.
The overall objective of this project is to develop a feedback-driven intraspinal microstimulation (ISMS) system. We hypothesize that ISMS will enhance the functionality of stepping by reducing muscle fatigue and producing synergistic movements by activating neural networks in the spinal cord. In the present pilot study, the controller was tested with ISMS and external sensors (force plates, gyroscopes, and accelerometers). Cats were partially supported in a sling and bi-laterally stepped overground on a 4-m instrumented walkway. The walkway had variable friction. Limb angle was controlled to within 10° even in the presence of variable friction. Peak ground reaction forces in each limb were approximately 12% of body weight (12.5% was full load bearing in this experimental setup); rarely, the total supportive force briefly decreased to as low as 4.1%. Magnetic resonance images were acquired of the excised spinal cord and the implanted array. The majority of electrodes (75%) were implanted successfully into their target regions. This represents the first successful application of ISMS for overground walking.
doi:10.1109/IEMBS.2011.6091435
PMCID: PMC3276678  PMID: 22255658
13.  Bilateral Bulbospinal Projections to Pudendal Motoneuron Circuitry after Chronic Spinal Cord Hemisection Injury as Revealed by Transsynaptic Tracing with Pseudorabies Virus 
Journal of Neurotrauma  2011;28(4):595-605.
Abstract
Complications of spinal cord injury in males include losing brainstem control of pudendal nerve–innervated perineal muscles involved in erection and ejaculation. We previously described, in adult male rats, a bulbospinal pathway originating in a discrete area within the medullary gigantocellularis (GiA/Gi), and lateral paragigantocellularis (LPGi) nuclei, which when electrically microstimulated unilaterally, produces a bilateral inhibition of pudendal motoneuron reflex circuitry after crossing to the contralateral spinal cord below T8. Microstimulation following a long-term lateral hemisection, however, revealed reflex inhibition from both sides of the medulla, suggesting the development or unmasking of an injury-induced bulbospinal pathway crossing the midline cranial to the spinal lesion. In the present study, we investigated this pathway anatomically using the transsynaptic neuronal tracer pseudorabies virus (PRV) injected unilaterally into the bulbospongiosus muscle in uninjured controls, and ipsilateral to a chronic (1–2 months) unilateral lesion of the lateral funiculus. At 4.75 days post-injection, PRV-labeled cells were found bilaterally in the GiA/Gi/LPGi with equal side-to-side labeling in uninjured controls, and with significantly greater labeling contralateral to the lesion/injection in lesioned animals. The finding of PRV-labeled neurons on both sides of the medulla after removing the mid-thoracic spinal pathway on one side provides anatomical evidence for the bilaterality in both the brainstem origin and the lumbosacral pudendal circuit termination of the spared lateral funicular bulbospinal pathway. This also suggests that this bilaterality may contribute to the quick functional recovery of bladder and sexual functions observed in animals and humans with lateral hemisection injury.
doi:10.1089/neu.2009.1180
PMCID: PMC3070146  PMID: 21265606
animal studies; electrophysiology; immunohistochemistry; in vivo studies; spinal cord injury
14.  Two Faces of Chondroitin Sulfate Proteoglycan in Spinal Cord Repair: A Role in Microglia/Macrophage Activation 
PLoS Medicine  2008;5(8):e171.
Background
Chondroitin sulfate proteoglycan (CSPG) is a major component of the glial scar. It is considered to be a major obstacle for central nervous system (CNS) recovery after injury, especially in light of its well-known activity in limiting axonal growth. Therefore, its degradation has become a key therapeutic goal in the field of CNS regeneration. Yet, the abundant de novo synthesis of CSPG in response to CNS injury is puzzling. This apparent dichotomy led us to hypothesize that CSPG plays a beneficial role in the repair process, which might have been previously overlooked because of nonoptimal regulation of its levels. This hypothesis is tested in the present study.
Methods and Findings
We inflicted spinal cord injury in adult mice and examined the effects of CSPG on the recovery process. We used xyloside to inhibit CSPG formation at different time points after the injury and analyzed the phenotype acquired by the microglia/macrophages in the lesion site. To distinguish between the resident microglia and infiltrating monocytes, we used chimeric mice whose bone marrow-derived myeloid cells expressed GFP. We found that CSPG plays a key role during the acute recovery stage after spinal cord injury in mice. Inhibition of CSPG synthesis immediately after injury impaired functional motor recovery and increased tissue loss. Using the chimeric mice we found that the immediate inhibition of CSPG production caused a dramatic effect on the spatial organization of the infiltrating myeloid cells around the lesion site, decreased insulin-like growth factor 1 (IGF-1) production by microglia/macrophages, and increased tumor necrosis factor alpha (TNF-α) levels. In contrast, delayed inhibition, allowing CSPG synthesis during the first 2 d following injury, with subsequent inhibition, improved recovery. Using in vitro studies, we showed that CSPG directly activated microglia/macrophages via the CD44 receptor and modulated neurotrophic factor secretion by these cells.
Conclusions
Our results show that CSPG plays a pivotal role in the repair of injured spinal cord and in the recovery of motor function during the acute phase after the injury; CSPG spatially and temporally controls activity of infiltrating blood-borne monocytes and resident microglia. The distinction made in this study between the beneficial role of CSPG during the acute stage and its deleterious effect at later stages emphasizes the need to retain the endogenous potential of this molecule in repair by controlling its levels at different stages of post-injury repair.
Michal Schwartz and colleagues describe the role of chondroitin sulfate proteoglycan in the repair of injured tissue and in the recovery of motor function during the acute phase after spinal cord injury.
Editors' Summary
Background.
Every year, spinal cord injuries paralyze about 10,000 people in the United States. The spinal cord, which contains bundles of nervous system cells called neurons, is the communication superhighway between the brain and the body. Messages from the brain travel down the spinal cord to control movement, breathing, and other bodily functions; messages from the skin and other sensory organs travel up the spinal cord to keep the brain informed about the body. All these messages are transmitted along axons, long extensions on the neurons. The spinal cord is protected by the bones of the spine but if these are displaced or broken, the axons can be compressed or cut, which interrupts the information flow. Damage near the top of the spinal cord paralyzes the arms and legs (tetraplegia); damage lower down paralyzes the legs only (paraplegia). Spinal cord injuries also cause other medical problems, including the loss of bowel and bladder control. Currently there is no effective treatment for spinal cord injuries. Treatment with drugs to reduce inflammation has, at best, only modest effects. Moreover, because damaged axons rarely regrow, most spinal cord injuries are permanent.
Why Was This Study Done?
One barrier to recovery after a spinal cord injury seems to be an inappropriate immune response to the injury. After an injury, microglia (immune system cells that live in the nervous system), and macrophages (blood-borne immune system cells that infiltrate the injury) become activated. Microglia/macrophage activation can be either beneficial (the cells make IGF-1, a protein that stimulates axon growth) or destructive (the cells make TNF-α, a protein that kills neurons), so studies of microglia/macrophage activation might suggest ways to treat spinal cord injuries. Another possible barrier to recovery is “chondroitin sulfate proteoglycan” (CSPG). This is a major component of the scar tissue (the “glial scar”) that forms around spinal cord injuries. CSPG limits axon regrowth, so attempts have been made to improve spinal cord repair by removing CSPG. But if CSPG prevents spinal cord repair, why is so much of it made immediately after an injury? In this study, the researchers investigate this paradox by asking whether CSPG made in the right place and in the right amount might have a beneficial role in spinal cord repair that has been overlooked.
What Did the Researchers Do and Find?
The researchers bruised a small section of the spinal cord of mice to cause hind limb paralysis, and then monitored the recovery of movement in these animals. They also examined the injured tissue microscopically, looked for microglia and infiltrating macrophages at the injury site, and measured the production of IGF-1 and TNF-α by these cells. Inhibition of CSPG synthesis immediately after injury impaired the functional recovery of the mice and increased tissue loss at the injury site. It also altered the spatial organization of infiltrating macrophages at the injury site, reduced IGF-1 production by these microglia/macrophages, and increased TNF-α levels. In contrast, when CSPG synthesis was not inhibited until two days after the injury, the mice recovered well from spinal cord injury. Furthermore, the interaction of CSPG with a cell-surface protein called CD44 activated microglia/macrophages growing in dishes and increased their production of IGF-1 but not of molecules that kill neurons.
What Do These Findings Mean?
These findings suggest that, immediately after a spinal cord injury, CSPG is needed for the repair of injured neurons and the recovery of movement, but that later on the presence of CSPG hinders repair. The findings also indicate that CSPG has these effects, at least in part, because it regulates the activity and localization of microglia and macrophages at the injury site and thus modulates local immune responses to the damage. Results obtained from experiments done in animals do not always accurately reflect the situation in people, so these findings need to be confirmed in patients with spinal cord injuries. However, they suggest that the effect of CSPG on spinal cord repair is not an inappropriate response to the injury, as is widely believed. Consequently, careful manipulation of CSPG levels might improve outcomes for people with spinal cord injuries.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050171.
The MedlinePlus encyclopedia provides information about spinal cord injuries; MedlinePlus provides an interactive tutorial and a list of links to additional information about spinal cord injuries (in English and Spanish)
The US National Institute of Neurological Disorders and Stroke also provides information about spinal cord injury (in English and Spanish)
Wikipedia has a page on glial scars (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.0050171
PMCID: PMC2517615  PMID: 18715114
15.  Convergence of Pyramidal and Medial Brain Stem Descending Pathways Onto Macaque Cervical Spinal Interneurons 
Journal of Neurophysiology  2010;103(5):2821-2832.
We investigated the control of spinal interneurons by corticospinal and medial brain stem descending tracts in two macaque monkeys. Stimulating electrodes were implanted in the left pyramidal tract (PT), and the right medial longitudinal fasciculus (MLF), which contains reticulospinal, vestibulospinal, and some tectospinal fibers. Single unit discharge was recorded from 163 interneurons in the intermediate zone of the right spinal cord (segmental levels C6–C8) in the awake state; inputs from descending pathways were assessed from the responses to stimulation through the PT and MLF electrodes. Convergent input from both pathways was the most common finding (71/163 cells); responses to PT and MLF stimulation were of similar amplitude. Interneuron discharge was also recorded while the animal performed a reach and grasp task with the right hand; the output connections of the recorded cells were determined by delivering intraspinal microstimulation (ISMS) at the recording sites. Convergent input from MLF/PT stimulation was also common when analysis was restricted to cells that increased their rate during grasp (14/23 cells) or to cells recorded at sites where ISMS elicited finger or wrist movements (23/57 cells). We conclude that medial brain stem and corticospinal descending pathways have largely overlapping effects on spinal interneurons, including those involved in the control of the hand. This may imply a more important role for the brain stem in coordinating hand movements in primates than commonly assumed; brain stem pathways could contribute to the restoration of function seen after lesions to the corticospinal tract.
doi:10.1152/jn.00491.2009
PMCID: PMC2867561  PMID: 20457863
16.  Muscle Plasticity in Rat Following Spinal Transection and Chronic Intraspinal Microstimulation 
Intraspinal microstimulation (ISMS) employs electrical stimulation of the ventral grey matter to reactivate paralyzed skeletal muscle. This work evaluated the transformations in the quadriceps muscle that occurred following complete transection and chronic stimulation with ISMS or a standard nerve cuff (NCS). Stimulation was applied for 30 days, 4 hours/day. Both methods induced significant increases in time-to-peak tension (ISMS 35%, NCS 25%) and ½ rise-time (ISMS 39%, NCS 25%) compared to intact controls (IC). Corresponding increases in type-IIA myosin heavy chain (MHC) and decreases in type-IID MHC were noted compared to IC. These results were unexpected because ISMS recruits motor units in a near-normal physiological order while NCS recruits motor units in a reversed order. Spinal cord transection and 30 days of stimulation did not alter either recruitment profile. The slope of the force recruitment curves obtained through ISMS following transection and 30 days of stimulation was similar to that obtained in intact animals, and 3.4-fold shallower than that obtained through NCS. The transformations observed in the current work are best explained by the near maximal level of motor unit recruitment, the total daily time of activity and the tonic nature of the stimulation paradigm.
doi:10.1109/TNSRE.2010.2052832
PMCID: PMC3037113  PMID: 20813653
Functional electrical stimulation; muscle plasticity; spinal motoneurons
17.  Restoring Motor Functions in Paralyzed Limbs through Intraspinal Multielectrode Microstimulation Using Fuzzy Logic Control and Lag Compensator 
Basic and Clinical Neuroscience  2013;4(3):232-243.
In this paper, a control strategy is proposed for control of ankle movement on animals using intraspinal microstimulation (ISMS). The proposed method is based on fuzzy logic control. Fuzzy logic control is a methodology of intelligent control that mimics human decision making process. This type of control method can be very useful for the complex uncertain systems that their mathematical model is unknown. To increase the stability and speed of the system's response and reduce the steady-state error, we combine the FLC with a lead (lag) compensator. The experiments are conducted on five rats. Microelectrodes are implanted into the spinal cord to provide selective stimulation of plantarflexor and dorsiflexor. The results show that motor functions can be restored using ISMS. Despite the complexity of the spinal neuronal networks and simplicity of the proposed control strategy, our results show that the proposed strategy can provide acceptable tracking control with fast convergence.
PMCID: PMC4202566  PMID: 25337352
Functional Electrical Stimulation; Intraspinal Microstimulation; Fuzzy Logic Control; Motor Function
18.  Spinal primitives and intra-spinal micro-stimulation (ISMS) based prostheses: a neurobiological perspective on the “known unknowns” in ISMS and future prospects 
The current literature on Intra-Spinal Micro-Stimulation (ISMS) for motor prostheses is reviewed in light of neurobiological data on spinal organization, and a neurobiological perspective on output motor modularity, ISMS maps, stimulation combination effects, and stability. By comparing published data in these areas, the review identifies several gaps in current knowledge that are crucial to the development of effective intraspinal neuroprostheses. Gaps can be categorized into a lack of systematic and reproducible details of: (a) Topography and threshold for ISMS across the segmental motor system, the topography of autonomic recruitment by ISMS, and the coupling relations between these two types of outputs in practice. (b) Compositional rules for ISMS motor responses tested across the full range of the target spinal topographies. (c) Rules for ISMS effects' dependence on spinal cord state and neural dynamics during naturally elicited or ISMS triggered behaviors. (d) Plasticity of the compositional rules for ISMS motor responses, and understanding plasticity of ISMS topography in different spinal cord lesion states, disease states, and following rehabilitation. All these knowledge gaps to a greater or lesser extent require novel electrode technology in order to allow high density chronic recording and stimulation. The current lack of this technology may explain why these prominent gaps in the ISMS literature currently exist. It is also argued that given the “known unknowns” in the current ISMS literature, it may be prudent to adopt and develop control schemes that can manage the current results with simple superposition and winner-take-all interactions, but can also incorporate the possible plastic and stochastic dynamic interactions that may emerge in fuller analyses over longer terms, and which have already been noted in some simpler model systems.
doi:10.3389/fnins.2015.00072
PMCID: PMC4367173  PMID: 25852454
intraspinal microstimulation (ISMS); vector superposition; primitives; pattern generators; spinal motor maps
19.  Electronic bypass of spinal lesions: activation of lower motor neurons directly driven by cortical neural signals 
Background
Lower motor neurons in the spinal cord lose supraspinal inputs after complete spinal cord injury, leading to a loss of volitional control below the injury site. Extensive locomotor training with spinal cord stimulation can restore locomotion function after spinal cord injury in humans and animals. However, this locomotion is non-voluntary, meaning that subjects cannot control stimulation via their natural “intent”. A recent study demonstrated an advanced system that triggers a stimulator using forelimb stepping electromyographic patterns to restore quadrupedal walking in rats with spinal cord transection. However, this indirect source of “intent” may mean that other non-stepping forelimb activities may false-trigger the spinal stimulator and thus produce unwanted hindlimb movements.
Methods
We hypothesized that there are distinguishable neural activities in the primary motor cortex during treadmill walking, even after low-thoracic spinal transection in adult guinea pigs. We developed an electronic spinal bridge, called “Motolink”, which detects these neural patterns and triggers a “spinal” stimulator for hindlimb movement. This hardware can be head-mounted or carried in a backpack. Neural data were processed in real-time and transmitted to a computer for analysis by an embedded processor. Off-line neural spike analysis was conducted to calculate and preset the spike threshold for “Motolink” hardware.
Results
We identified correlated activities of primary motor cortex neurons during treadmill walking of guinea pigs with spinal cord transection. These neural activities were used to predict the kinematic states of the animals. The appropriate selection of spike threshold value enabled the “Motolink” system to detect the neural “intent” of walking, which triggered electrical stimulation of the spinal cord and induced stepping-like hindlimb movements.
Conclusion
We present a direct cortical “intent”-driven electronic spinal bridge to restore hindlimb locomotion after complete spinal cord injury.
doi:10.1186/1743-0003-11-107
PMCID: PMC4094416  PMID: 24990580
Spinal cord injury; Multielectrode array; Extracellular recording; Neural spikes; Functional electrical stimulation; Intraspinal microstimulation; Intracortical microstimulation; Locomotion; Neuromotor prostheses
20.  Thoracic Hemisection in Rats Results in Initial Recovery Followed by a Late Decrement in Locomotor Movements, with Changes in Coordination Correlated with Serotonergic Innervation of the Ventral Horn 
PLoS ONE  2015;10(11):e0143602.
Lateral thoracic hemisection of the rodent spinal cord is a popular model of spinal cord injury, in which the effects of various treatments, designed to encourage locomotor recovery, are tested. Nevertheless, there are still inconsistencies in the literature concerning the details of spontaneous locomotor recovery after such lesions, and there is a lack of data concerning the quality of locomotion over a long time span after the lesion. In this study, we aimed to address some of these issues. In our experiments, locomotor recovery was assessed using EMG and CatWalk recordings and analysis. Our results showed that after hemisection there was paralysis in both hindlimbs, followed by a substantial recovery of locomotor movements, but even at the peak of recovery, which occurred about 4 weeks after the lesion, some deficits of locomotion remained present. The parameters that were abnormal included abduction, interlimb coordination and speed of locomotion. Locomotor performance was stable for several weeks, but about 3–4 months after hemisection secondary locomotor impairment was observed with changes in parameters, such as speed of locomotion, interlimb coordination, base of hindlimb support, hindlimb abduction and relative foot print distance. Histological analysis of serotonergic innervation at the lumbar ventral horn below hemisection revealed a limited restoration of serotonergic fibers on the ipsilateral side of the spinal cord, while on the contralateral side of the spinal cord it returned to normal. In addition, the length of these fibers on both sides of the spinal cord correlated with inter- and intralimb coordination. In contrast to data reported in the literature, our results show there is not full locomotor recovery after spinal cord hemisection. Secondary deterioration of certain locomotor functions occurs with time in hemisected rats, and locomotor recovery appears partly associated with reinnervation of spinal circuitry by serotonergic fibers.
doi:10.1371/journal.pone.0143602
PMCID: PMC4659566  PMID: 26606275
21.  Large Animal Model for Development of Functional Restoration Paradigms Using Epidural and Intraspinal Stimulation 
PLoS ONE  2013;8(12):e81443.
Restoration of movement following spinal cord injury (SCI) has been achieved using electrical stimulation of peripheral nerves and skeletal muscles. However, practical limitations such as the rapid onset of muscle fatigue hinder clinical application of these technologies. Recently, direct stimulation of alpha motor neurons has shown promise for evoking graded, controlled, and sustained muscle contractions in rodent and feline animal models while overcoming some of these limitations. However, small animal models are not optimal for the development of clinical spinal stimulation techniques for functional restoration of movement. Furthermore, variance in surgical procedure, targeting, and electrode implantation techniques can compromise therapeutic outcomes and impede comparison of results across studies. Herein, we present a protocol and large animal model that allow standardized development, testing, and optimization of novel clinical strategies for restoring motor function following spinal cord injury. We tested this protocol using both epidural and intraspinal stimulation in a porcine model of spinal cord injury, but the protocol is suitable for the development of other novel therapeutic strategies. This protocol will help characterize spinal circuits vital for selective activation of motor neuron pools. In turn, this will expedite the development and validation of high-precision therapeutic targeting strategies and stimulation technologies for optimal restoration of motor function in humans.
doi:10.1371/journal.pone.0081443
PMCID: PMC3855281  PMID: 24339929
22.  Neuromodulation of lower limb motor control in restorative neurology 
Clinical Neurology and Neurosurgery  2012;114(5):489-497.
One consequence of central nervous system injury or disease is the impairment of neural control of movement, resulting in spasticity and paralysis. To enhance recovery, restorative neurology procedures modify altered, yet preserved nervous system function. This review focuses on functional electrical stimulation (FES) and spinal cord stimulation (SCS) that utilize remaining capabilities of the distal apparatus of spinal cord, peripheral nerves and muscles in upper motor neuron dysfunctions. FES for the immediate generation of lower limb movement along with current rehabilitative techniques is reviewed. The potential of SCS for controlling spinal spasticity and enhancing lower limb function in multiple sclerosis and spinal cord injury is discussed. The necessity for precise electrode placement and appropriate stimulation parameter settings to achieve therapeutic specificity is elaborated. This will lead to our human work of epidural and transcutaneous stimulation targeting the lumbar spinal cord for enhancing motor functions in spinal cord injured people, supplemented by pertinent human research of other investigators. We conclude that the concept of restorative neurology recently received new appreciation by accumulated evidence for locomotor circuits residing in the human spinal cord. Technological and clinical advancements need to follow for a major impact on the functional recovery in individuals with severe damage to their motor system.
doi:10.1016/j.clineuro.2012.03.013
PMCID: PMC3341569  PMID: 22464657
Functional electrical stimulation; Locomotion; Motor control; Multiple sclerosis; Neuromodulation; Restorative neurology; Spinal cord injury; Spinal cord stimulation
23.  Changes in Afferent Activity After Spinal Cord Injury 
Neurourology and urodynamics  2010;29(1):63-76.
Aims
To summarize the changes that occur in the properties of bladder afferent neurons following spinal cord injury.
Methods
Literature review of anatomical, immunohistochemical, and pharmacologic studies of normal and dysfunctional bladder afferent pathways.
Results
Studies in animals indicate that the micturition reflex is mediated by a spinobulbospinal pathway passing through coordination centers (periaqueductal gray and pontine micturition center) located in the rostral brain stem. This reflex pathway, which is activated by small myelinated (Aδ) bladder afferent nerves, is in turn modulated by higher centers in the cerebral cortex involved in the voluntary control of micturition. Spinal cord injury at cervical or thoracic levels disrupts voluntary voiding, as well as the normal reflex pathways that coordinate bladder and sphincter function. Following spinal cord injury, the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. The recovery of bladder function after spinal cord injury is dependent in part on the plasticity of bladder afferent pathways and the unmasking of reflexes triggered by unmyelinated, capsaicin-sensitive, C-fiber bladder afferent neurons. Plasticity is associated with morphologic, chemical, and electrical changes in bladder afferent neurons and appears to be mediated in part by neurotrophic factors released in the spinal cord and the peripheral target organs.
Conclusions
Spinal cord injury at sites remote from the lumbosacral spinal cord can indirectly influence properties of bladder afferent neurons by altering the function and chemical environment in the bladder or the spinal cord.
doi:10.1002/nau.20761
PMCID: PMC2891065  PMID: 20025033
afferent neurons; micturition; neuropeptides; neuroplasticity; neurotrophic factors; urinary bladder; voltage-gated ion channels
24.  A Mixed-Signal VLSI System for Producing Temporally Adapting Intraspinal Microstimulation Patterns for Locomotion 
Neural pathways can be artificially activated through the use of electrical stimulation. For individuals with a spinal cord injury, intraspinal microstimulation, using electrical currents on the order of 125 μA, can produce muscle contractions and joint torques in the lower extremities suitable for restoring walking. The work presented here demonstrates an integrated circuit implementing a state-based control strategy where sensory feedback and intrinsic feed forward control shape the stimulation waveforms produced on-chip. Fabricated in a 0.5 μm process, the device was successfully used in vivo to produce walking movements in a model of spinal cord injury. This work represents progress towards an implantable solution to be used for restoring walking in individuals with spinal cord injuries.
doi:10.1109/TBCAS.2015.2501419
PMCID: PMC4970939  PMID: 26978832
Central pattern generator (CPG); intraspinal microstimulation; locomotion; mixed signal VLSI; neural prostheses; neural stimulation
25.  Prediction of Bladder Outcomes after Traumatic Spinal Cord Injury: A Longitudinal Cohort Study 
PLoS Medicine  2016;13(6):e1002041.
Background
Neurogenic bladder dysfunction represents one of the most common and devastating sequelae of traumatic spinal cord injury (SCI). As early prediction of bladder outcomes is essential to counsel patients and to plan neurourological management, we aimed to develop and validate a model to predict urinary continence and complete bladder emptying 1 y after traumatic SCI.
Methods and Findings
Using multivariate logistic regression analysis from the data of 1,250 patients with traumatic SCI included in the European Multicenter Spinal Cord Injury study, we developed two prediction models of urinary continence and complete bladder emptying 1 y after traumatic SCI and performed an external validation in 111 patients. As predictors, we evaluated age, gender, and all variables of the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) and of the Spinal Cord Independence Measure (SCIM). Urinary continence and complete bladder emptying 1 y after SCI were assessed through item 6 of SCIM. The full model relies on lower extremity motor score (LEMS), light-touch sensation in the S3 dermatome of ISNCSI, and SCIM subscale respiration and sphincter management: the area under the receiver operating characteristics curve (aROC) was 0.936 (95% confidence interval [CI]: 0.922–0.951). The simplified model is based on LEMS only: the aROC was 0.912 (95% CI: 0.895–0.930). External validation of the full and simplified models confirmed the excellent predictive power: the aROCs were 0.965 (95% CI: 0.934–0.996) and 0.972 (95% CI 0.943–0.999), respectively. This study is limited by the substantial number of patients with a missing 1-y outcome and by differences between derivation and validation cohort.
Conclusions
Our study provides two simple and reliable models to predict urinary continence and complete bladder emptying 1 y after traumatic SCI. Early prediction of bladder function might optimize counselling and patient-tailored rehabilitative interventions and improve patient stratification in future clinical trials.
Thomas Kessler and colleagues identify and validate two models to predict urinary continence and complete bladder emptying one year after traumatic spinal cord injury.
Author Summary
Why Was This Study Done?
Neurogenic bladder dysfunction is one of the most common and devastating sequelae of traumatic spinal cord injury.
Recovery of bladder function represents an absolute priority for individuals affected by spinal cord injury, and it is often considered to be more important than recovery of ambulation.
There is a valid rule to predict locomotion and upper limb function in patients with spinal cord injury, but no similar tool for bladder function is available.
What Did the Researchers Do and Find?
Based on data from 1,250 patients with traumatic spinal cord injury included in the European Multicenter Spinal Cord Injury (www.emsci.org) study, we derived two simple and reliable models to predict urinary continence and complete bladder emptying 1 y after traumatic spinal cord injury.
Our models have been validated in an independent cohort of 111 patients with traumatic spinal cord injury.
What Do These Findings Mean?
Our models allow early prediction of bladder outcome after traumatic spinal cord injury, which is crucial to counsel patients, to set rehabilitative goals, and to orient patient-tailored interventions.
Our models could help promptly identifying patients who are not likely to have favourable bladder outcomes despite standard therapies and who could benefit more from investigational therapies.
Our models may improve patient stratification in future clinical trials assessing treatments for bladder dysfunction in patients with traumatic spinal cord injury.
doi:10.1371/journal.pmed.1002041
PMCID: PMC4915662  PMID: 27327967

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