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Sample records for motor vehicle-related spinal

  1. Motor Vehicle Related Child Deaths: A Plea for Action.

    ERIC Educational Resources Information Center

    Toledo, Jose R.; And Others

    This paper reviews the literature concerning motor related child deaths, emphasizes that automobile related incidents are the major cause of death in children below 14 and over 1 year of age, and provides suggestions about what pediatricians can do to reduce highway fatalities among children. Special attention is given to investigations of the use…

  2. Role of commercial drivers in motor vehicle related injuries in Ghana

    PubMed Central

    Mock, C.; Amegashie, J.; Darteh, K.

    1999-01-01

    Introduction—In many low income countries, commercial vehicles are the major source of motorized transport. Drivers of such vehicles may be an important focus for road safety efforts. Aims—An estimation of the percentage of motor vehicle related injuries that involved commercial vehicles in Ghana was sought. The knowledge, attitude, and practices of commercial drivers with regards to road safety was then evaluated. Methods—A community based survey was carried out, involving 21 105 persons. As well, focus group discussions were held with 30 commercial drivers. Results—In the survey, 122 motor vehicle related injuries were reported for the preceding year. The majority (81%) of these involved commercial vehicles, principally buses (40%) and taxis (24%). The involvement of commercial vehicles was the same for both motor vehicle crashes (81%) and pedestrian injuries (82%). However, motor vehicle related injuries in children were especially likely to involve commercial vehicles (95%), in comparison with adults (79%). The focus groups indicated that commercial drivers had a good general attitude towards road safety. Most believed that actions could be taken that would lower the risk of crashes and injuries, including vision examinations, using seat belts, and avoiding alcohol. However, this knowledge was not fully implemented. For example, few drivers had ever had their vision checked and most used seat belts only for long journeys. Conclusions—In Ghana, commercial drivers are an important group to target in road safety programs. They are also a potentially useful group to include in building coalitions to implement such road safety measures. PMID:10628914

  3. 41 CFR 102-34.320 - What Government-issued charge cards may I use to purchase fuel and motor vehicle related services?

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... charge cards may I use to purchase fuel and motor vehicle related services? 102-34.320 Section 102-34.320....320 What Government-issued charge cards may I use to purchase fuel and motor vehicle related services? (a) You may use a fleet charge card specifically issued for this purpose. These cards are designed...

  4. 41 CFR 102-34.320 - What Government-issued charge cards may I use to purchase fuel and motor vehicle related services?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... charge cards may I use to purchase fuel and motor vehicle related services? 102-34.320 Section 102-34.320....320 What Government-issued charge cards may I use to purchase fuel and motor vehicle related services? (a) You may use a fleet charge card specifically issued for this purpose. These cards are designed...

  5. 41 CFR 102-34.320 - What Government-issued charge cards may I use to purchase fuel and motor vehicle related services?

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... charge cards may I use to purchase fuel and motor vehicle related services? 102-34.320 Section 102-34.320....320 What Government-issued charge cards may I use to purchase fuel and motor vehicle related services? (a) You may use a fleet charge card specifically issued for this purpose. These cards are designed...

  6. Motor vehicle related injuries among American Indian and Alaskan Native youth, 1981–92: analysis of a national hospital discharge database

    PubMed Central

    Quinlan, K.; Wallace, L; Furner, S.; Brewer, R.; Bolen, J.; Schieber, R.

    1998-01-01

    Objective—To describe national trends in hospitalizations for motor vehicle related injuries among children and youth (0–24 years) of the United States Indian Health Service (IHS) from 1981–92. Design—Descriptive epidemiologic study of the E coded national hospital discharge database of the IHS. Results—From 1981 to 1992, the age standardized annual incidence of motor vehicle related injury hospitalizations (per 100 000 population) among American Indian and Alaskan Native (AI/AN) youth decreased more than 65% from 269 to 93. Substantial declines in hospitalization rates for all age and sex groups, all IHS areas, and most injury types were seen over this time. Injuries to vehicle occupants accounted for 78% of all motor vehicle related injury hospitalizations. The annual incidence of hospitalization (per 100 000 population) ranged from 291 in the Billings (Wyoming/Montana) and Aberdeen (the Dakotas) areas to 38 in the Portland area (Pacific Northwest). Conclusions—National motor vehicle related injury hospitalization rates of AI/AN children and youth decreased significantly from 1981–92. This may be due to a reduction in the incidence of severe motor vehicle related trauma, changing patterns of medical practice, and changes in the use of services. Additional measures, such as passage and enforcement of tribal laws requiring the use of occupant restraints and stronger laws to prevent alcohol impaired driving, might further reduce the incidence of serious motor vehicle related injuries in this high risk population. PMID:9887418

  7. Spinal metaplasticity in respiratory motor control

    PubMed Central

    Fields, Daryl P.; Mitchell, Gordon S.

    2015-01-01

    A hallmark feature of the neural system controlling breathing is its ability to exhibit plasticity. Less appreciated is the ability to exhibit metaplasticity, a change in the capacity to express plasticity (i.e., “plastic plasticity”). Recent advances in our understanding of cellular mechanisms giving rise to respiratory motor plasticity lay the groundwork for (ongoing) investigations of metaplasticity. This detailed understanding of respiratory metaplasticity will be essential as we harness metaplasticity to restore breathing capacity in clinical disorders that compromise breathing, such as cervical spinal injury, motor neuron disease and other neuromuscular diseases. In this brief review, we discuss key examples of metaplasticity in respiratory motor control, and our current understanding of mechanisms giving rise to spinal plasticity and metaplasticity in phrenic motor output; particularly after pre-conditioning with intermittent hypoxia. Progress in this area has led to the realization that similar mechanisms are operative in other spinal motor networks, including those governing limb movement. Further, these mechanisms can be harnessed to restore respiratory and non-respiratory motor function after spinal injury. PMID:25717292

  8. Reducing Motor Vehicle-Related Injuries at an Arizona Indian Reservation: Ten Years of Application of Evidence-Based Strategies.

    PubMed

    Piontkowski, Stephen R; Peabody, Jon S; Reede, Christine; Velascosoltero, José; Tsatoke, Gordon; Shelhamer, Timothy; Hicks, Kenny R

    2015-12-01

    Unintentional injury is a significant public health burden for American Indians and Alaska Natives and was the leading cause of death among those aged 1 to 44 years between 1999 and 2004. Of those deaths, motor vehicle-related deaths cause the most mortality, justifying the need for intervention at an American Indian Reservation in Arizona (United States). We describe motor vehicle injury prevention program operations from 2004 through 2013. This community-based approach led by a multidisciplinary team primarily comprised of environmental public health and law enforcement personnel implemented evidence-based strategies to reduce the impact of motor vehicle-related injuries and deaths, focusing on reducing impaired driving and increasing occupant restraint use. Strategies included: mass media campaigns to enhance awareness and outreach; high-visibility sobriety checkpoints; passing and enforcing 0.08% blood alcohol concentration limits for drivers and primary occupant restraint laws; and child car seat distribution and education. Routine monitoring and evaluation data showed a significant 5% to 7% annual reduction of motor vehicle crashes (MVCs), nighttime MVCs, MVCs with injuries/fatalities, and nighttime MVCs with injuries/fatalities between 2004 and 2013, but the annual percent change in arrests for driving under the influence (DUI) was not significant. There was also a 144% increase in driver/front seat passenger seat belt use, from 19% in 2011 before the primary occupant restraint law was enacted to 47% during the first full year of enforcement (2013). Car seat checkpoint data also suggested a 160% increase in car seat use, from less than 20% to 52% in 2013. Implementation of evidence-based strategies in injury prevention, along with employment of key program approaches such as strong partnership building, community engagement, and consistent staffing and funding, can narrow the public health disparity gap experienced among American Indian and Alaska Native

  9. Reducing Motor Vehicle-Related Injuries at an Arizona Indian Reservation: Ten Years of Application of Evidence-Based Strategies

    PubMed Central

    Piontkowski, Stephen R; Peabody, Jon S; Reede, Christine; Velascosoltero, José; Tsatoke, Gordon; Shelhamer, Timothy; Hicks, Kenny R

    2015-01-01

    Unintentional injury is a significant public health burden for American Indians and Alaska Natives and was the leading cause of death among those aged 1 to 44 years between 1999 and 2004. Of those deaths, motor vehicle-related deaths cause the most mortality, justifying the need for intervention at an American Indian Reservation in Arizona (United States). We describe motor vehicle injury prevention program operations from 2004 through 2013. This community-based approach led by a multidisciplinary team primarily comprised of environmental public health and law enforcement personnel implemented evidence-based strategies to reduce the impact of motor vehicle-related injuries and deaths, focusing on reducing impaired driving and increasing occupant restraint use. Strategies included: mass media campaigns to enhance awareness and outreach; high-visibility sobriety checkpoints; passing and enforcing 0.08% blood alcohol concentration limits for drivers and primary occupant restraint laws; and child car seat distribution and education. Routine monitoring and evaluation data showed a significant 5% to 7% annual reduction of motor vehicle crashes (MVCs), nighttime MVCs, MVCs with injuries/fatalities, and nighttime MVCs with injuries/fatalities between 2004 and 2013, but the annual percent change in arrests for driving under the influence (DUI) was not significant. There was also a 144% increase in driver/front seat passenger seat belt use, from 19% in 2011 before the primary occupant restraint law was enacted to 47% during the first full year of enforcement (2013). Car seat checkpoint data also suggested a 160% increase in car seat use, from less than 20% to 52% in 2013. Implementation of evidence-based strategies in injury prevention, along with employment of key program approaches such as strong partnership building, community engagement, and consistent staffing and funding, can narrow the public health disparity gap experienced among American Indian and Alaska Native

  10. Reducing Motor Vehicle-Related Injuries at an Arizona Indian Reservation: Ten Years of Application of Evidence-Based Strategies.

    PubMed

    Piontkowski, Stephen R; Peabody, Jon S; Reede, Christine; Velascosoltero, José; Tsatoke, Gordon; Shelhamer, Timothy; Hicks, Kenny R

    2015-12-01

    Unintentional injury is a significant public health burden for American Indians and Alaska Natives and was the leading cause of death among those aged 1 to 44 years between 1999 and 2004. Of those deaths, motor vehicle-related deaths cause the most mortality, justifying the need for intervention at an American Indian Reservation in Arizona (United States). We describe motor vehicle injury prevention program operations from 2004 through 2013. This community-based approach led by a multidisciplinary team primarily comprised of environmental public health and law enforcement personnel implemented evidence-based strategies to reduce the impact of motor vehicle-related injuries and deaths, focusing on reducing impaired driving and increasing occupant restraint use. Strategies included: mass media campaigns to enhance awareness and outreach; high-visibility sobriety checkpoints; passing and enforcing 0.08% blood alcohol concentration limits for drivers and primary occupant restraint laws; and child car seat distribution and education. Routine monitoring and evaluation data showed a significant 5% to 7% annual reduction of motor vehicle crashes (MVCs), nighttime MVCs, MVCs with injuries/fatalities, and nighttime MVCs with injuries/fatalities between 2004 and 2013, but the annual percent change in arrests for driving under the influence (DUI) was not significant. There was also a 144% increase in driver/front seat passenger seat belt use, from 19% in 2011 before the primary occupant restraint law was enacted to 47% during the first full year of enforcement (2013). Car seat checkpoint data also suggested a 160% increase in car seat use, from less than 20% to 52% in 2013. Implementation of evidence-based strategies in injury prevention, along with employment of key program approaches such as strong partnership building, community engagement, and consistent staffing and funding, can narrow the public health disparity gap experienced among American Indian and Alaska Native

  11. Fictive motor patterns in chronic spinal cats.

    PubMed

    Pearson, K G; Rossignol, S

    1991-12-01

    1. Fictive motor patterns were recorded in hind leg nerves of 10 adult chronic spinal cats (spinalized at T13). Four of these animals had been trained to step with their hind legs on a treadmill (late-spinal animals), whereas the remainder received no training and were examined a short time after spinalization (early-spinal animals). 2. A fictive pattern resembling the locomotor pattern for stepping was evoked in all animals in response to stimulation of the skin of the perineal region. (2-[2,6-Dichloroaniline]-2-imidazoline) hydrochloride (Clonidine) at doses ranging from 100 to 500 micrograms/kg iv facilitated the production of this pattern, particularly in early-spinal animals. 3. The fictive locomotor pattern in late-spinal animals was more complex than that occurring in early-spinal animals. In the latter the pattern consisted of an alternation of activity in flexor and extensor nerves, and changing leg position did not qualitatively alter the pattern, whereas in late-spinal animals the relative durations of the bursts in different flexors were usually not the same, and the pattern of flexor activity was dependent on leg position. 4. Moving the legs from extension to flexion progressively decreased the duration of flexor bursts, increased the cycle period, and decreased the ease with which the pattern could be evoked in both early- and late-spinal animals. 5. 1-beta-3,4-Dihydroxyphenylalanine (DOPA)/Isonocotinic acid 2-[(2-benzylcarbamoyl)ethyl]hydrazide (Nialamide) treatment following Clonidine in early-spinal animals increased the complexity of flexor burst activity. This, and other observations, indicates that DOPA and Clonidine do not have strictly identical actions on the locomotor pattern generator. 6. Stimulation of the paws in late-spinal animals produced two patterns of activity distinctly different from the locomotor pattern. of activity distinctly different from the locomotor pattern. One was a short sequence of high-frequency rhythmic activity (at

  12. Descending motor pathways and the spinal motor system - Limbic and non-limbic components

    NASA Technical Reports Server (NTRS)

    Holstege, Gert

    1991-01-01

    Research on descending motor pathways to caudal brainstem and spinal cord in the spinal motor system is reviewed. Particular attention is given to somatic and autonomic motoneurons in the spinal cord and brainstem, local projections to motoneurons, bulbospinal interneurons projecting to motoneurons, descending pathways of somatic motor control systems, and descending pathways involved in limbic motor control systems.

  13. Chlorpheniramine produces spinal motor, proprioceptive and nociceptive blockades in rats.

    PubMed

    Tzeng, Jann-Inn; Lin, Heng-Teng; Chen, Yu-Wen; Hung, Ching-Hsia; Wang, Jhi-Joung

    2015-04-01

    This study aimed to assess the local anesthetic effects of chlorpheniramine in spinal anesthesia and is compared with mepivacaine, a widely-used local anesthetic. Spinal anesthesia with chlorpheniramine and mepivacaine was constructed in a dosage-dependent fashion after the rats were injected intrathecally. The spinal block effect of chlorpheniramine in motor function, nociception, and proprioception was compared to that of mepivacaine. We revealed that intrathecal chlorpheniramine and mepivacaine exhibited a dose-dependent spinal block of motor function, nociception, and proprioception. On the 50% effective dose (ED50) basis, the ranks of potencies in motor function, nociception, and proprioception were chlorpheniramine>mepivacaine (P<0.01 for the differences). On the equianesthetic basis (ED25, ED50, ED75), the duration of spinal anesthesia with chlorpheniramine was greater than that of mepivacaine (P<0.01 for the differences). Instead of mepivacaine, chlorpheniramine produced a greater duration of sensory blockade than the motor blockade. These preclinical data showed that chlorpheniramine has a better sensory-selective action over motor block to produce more potent and long-lasting spinal anesthesia than mepivacaine.

  14. Pleiotrophin is a neurotrophic factor for spinal motor neurons.

    PubMed

    Mi, Ruifa; Chen, Weiran; Höke, Ahmet

    2007-03-13

    Regeneration in the peripheral nervous system is poor after chronic denervation. Denervated Schwann cells act as a "transient target" by secreting growth factors to promote regeneration of axons but lose this ability with chronic denervation. We discovered that the mRNA for pleiotrophin (PTN) was highly up-regulated in acutely denervated distal sciatic nerves, but high levels of PTN mRNA were not maintained in chronically denervated nerves. PTN protected spinal motor neurons against chronic excitotoxic injury and caused increased outgrowth of motor axons out of the spinal cord explants and formation of "miniventral rootlets." In neonatal mice, PTN protected the facial motor neurons against cell death induced by deprivation from target-derived growth factors. Similarly, PTN significantly enhanced regeneration of myelinated axons across a graft in the transected sciatic nerve of adult rats. Our findings suggest a neurotrophic role for PTN that may lead to previously unrecognized treatment options for motor neuron disease and motor axonal regeneration.

  15. Motor neurons and the generation of spinal motor neuron diversity

    PubMed Central

    Stifani, Nicolas

    2014-01-01

    Motor neurons (MNs) are neuronal cells located in the central nervous system (CNS) controlling a variety of downstream targets. This function infers the existence of MN subtypes matching the identity of the targets they innervate. To illustrate the mechanism involved in the generation of cellular diversity and the acquisition of specific identity, this review will focus on spinal MNs (SpMNs) that have been the core of significant work and discoveries during the last decades. SpMNs are responsible for the contraction of effector muscles in the periphery. Humans possess more than 500 different skeletal muscles capable to work in a precise time and space coordination to generate complex movements such as walking or grasping. To ensure such refined coordination, SpMNs must retain the identity of the muscle they innervate. Within the last two decades, scientists around the world have produced considerable efforts to elucidate several critical steps of SpMNs differentiation. During development, SpMNs emerge from dividing progenitor cells located in the medial portion of the ventral neural tube. MN identities are established by patterning cues working in cooperation with intrinsic sets of transcription factors. As the embryo develop, MNs further differentiate in a stepwise manner to form compact anatomical groups termed pools connecting to a unique muscle target. MN pools are not homogeneous and comprise subtypes according to the muscle fibers they innervate. This article aims to provide a global view of MN classification as well as an up-to-date review of the molecular mechanisms involved in the generation of SpMN diversity. Remaining conundrums will be discussed since a complete understanding of those mechanisms constitutes the foundation required for the elaboration of prospective MN regeneration therapies. PMID:25346659

  16. Ubiquity of motor networks in the spinal cord of vertebrates.

    PubMed

    Cazalets, J R; Bertrand, S

    2000-11-15

    In a recent paper, we found that it is possible to record motor activity in sacral segments in the in vitro neonatal rat spinal cord preparation. This motor activity recorded in segments that are not innervating hindlimbs is driven by the lumbar locomotor network. Indeed, compartimentalizations of the cord with Vaseline walls or section experiments, reveals that the sacral segments possess their own rhythmogenic capabilities but that in an intact spinal cord they are driven by the lumbar locomotor network. In this review, these recent findings are placed in the context of spinal motor network interactions. As previously suspected, the motor networks do not operate in isolation but interact with each other according to behavioural needs. These interactions provide some insight into the discrepancies observed in several studies dealing with the localization of the lumbar locomotor network in the neonatal rat spinal cord. In conclusion, the spinal cord of quadrupeds appears as an heterogeneous structure where it is possible to identify neuronal networks that are crucial for the genesis of locomotor-related activities. PMID:11165798

  17. Iterative Role of Notch Signaling in Spinal Motor Neuron Diversification.

    PubMed

    Tan, G Christopher; Mazzoni, Esteban O; Wichterle, Hynek

    2016-07-26

    The motor neuron progenitor domain in the ventral spinal cord gives rise to multiple subtypes of motor neurons and glial cells. Here, we examine whether progenitors found in this domain are multipotent and which signals contribute to their cell-type-specific differentiation. Using an in vitro neural differentiation model, we demonstrate that motor neuron progenitor differentiation is iteratively controlled by Notch signaling. First, Notch controls the timing of motor neuron genesis by repressing Neurogenin 2 (Ngn2) and maintaining Olig2-positive progenitors in a proliferative state. Second, in an Ngn2-independent manner, Notch contributes to the specification of median versus hypaxial motor column identity and lateral versus medial divisional identity of limb-innervating motor neurons. Thus, motor neuron progenitors are multipotent, and their diversification is controlled by Notch signaling that iteratively increases cellular diversity arising from a single neural progenitor domain. PMID:27425621

  18. Experience-dependent development of spinal motor neurons

    NASA Technical Reports Server (NTRS)

    Inglis, F. M.; Zuckerman, K. E.; Kalb, R. G.; Walton, K. D. (Principal Investigator)

    2000-01-01

    Locomotor activity in many species undergoes pronounced alterations in early postnatal life, and environmental cues may be responsible for modifying this process. To determine how these events are reflected in the nervous system, we studied rats reared under two different conditions-the presence or absence of gravity-in which the performance of motor operations differed. We found a significant effect of rearing environment on the size and complexity of dendritic architecture of spinal motor neurons, particularly those that are likely to participate in postural control. These results provide evidence that neurons subserving motor function undergo activity-dependent maturation in early postnatal life in a manner analogous to sensory systems.

  19. Changes in spinal reflex excitability associated with motor sequence learning.

    PubMed

    Lungu, Ovidiu; Frigon, Alain; Piché, Mathieu; Rainville, Pierre; Rossignol, Serge; Doyon, Julien

    2010-05-01

    There is ample evidence that motor sequence learning is mediated by changes in brain activity. Yet the question of whether this form of learning elicits changes detectable at the spinal cord level has not been addressed. To date, studies in humans have revealed that spinal reflex activity may be altered during the acquisition of various motor skills, but a link between motor sequence learning and changes in spinal excitability has not been demonstrated. To address this issue, we studied the modulation of H-reflex amplitude evoked in the flexor carpi radialis muscle of 14 healthy individuals between blocks of movements that involved the implicit acquisition of a sequence versus other movements that did not require learning. Each participant performed the task in three conditions: "sequence"-externally triggered, repeating and sequential movements, "random"-similar movements, but performed in an arbitrary order, and "simple"- involving alternating movements in a left-right or up-down direction only. When controlling for background muscular activity, H-reflex amplitude was significantly more reduced in the sequence (43.8 +/- 1.47%. mean +/- SE) compared with the random (38.2 +/- 1.60%) and simple (31.5 +/- 1.82%) conditions, while the M-response was not different across conditions. Furthermore, H-reflex changes were observed from the beginning of the learning process up to when subjects reached asymptotic performance on the motor task. Changes also persisted for >60 s after motor activity ceased. Such findings suggest that the excitability in some spinal reflex circuits is altered during the implicit learning process of a new motor sequence.

  20. Respiratory chain deficiency in aged spinal motor neurons☆

    PubMed Central

    Rygiel, Karolina A.; Grady, John P.; Turnbull, Doug M.

    2014-01-01

    Sarcopenia, muscle wasting, and strength decline with age, is an important cause of loss of mobility in the elderly individuals. The underlying mechanisms are uncertain but likely to involve defects of motor nerve, neuromuscular junction, and muscle. Loss of motor neurons with age and subsequent denervation of skeletal muscle has been recognized as one of the contributing factors. This study investigated aspects of mitochondrial biology in spinal motor neurons from elderly subjects. We found that protein components of complex I of mitochondrial respiratory chain were reduced or absent in a proportion of aged motor neurons–a phenomenon not observed in fetal tissue. Further investigation showed that complex I-deficient cells had reduced mitochondrial DNA content and smaller soma size. We propose that mitochondrial dysfunction in these motor neurons could lead to the cell loss and ultimately denervation of muscle fibers. PMID:24684792

  1. Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy.

    PubMed

    Martinez, Tara L; Kong, Lingling; Wang, Xueyong; Osborne, Melissa A; Crowder, Melissa E; Van Meerbeke, James P; Xu, Xixi; Davis, Crystal; Wooley, Joe; Goldhamer, David J; Lutz, Cathleen M; Rich, Mark M; Sumner, Charlotte J

    2012-06-20

    The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power.

  2. Dynamic Characteristic Analysis of Spinal Motor Control Between 11- and 15-Year-Old Children.

    PubMed

    Chow, Daniel H; Lau, Newman M

    2016-07-01

    Spinal motor control can provide substantial insight for the causes of spinal musculoskeletal disorders. Its dynamic characteristics however, have not been fully investigated. The objective of this study is to explore the dynamic characteristics of spinal motor control via the fractional Brownian motion mathematical technique. Spinal curvatures and repositioning errors of different spinal regions in 64 children age 11- or 15-years old during upright stance were measured and compared for the effects of age and gender. With the application of the fractional Brownian motion analytical technique to the changes of spinal curvatures, distinct persistent movement behaviors could be determined, which could be interpreted physiologically as open-loop behaviors. Moreover, it was found that the spinal motor control of 15-year-old children was better than that of 11-year-old children with smaller repositioning error and less curvature variability as well as shorter response time and smaller curvature deformation.

  3. Serotonin Promotes Development and Regeneration of Spinal Motor Neurons in Zebrafish.

    PubMed

    Barreiro-Iglesias, Antón; Mysiak, Karolina S; Scott, Angela L; Reimer, Michell M; Yang, Yujie; Becker, Catherina G; Becker, Thomas

    2015-11-01

    In contrast to mammals, zebrafish regenerate spinal motor neurons. During regeneration, developmental signals are re-deployed. Here, we show that, during development, diffuse serotonin promotes spinal motor neuron generation from pMN progenitor cells, leaving interneuron numbers unchanged. Pharmacological manipulations and receptor knockdown indicate that serotonin acts at least in part via 5-HT1A receptors. In adults, serotonin is supplied to the spinal cord mainly (90%) by descending axons from the brain. After a spinal lesion, serotonergic axons degenerate caudal to the lesion but sprout rostral to it. Toxin-mediated ablation of serotonergic axons also rostral to the lesion impaired regeneration of motor neurons only there. Conversely, intraperitoneal serotonin injections doubled numbers of new motor neurons and proliferating pMN-like progenitors caudal to the lesion. Regeneration of spinal-intrinsic serotonergic interneurons was unaltered by these manipulations. Hence, serotonin selectively promotes the development and adult regeneration of motor neurons in zebrafish.

  4. Serotonin Promotes Development and Regeneration of Spinal Motor Neurons in Zebrafish

    PubMed Central

    Barreiro-Iglesias, Antón; Mysiak, Karolina S.; Scott, Angela L.; Reimer, Michell M.; Yang (杨宇婕), Yujie; Becker, Catherina G.; Becker, Thomas

    2015-01-01

    Summary In contrast to mammals, zebrafish regenerate spinal motor neurons. During regeneration, developmental signals are re-deployed. Here, we show that, during development, diffuse serotonin promotes spinal motor neuron generation from pMN progenitor cells, leaving interneuron numbers unchanged. Pharmacological manipulations and receptor knockdown indicate that serotonin acts at least in part via 5-HT1A receptors. In adults, serotonin is supplied to the spinal cord mainly (90%) by descending axons from the brain. After a spinal lesion, serotonergic axons degenerate caudal to the lesion but sprout rostral to it. Toxin-mediated ablation of serotonergic axons also rostral to the lesion impaired regeneration of motor neurons only there. Conversely, intraperitoneal serotonin injections doubled numbers of new motor neurons and proliferating pMN-like progenitors caudal to the lesion. Regeneration of spinal-intrinsic serotonergic interneurons was unaltered by these manipulations. Hence, serotonin selectively promotes the development and adult regeneration of motor neurons in zebrafish. PMID:26565906

  5. Basic fibroblast growth factor attenuates the degeneration of injured spinal cord motor endplates

    PubMed Central

    Wang, Jianlong; Sun, Jianfeng; Tang, Yongxiang; Guo, Gangwen; Zhou, Xiaozhe; Chen, Yanliang; Shen, Minren

    2013-01-01

    The distal end of the spinal cord and neuromuscular junction may develop secondary degeneration and damage following spinal cord injury because of the loss of neural connections. In this study, a rat model of spinal cord injury, established using a modified Allen's method, was injected with basic fibroblast growth factor solution via subarachnoid catheter. After injection, rats with spinal cord injury displayed higher scores on the Basso, Beattie and Bresnahan locomotor scale. Motor function was also well recovered and hematoxylin-eosin staining showed that spinal glial scar hyperplasia was not apparent. Additionally, anterior tibial muscle fibers slowly, but progressively, atrophied. nohistochemical staining showed that the absorbance values of calcitonin gene related peptide and acetylcholinesterase in anterior tibial muscle and spinal cord were similar, and injection of basic broblast growth factor increased this absorbance. Results showed that after spinal cord injury, the distal motor neurons and motor endplate degenerated. Changes in calcitonin gene related peptide and acetylcholinesterase in the spinal cord anterior horn motor neurons and motor endplate then occurred that were consistent with this regeneration. Our findings indicate that basic fibroblast growth factor can protect the endplate through attenuating the decreased expression of calcitonin gene related peptide and acetylcholinesterase in anterior horn motor neurons of the injured spinal cord. PMID:25206531

  6. Therapy induces widespread reorganization of motor cortex after complete spinal transection that supports motor recovery.

    PubMed

    Ganzer, Patrick D; Manohar, Anitha; Shumsky, Jed S; Moxon, Karen A

    2016-05-01

    Reorganization of the somatosensory system and its relationship to functional recovery after spinal cord injury (SCI) has been well studied. However, little is known about the impact of SCI on organization of the motor system. Recent studies suggest that step-training paradigms in combination with spinal stimulation, either electrically or through pharmacology, are more effective than step training alone at inducing recovery and that reorganization of descending corticospinal circuits is necessary. However, simpler, passive exercise combined with pharmacotherapy has also shown functional improvement after SCI and reorganization of, at least, the sensory cortex. In this study we assessed the effect of passive exercise and serotonergic (5-HT) pharmacological therapies on behavioral recovery and organization of the motor cortex. We compared the effects of passive hindlimb bike exercise to bike exercise combined with daily injections of 5-HT agonists in a rat model of complete mid-thoracic transection. 5-HT pharmacotherapy combined with bike exercise allowed the animals to achieve unassisted weight support in the open field. This combination of therapies also produced extensive expansion of the axial trunk motor cortex into the deafferented hindlimb motor cortex and, surprisingly, reorganization within the caudal and even the rostral forelimb motor cortex areas. The extent of the axial trunk expansion was correlated to improvement in behavioral recovery of hindlimbs during open field locomotion, including weight support. From a translational perspective, these data suggest a rationale for developing and optimizing cost-effective, non-invasive, pharmacological and passive exercise regimes to promote plasticity that supports restoration of movement after spinal cord injury. PMID:26826448

  7. Therapy induces widespread reorganization of motor cortex after complete spinal transection that supports motor recovery.

    PubMed

    Ganzer, Patrick D; Manohar, Anitha; Shumsky, Jed S; Moxon, Karen A

    2016-05-01

    Reorganization of the somatosensory system and its relationship to functional recovery after spinal cord injury (SCI) has been well studied. However, little is known about the impact of SCI on organization of the motor system. Recent studies suggest that step-training paradigms in combination with spinal stimulation, either electrically or through pharmacology, are more effective than step training alone at inducing recovery and that reorganization of descending corticospinal circuits is necessary. However, simpler, passive exercise combined with pharmacotherapy has also shown functional improvement after SCI and reorganization of, at least, the sensory cortex. In this study we assessed the effect of passive exercise and serotonergic (5-HT) pharmacological therapies on behavioral recovery and organization of the motor cortex. We compared the effects of passive hindlimb bike exercise to bike exercise combined with daily injections of 5-HT agonists in a rat model of complete mid-thoracic transection. 5-HT pharmacotherapy combined with bike exercise allowed the animals to achieve unassisted weight support in the open field. This combination of therapies also produced extensive expansion of the axial trunk motor cortex into the deafferented hindlimb motor cortex and, surprisingly, reorganization within the caudal and even the rostral forelimb motor cortex areas. The extent of the axial trunk expansion was correlated to improvement in behavioral recovery of hindlimbs during open field locomotion, including weight support. From a translational perspective, these data suggest a rationale for developing and optimizing cost-effective, non-invasive, pharmacological and passive exercise regimes to promote plasticity that supports restoration of movement after spinal cord injury.

  8. Human spinal cord injury: motor unit properties and behaviour.

    PubMed

    Thomas, C K; Bakels, R; Klein, C S; Zijdewind, I

    2014-01-01

    Spinal cord injury (SCI) results in widespread variation in muscle function. Review of motor unit data shows that changes in the amount and balance of excitatory and inhibitory inputs after SCI alter management of motoneurons. Not only are units recruited up to higher than usual relative forces when SCI leaves few units under voluntary control, the force contribution from recruitment increases due to elevation of twitch/tetanic force ratios. Force gradation and precision are also coarser with reduced unit numbers. Maximal unit firing rates are low in hand muscles, limiting voluntary strength, but are low, normal or high in limb muscles. Unit firing rates during spasms can exceed voluntary rates, emphasizing that deficits in descending drive limit force production. SCI also changes muscle properties. Motor unit weakness and fatigability seem universal across muscles and species, increasing the muscle weakness that arises from paralysis of units, motoneuron death and sensory impairment. Motor axon conduction velocity decreases after human SCI. Muscle contractile speed is also reduced, which lowers the stimulation frequencies needed to grade force when paralysed muscles are activated with patterned electrical stimulation. This slowing does not necessarily occur in hind limb muscles after cord transection in cats and rats. The nature, duration and level of SCI underlie some of these species differences, as do variations in muscle function, daily usage, tract control and fibre-type composition. Exploring this diversity is important to promote recovery of the hand, bowel, bladder and locomotor function most wanted by people with SCI. PMID:23901835

  9. Motor-circuit communication matrix from spinal cord to brainstem neurons revealed by developmental origin.

    PubMed

    Pivetta, Chiara; Esposito, Maria Soledad; Sigrist, Markus; Arber, Silvia

    2014-01-30

    Accurate motor-task execution relies on continuous comparison of planned and performed actions. Motor-output pathways establish internal circuit collaterals for this purpose. Here we focus on motor collateral organization between spinal cord and upstream neurons in the brainstem. We used a newly developed mouse genetic tool intersectionally with viruses to uncover the connectivity rules of these ascending pathways by capturing the transient expression of neuronal subpopulation determinants. We reveal a widespread and diverse network of spinal dual-axon neurons, with coincident input to forelimb motor neurons and the lateral reticular nucleus (LRN) in the brainstem. Spinal information to the LRN is not segregated by motor pool or neurotransmitter identity. Instead, it is organized according to the developmental domain origin of the progenitor cells. Thus, excerpts of most spinal information destined for action are relayed to supraspinal centers through exquisitely organized ascending connectivity modules, enabling precise communication between command and execution centers of movement.

  10. Rebuilding motor function of the spinal cord based on functional electrical stimulation

    PubMed Central

    Shen, Xiao-yan; Du, Wei; Huang, Wei; Chen, Yi

    2016-01-01

    Rebuilding the damaged motor function caused by spinal cord injury is one of the most serious challenges in clinical neuroscience. The function of the neural pathway under the damaged sites can be rebuilt using functional electrical stimulation technology. In this study, the locations of motor function sites in the lumbosacral spinal cord were determined with functional electrical stimulation technology. A three-dimensional map of the lumbosacral spinal cord comprising the relationship between the motor function sites and the corresponding muscle was drawn. Based on the individual experimental parameters and normalized coordinates of the motor function sites, the motor function sites that control a certain muscle were calculated. Phasing pulse sequences were delivered to the determined motor function sites in the spinal cord and hip extension, hip flexion, ankle plantarflexion, and ankle dorsiflexion movements were successfully achieved. The results show that the map of the spinal cord motor function sites was valid. This map can provide guidance for the selection of electrical stimulation sites during the rebuilding of motor function after spinal cord injury.

  11. Rebuilding motor function of the spinal cord based on functional electrical stimulation.

    PubMed

    Shen, Xiao-Yan; Du, Wei; Huang, Wei; Chen, Yi

    2016-08-01

    Rebuilding the damaged motor function caused by spinal cord injury is one of the most serious challenges in clinical neuroscience. The function of the neural pathway under the damaged sites can be rebuilt using functional electrical stimulation technology. In this study, the locations of motor function sites in the lumbosacral spinal cord were determined with functional electrical stimulation technology. A three-dimensional map of the lumbosacral spinal cord comprising the relationship between the motor function sites and the corresponding muscle was drawn. Based on the individual experimental parameters and normalized coordinates of the motor function sites, the motor function sites that control a certain muscle were calculated. Phasing pulse sequences were delivered to the determined motor function sites in the spinal cord and hip extension, hip flexion, ankle plantarflexion, and ankle dorsiflexion movements were successfully achieved. The results show that the map of the spinal cord motor function sites was valid. This map can provide guidance for the selection of electrical stimulation sites during the rebuilding of motor function after spinal cord injury. PMID:27651782

  12. Rebuilding motor function of the spinal cord based on functional electrical stimulation.

    PubMed

    Shen, Xiao-Yan; Du, Wei; Huang, Wei; Chen, Yi

    2016-08-01

    Rebuilding the damaged motor function caused by spinal cord injury is one of the most serious challenges in clinical neuroscience. The function of the neural pathway under the damaged sites can be rebuilt using functional electrical stimulation technology. In this study, the locations of motor function sites in the lumbosacral spinal cord were determined with functional electrical stimulation technology. A three-dimensional map of the lumbosacral spinal cord comprising the relationship between the motor function sites and the corresponding muscle was drawn. Based on the individual experimental parameters and normalized coordinates of the motor function sites, the motor function sites that control a certain muscle were calculated. Phasing pulse sequences were delivered to the determined motor function sites in the spinal cord and hip extension, hip flexion, ankle plantarflexion, and ankle dorsiflexion movements were successfully achieved. The results show that the map of the spinal cord motor function sites was valid. This map can provide guidance for the selection of electrical stimulation sites during the rebuilding of motor function after spinal cord injury.

  13. Rebuilding motor function of the spinal cord based on functional electrical stimulation

    PubMed Central

    Shen, Xiao-yan; Du, Wei; Huang, Wei; Chen, Yi

    2016-01-01

    Rebuilding the damaged motor function caused by spinal cord injury is one of the most serious challenges in clinical neuroscience. The function of the neural pathway under the damaged sites can be rebuilt using functional electrical stimulation technology. In this study, the locations of motor function sites in the lumbosacral spinal cord were determined with functional electrical stimulation technology. A three-dimensional map of the lumbosacral spinal cord comprising the relationship between the motor function sites and the corresponding muscle was drawn. Based on the individual experimental parameters and normalized coordinates of the motor function sites, the motor function sites that control a certain muscle were calculated. Phasing pulse sequences were delivered to the determined motor function sites in the spinal cord and hip extension, hip flexion, ankle plantarflexion, and ankle dorsiflexion movements were successfully achieved. The results show that the map of the spinal cord motor function sites was valid. This map can provide guidance for the selection of electrical stimulation sites during the rebuilding of motor function after spinal cord injury. PMID:27651782

  14. High yield extraction of pure spinal motor neurons, astrocytes and microglia from single embryo and adult mouse spinal cord

    PubMed Central

    Beaudet, Marie-Josée; Yang, Qiurui; Cadau, Sébastien; Blais, Mathieu; Bellenfant, Sabrina; Gros-Louis, François; Berthod, François

    2015-01-01

    Extraction of mouse spinal motor neurons from transgenic mouse embryos recapitulating some aspects of neurodegenerative diseases like amyotrophic lateral sclerosis has met with limited success. Furthermore, extraction and long-term culture of adult mouse spinal motor neurons and glia remain also challenging. We present here a protocol designed to extract and purify high yields of motor neurons and glia from individual spinal cords collected on embryos and adult (5-month-old) normal or transgenic mice. This method is based on mild digestion of tissue followed by gradient density separation allowing to obtain two millions motor neurons over 92% pure from one E14.5 single embryo and more than 30,000 from an adult mouse. These cells can be cultured more than 14 days in vitro at a density of 100,000 cells/cm2 to maintain optimal viability. Functional astrocytes and microglia and small gamma motor neurons can be purified at the same time. This protocol will be a powerful and reliable method to obtain motor neurons and glia to better understand mechanisms underlying spinal cord diseases. PMID:26577180

  15. Augmentation of Voluntary Locomotor Activity by Transcutaneous Spinal Cord Stimulation in Motor-Incomplete Spinal Cord-Injured Individuals.

    PubMed

    Hofstoetter, Ursula S; Krenn, Matthias; Danner, Simon M; Hofer, Christian; Kern, Helmut; McKay, William B; Mayr, Winfried; Minassian, Karen

    2015-10-01

    The level of sustainable excitability within lumbar spinal cord circuitries is one of the factors determining the functional outcome of locomotor therapy after motor-incomplete spinal cord injury. Here, we present initial data using noninvasive transcutaneous lumbar spinal cord stimulation (tSCS) to modulate this central state of excitability during voluntary treadmill stepping in three motor-incomplete spinal cord-injured individuals. Stimulation was applied at 30 Hz with an intensity that generated tingling sensations in the lower limb dermatomes, yet without producing muscle reflex activity. This stimulation changed muscle activation, gait kinematics, and the amount of manual assistance required from the therapists to maintain stepping with some interindividual differences. The effect on motor outputs during treadmill-stepping was essentially augmentative and step-phase dependent despite the invariant tonic stimulation. The most consistent modification was found in the gait kinematics, with the hip flexion during swing increased by 11.3° ± 5.6° across all subjects. This preliminary work suggests that tSCS provides for a background increase in activation of the lumbar spinal locomotor circuitry that has partially lost its descending drive. Voluntary inputs and step-related feedback build upon the stimulation-induced increased state of excitability in the generation of locomotor activity. Thus, tSCS essentially works as an electrical neuroprosthesis augmenting remaining motor control.

  16. Cerebral activation is correlated to regional atrophy of the spinal cord and functional motor disability in spinal cord injured individuals.

    PubMed

    Lundell, H; Christensen, M S; Barthélemy, D; Willerslev-Olsen, M; Biering-Sørensen, F; Nielsen, J B

    2011-01-15

    Recovery of function following lesions in the nervous system requires adaptive changes in surviving circuitries. Here we investigate whether changes in cerebral activation are correlated to spinal cord atrophy and recovery of functionality in individuals with incomplete spinal cord injury (SCI). 19 chronic SCI individuals and 7 age-comparable controls underwent functional magnetic resonance imaging (fMRI) while performing rhythmic dorsiflexion of the ankle. A significant negative correlation was found between the activation in the ipsilateral motor (M1) and bilateral premotor cortex (PMC) on one hand and the functional ability of the SCI participants measured by the clinical motor score on the other. There was no significant correlation between activation in any other cerebral area and the motor score. Activation in ipsilateral somatosensory cortex (S1), M1 and PMC was negatively correlated to the width of the spinal cord in the left-right direction, where the corticospinal tract is located, but not in the antero-posterior direction. There was a tendency for a negative correlation between cerebral activation in ipsilateral S1, M1 and PMC and the amplitude of motor evoked potentials in the tibialis anterior muscle elicited by transcranial magnetic stimulation, but this did not reach statistical significance. There was no correlation between motor score or spinal cord dimensions and the volume of the cortical motor areas. The observations show that lesion of descending tracts in the lateral part of the spinal cord results in increased activation in ipsilateral motor and sensory areas, which may help to compensate for the functional deficit following SCI. PMID:20851198

  17. Targeted, activity-dependent spinal stimulation produces long-lasting motor recovery in chronic cervical spinal cord injury

    PubMed Central

    McPherson, Jacob G.; Miller, Robert R.; Perlmutter, Steve I.

    2015-01-01

    Use-dependent movement therapies can lead to partial recovery of motor function after neurological injury. We attempted to improve recovery by developing a neuroprosthetic intervention that enhances movement therapy by directing spike timing-dependent plasticity in spared motor pathways. Using a recurrent neural–computer interface in rats with a cervical contusion of the spinal cord, we synchronized intraspinal microstimulation below the injury with the arrival of functionally related volitional motor commands signaled by muscle activity in the impaired forelimb. Stimulation was delivered during physical retraining of a forelimb behavior and throughout the day for 3 mo. Rats receiving this targeted, activity-dependent spinal stimulation (TADSS) exhibited markedly enhanced recovery compared with animals receiving targeted but open-loop spinal stimulation and rats receiving physical retraining alone. On a forelimb reach and grasp task, TADSS animals recovered 63% of their preinjury ability, more than two times the performance level achieved by the other therapy groups. Therapeutic gains were maintained for 3 additional wk without stimulation. The results suggest that activity-dependent spinal stimulation can induce neural plasticity that improves behavioral recovery after spinal cord injury. PMID:26371306

  18. Targeted, activity-dependent spinal stimulation produces long-lasting motor recovery in chronic cervical spinal cord injury.

    PubMed

    McPherson, Jacob G; Miller, Robert R; Perlmutter, Steve I

    2015-09-29

    Use-dependent movement therapies can lead to partial recovery of motor function after neurological injury. We attempted to improve recovery by developing a neuroprosthetic intervention that enhances movement therapy by directing spike timing-dependent plasticity in spared motor pathways. Using a recurrent neural-computer interface in rats with a cervical contusion of the spinal cord, we synchronized intraspinal microstimulation below the injury with the arrival of functionally related volitional motor commands signaled by muscle activity in the impaired forelimb. Stimulation was delivered during physical retraining of a forelimb behavior and throughout the day for 3 mo. Rats receiving this targeted, activity-dependent spinal stimulation (TADSS) exhibited markedly enhanced recovery compared with animals receiving targeted but open-loop spinal stimulation and rats receiving physical retraining alone. On a forelimb reach and grasp task, TADSS animals recovered 63% of their preinjury ability, more than two times the performance level achieved by the other therapy groups. Therapeutic gains were maintained for 3 additional wk without stimulation. The results suggest that activity-dependent spinal stimulation can induce neural plasticity that improves behavioral recovery after spinal cord injury. PMID:26371306

  19. Spinal motor outputs during step-to-step transitions of diverse human gaits.

    PubMed

    La Scaleia, Valentina; Ivanenko, Yuri P; Zelik, Karl E; Lacquaniti, Francesco

    2014-01-01

    Aspects of human motor control can be inferred from the coordination of muscles during movement. For instance, by combining multimuscle electromyographic (EMG) recordings with human neuroanatomy, it is possible to estimate alpha-motoneuron (MN) pool activations along the spinal cord. It has previously been shown that the spinal motor output fluctuates with the body's center-of-mass motion, with bursts of activity around foot-strike and foot lift-off during walking. However, it is not known whether these MN bursts are generalizable to other ambulation tasks, nor is it clear if the spatial locus of the activity (along the rostrocaudal axis of the spinal cord) is fixed or variable. Here we sought to address these questions by investigating the spatiotemporal characteristics of the spinal motor output during various tasks: walking forward, backward, tiptoe and uphill. We reconstructed spinal maps from 26 leg muscle EMGs, including some intrinsic foot muscles. We discovered that the various walking tasks shared qualitative similarities in their temporal spinal activation profiles, exhibiting peaks around foot-strike and foot-lift. However, we also observed differences in the segmental level and intensity of spinal activations, particularly following foot-strike. For example, forward level-ground walking exhibited a mean motor output roughly 2 times lower than the other gaits. Finally, we found that the reconstruction of the spinal motor output from multimuscle EMG recordings was relatively insensitive to the subset of muscles analyzed. In summary, our results suggested temporal similarities, but spatial differences in the segmental spinal motor outputs during the step-to-step transitions of disparate walking behaviors.

  20. Effects of limb exercise after spinal cord injury on motor neuron dendrite structure.

    PubMed

    Gazula, Valeswara-Rao; Roberts, Melinda; Luzzio, Christopher; Jawad, Abbas F; Kalb, Robert Gordon

    2004-08-16

    An integration center subserving locomotor leg movements resides in the upper lumbar spinal cord. If this neuronal network is preserved after a spinal cord injury, it is possible to stimulate this circuitry to initiate and promote walking. The several effective approaches (electrical stimulation, pharmacologic agents, physical therapy training programs) may all share a common modus operandi of altering synaptic activity within segmental spinal cord. To understand the neural substrate for the use-dependent behavioral improvement, we studied the dendritic architecture of spinal motor neurons. In the first experiment, we compared three groups of animals: animals with an intact spinal cord, animals that had a complete spinal cord transection (SCT) and animals with SCT who engaged in a daily exercise program of actively moving paralyzed hindlimbs through the motions of walking. When compared with animals with an intact spinal cord, the motor neurons from animals with SCT displayed marked atrophy, with loss of dendritic membrane and elimination of branching throughout the visible tree within transverse tissue slices. None of these regressive changes were found in the motor neurons from SCT animals that underwent exercise. In a second experiment, we inquired whether exercise of animals with an intact spinal cord influenced dendrite structure. Increased exercise had very modest effects on dendrite morphology, indicating an upper limit of use-dependent dendrite growth. Our findings suggest that the dendritic tree of motor neurons deprived of descending influences is rapidly pruned, and this finding is not observed in motor neurons after SCT if hindlimbs are exercised. The functional benefits of exercise after SCT injury may be subserved, in part, by stabilizing or remodeling the dendritic tree of motor neurons below the injury site.

  1. Targeting Motor End Plates for Delivery of Adenoviruses: An Approach to Maximize Uptake and Transduction of Spinal Cord Motor Neurons.

    PubMed

    Tosolini, Andrew Paul; Morris, Renée

    2016-01-01

    Gene therapy can take advantage of the skeletal muscles/motor neurons anatomical relationship to restrict gene expression to the spinal cord ventral horn. Furthermore, recombinant adenoviruses are attractive viral-vectors as they permit spatial and temporal modulation of transgene expression. In the literature, however, several inconsistencies exist with regard to the intramuscular delivery parameters of adenoviruses. The present study is an evaluation of the optimal injection sites on skeletal muscle, time course of expression and mice's age for maximum transgene expression in motor neurons. Targeting motor end plates yielded a 2.5-fold increase in the number of transduced motor neurons compared to injections performed away from this region. Peak adenoviral transgene expression in motor neurons was detected after seven days. Further, greater numbers of transduced motor neurons were found in juvenile (3-7 week old) mice as compared with adults (8+ weeks old). Adenoviral injections produced robust transgene expression in motor neurons and skeletal myofibres. In addition, dendrites of transduced motor neurons were shown to extend well into the white matter where the descending motor pathways are located. These results also provide evidence that intramuscular delivery of adenovirus can be a suitable gene therapy approach to treat spinal cord injury. PMID:27619631

  2. Targeting Motor End Plates for Delivery of Adenoviruses: An Approach to Maximize Uptake and Transduction of Spinal Cord Motor Neurons

    PubMed Central

    Tosolini, Andrew Paul; Morris, Renée

    2016-01-01

    Gene therapy can take advantage of the skeletal muscles/motor neurons anatomical relationship to restrict gene expression to the spinal cord ventral horn. Furthermore, recombinant adenoviruses are attractive viral-vectors as they permit spatial and temporal modulation of transgene expression. In the literature, however, several inconsistencies exist with regard to the intramuscular delivery parameters of adenoviruses. The present study is an evaluation of the optimal injection sites on skeletal muscle, time course of expression and mice’s age for maximum transgene expression in motor neurons. Targeting motor end plates yielded a 2.5-fold increase in the number of transduced motor neurons compared to injections performed away from this region. Peak adenoviral transgene expression in motor neurons was detected after seven days. Further, greater numbers of transduced motor neurons were found in juvenile (3–7 week old) mice as compared with adults (8+ weeks old). Adenoviral injections produced robust transgene expression in motor neurons and skeletal myofibres. In addition, dendrites of transduced motor neurons were shown to extend well into the white matter where the descending motor pathways are located. These results also provide evidence that intramuscular delivery of adenovirus can be a suitable gene therapy approach to treat spinal cord injury. PMID:27619631

  3. Simultaneous Brain–Cervical Cord fMRI Reveals Intrinsic Spinal Cord Plasticity during Motor Sequence Learning

    PubMed Central

    Cohen-Adad, Julien; Marchand-Pauvert, Veronique; Benali, Habib; Doyon, Julien

    2015-01-01

    The spinal cord participates in the execution of skilled movements by translating high-level cerebral motor representations into musculotopic commands. Yet, the extent to which motor skill acquisition relies on intrinsic spinal cord processes remains unknown. To date, attempts to address this question were limited by difficulties in separating spinal local effects from supraspinal influences through traditional electrophysiological and neuroimaging methods. Here, for the first time, we provide evidence for local learning-induced plasticity in intact human spinal cord through simultaneous functional magnetic resonance imaging of the brain and spinal cord during motor sequence learning. Specifically, we show learning-related modulation of activity in the C6–C8 spinal region, which is independent from that of related supraspinal sensorimotor structures. Moreover, a brain–spinal cord functional connectivity analysis demonstrates that the initial linear relationship between the spinal cord and sensorimotor cortex gradually fades away over the course of motor sequence learning, while the connectivity between spinal activity and cerebellum gains strength. These data suggest that the spinal cord not only constitutes an active functional component of the human motor learning network but also contributes distinctively from the brain to the learning process. The present findings open new avenues for rehabilitation of patients with spinal cord injuries, as they demonstrate that this part of the central nervous system is much more plastic than assumed before. Yet, the neurophysiological mechanisms underlying this intrinsic functional plasticity in the spinal cord warrant further investigations. PMID:26125597

  4. Simultaneous Brain-Cervical Cord fMRI Reveals Intrinsic Spinal Cord Plasticity during Motor Sequence Learning.

    PubMed

    Vahdat, Shahabeddin; Lungu, Ovidiu; Cohen-Adad, Julien; Marchand-Pauvert, Veronique; Benali, Habib; Doyon, Julien

    2015-06-01

    The spinal cord participates in the execution of skilled movements by translating high-level cerebral motor representations into musculotopic commands. Yet, the extent to which motor skill acquisition relies on intrinsic spinal cord processes remains unknown. To date, attempts to address this question were limited by difficulties in separating spinal local effects from supraspinal influences through traditional electrophysiological and neuroimaging methods. Here, for the first time, we provide evidence for local learning-induced plasticity in intact human spinal cord through simultaneous functional magnetic resonance imaging of the brain and spinal cord during motor sequence learning. Specifically, we show learning-related modulation of activity in the C6-C8 spinal region, which is independent from that of related supraspinal sensorimotor structures. Moreover, a brain-spinal cord functional connectivity analysis demonstrates that the initial linear relationship between the spinal cord and sensorimotor cortex gradually fades away over the course of motor sequence learning, while the connectivity between spinal activity and cerebellum gains strength. These data suggest that the spinal cord not only constitutes an active functional component of the human motor learning network but also contributes distinctively from the brain to the learning process. The present findings open new avenues for rehabilitation of patients with spinal cord injuries, as they demonstrate that this part of the central nervous system is much more plastic than assumed before. Yet, the neurophysiological mechanisms underlying this intrinsic functional plasticity in the spinal cord warrant further investigations.

  5. The organization of spinal motor neurons in a monotreme is consistent with a six-region schema of the mammalian spinal cord.

    PubMed

    Mitchelle, Amer; Watson, Charles

    2016-09-01

    The motor neurons in the spinal cord of an echidna (Tachyglossus aculeatus) have been mapped in Nissl-stained sections from spinal cord segments defined by spinal nerve anatomy. A medial motor column of motor neurons is found at all spinal cord levels, and a hypaxial column is found at most levels. The organization of the motor neuron clusters in the lateral motor column of the brachial (C5 to T3) and crural (L2 to S3) limb enlargements is very similar to the pattern previously revealed by retrograde tracing in placental mammals, and the motor neuron clusters have been tentatively identified according to the muscle groups they are likely to supply. The region separating the two limb enlargements (T4 to L1) contains preganglionic motor neurons that appear to represent the spinal sympathetic outflow. Immediately caudal to the crural limb enlargement is a short column of preganglionic motor neurons (S3 to S4), which it is believed represents the pelvic parasympathetic outflow. The rostral and caudal ends of the spinal cord contain neither a lateral motor column nor a preganglionic column. Branchial motor neurons (which are believed to supply the sternomastoid and trapezius muscles) are present at the lateral margin of the ventral horn in rostral cervical segments (C2-C4). These same segments contain the phrenic nucleus, which belongs to the hypaxial column. The presence or absence of the main spinal motor neuron columns in the different regions echidna spinal cord (and also in that of other amniote vertebrates) provides a basis for dividing the spinal cord into six main regions - prebrachial, brachial, postbrachial, crural, postcrural and caudal. The considerable biological and functional significance of this subdivision pattern is supported by recent studies on spinal cord hox gene expression in chicks and mice. On the other hand, the familiar 'segments' of the spinal cord are defined only by the anatomy of adjacent vertebrae, and are not demarcated by intrinsic gene

  6. The organization of spinal motor neurons in a monotreme is consistent with a six-region schema of the mammalian spinal cord.

    PubMed

    Mitchelle, Amer; Watson, Charles

    2016-09-01

    The motor neurons in the spinal cord of an echidna (Tachyglossus aculeatus) have been mapped in Nissl-stained sections from spinal cord segments defined by spinal nerve anatomy. A medial motor column of motor neurons is found at all spinal cord levels, and a hypaxial column is found at most levels. The organization of the motor neuron clusters in the lateral motor column of the brachial (C5 to T3) and crural (L2 to S3) limb enlargements is very similar to the pattern previously revealed by retrograde tracing in placental mammals, and the motor neuron clusters have been tentatively identified according to the muscle groups they are likely to supply. The region separating the two limb enlargements (T4 to L1) contains preganglionic motor neurons that appear to represent the spinal sympathetic outflow. Immediately caudal to the crural limb enlargement is a short column of preganglionic motor neurons (S3 to S4), which it is believed represents the pelvic parasympathetic outflow. The rostral and caudal ends of the spinal cord contain neither a lateral motor column nor a preganglionic column. Branchial motor neurons (which are believed to supply the sternomastoid and trapezius muscles) are present at the lateral margin of the ventral horn in rostral cervical segments (C2-C4). These same segments contain the phrenic nucleus, which belongs to the hypaxial column. The presence or absence of the main spinal motor neuron columns in the different regions echidna spinal cord (and also in that of other amniote vertebrates) provides a basis for dividing the spinal cord into six main regions - prebrachial, brachial, postbrachial, crural, postcrural and caudal. The considerable biological and functional significance of this subdivision pattern is supported by recent studies on spinal cord hox gene expression in chicks and mice. On the other hand, the familiar 'segments' of the spinal cord are defined only by the anatomy of adjacent vertebrae, and are not demarcated by intrinsic gene

  7. Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury.

    PubMed

    Wenger, Nikolaus; Moraud, Eduardo Martin; Gandar, Jerome; Musienko, Pavel; Capogrosso, Marco; Baud, Laetitia; Le Goff, Camille G; Barraud, Quentin; Pavlova, Natalia; Dominici, Nadia; Minev, Ivan R; Asboth, Leonie; Hirsch, Arthur; Duis, Simone; Kreider, Julie; Mortera, Andrea; Haverbeck, Oliver; Kraus, Silvio; Schmitz, Felix; DiGiovanna, Jack; van den Brand, Rubia; Bloch, Jocelyne; Detemple, Peter; Lacour, Stéphanie P; Bézard, Erwan; Micera, Silvestro; Courtine, Grégoire

    2016-02-01

    Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limited the therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here we developed stimulation protocols that reproduce the natural dynamics of motoneuron activation during locomotion. For this, we computed the spatiotemporal activation pattern of muscle synergies during locomotion in healthy rats. Computer simulations identified optimal electrode locations to target each synergy through the recruitment of proprioceptive feedback circuits. This framework steered the design of spatially selective spinal implants and real-time control software that modulate extensor and flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight-bearing capacity, endurance and skilled locomotion in several rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans. PMID:26779815

  8. Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury.

    PubMed

    Wenger, Nikolaus; Moraud, Eduardo Martin; Gandar, Jerome; Musienko, Pavel; Capogrosso, Marco; Baud, Laetitia; Le Goff, Camille G; Barraud, Quentin; Pavlova, Natalia; Dominici, Nadia; Minev, Ivan R; Asboth, Leonie; Hirsch, Arthur; Duis, Simone; Kreider, Julie; Mortera, Andrea; Haverbeck, Oliver; Kraus, Silvio; Schmitz, Felix; DiGiovanna, Jack; van den Brand, Rubia; Bloch, Jocelyne; Detemple, Peter; Lacour, Stéphanie P; Bézard, Erwan; Micera, Silvestro; Courtine, Grégoire

    2016-02-01

    Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limited the therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here we developed stimulation protocols that reproduce the natural dynamics of motoneuron activation during locomotion. For this, we computed the spatiotemporal activation pattern of muscle synergies during locomotion in healthy rats. Computer simulations identified optimal electrode locations to target each synergy through the recruitment of proprioceptive feedback circuits. This framework steered the design of spatially selective spinal implants and real-time control software that modulate extensor and flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight-bearing capacity, endurance and skilled locomotion in several rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans.

  9. Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury

    PubMed Central

    Wenger, Nikolaus; Moraud, Eduardo Martin; Gandar, Jerome; Musienko, Pavel; Capogrosso, Marco; Baud, Laetitia; Le Goff, Camille G.; Barraud, Quentin; Pavlova, Natalia; Dominici, Nadia; Minev, Ivan R.; Asboth, Leonie; Hirsch, Arthur; Duis, Simone; Kreider, Julie; Mortera, Andrea; Haverbeck, Oliver; Kraus, Silvio; Schmitz, Felix; DiGiovanna, Jack; van den Brand, Rubia; Bloch, Jocelyne; Detemple, Peter; Lacour, Stéphanie P.; Bézard, Erwan; Micera, Silvestro; Courtine, Grégoire

    2016-01-01

    Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limited this therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here, we developed novel stimulation protocols that reproduce the natural dynamics of motoneuron activation during locomotion. For this, we computed the spatiotemporal activation pattern of muscle synergies during locomotion in healthy rats. Computer simulations identified optimal electrode locations to target each synergy through the recruitment of proprioceptive feedback circuits. This framework steered the design of spatially selective spinal implants and real–time control software that modulate extensor versus flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight–bearing capacities, endurance and skilled locomotion in multiple rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans. PMID:26779815

  10. A Review on Locomotor Training after Spinal Cord Injury: Reorganization of Spinal Neuronal Circuits and Recovery of Motor Function

    PubMed Central

    2016-01-01

    Locomotor training is a classic rehabilitation approach utilized with the aim of improving sensorimotor function and walking ability in people with spinal cord injury (SCI). Recent studies have provided strong evidence that locomotor training of persons with clinically complete, motor complete, or motor incomplete SCI induces functional reorganization of spinal neuronal networks at multisegmental levels at rest and during assisted stepping. This neuronal reorganization coincides with improvements in motor function and decreased muscle cocontractions. In this review, we will discuss the manner in which spinal neuronal circuits are impaired and the evidence surrounding plasticity of neuronal activity after locomotor training in people with SCI. We conclude that we need to better understand the physiological changes underlying locomotor training, use physiological signals to probe recovery over the course of training, and utilize established and contemporary interventions simultaneously in larger scale research studies. Furthermore, the focus of our research questions needs to change from feasibility and efficacy to the following: what are the physiological mechanisms that make it work and for whom? The aforementioned will enable the scientific and clinical community to develop more effective rehabilitation protocols maximizing sensorimotor function recovery in people with SCI. PMID:27293901

  11. A Review on Locomotor Training after Spinal Cord Injury: Reorganization of Spinal Neuronal Circuits and Recovery of Motor Function.

    PubMed

    Smith, Andrew C; Knikou, Maria

    2016-01-01

    Locomotor training is a classic rehabilitation approach utilized with the aim of improving sensorimotor function and walking ability in people with spinal cord injury (SCI). Recent studies have provided strong evidence that locomotor training of persons with clinically complete, motor complete, or motor incomplete SCI induces functional reorganization of spinal neuronal networks at multisegmental levels at rest and during assisted stepping. This neuronal reorganization coincides with improvements in motor function and decreased muscle cocontractions. In this review, we will discuss the manner in which spinal neuronal circuits are impaired and the evidence surrounding plasticity of neuronal activity after locomotor training in people with SCI. We conclude that we need to better understand the physiological changes underlying locomotor training, use physiological signals to probe recovery over the course of training, and utilize established and contemporary interventions simultaneously in larger scale research studies. Furthermore, the focus of our research questions needs to change from feasibility and efficacy to the following: what are the physiological mechanisms that make it work and for whom? The aforementioned will enable the scientific and clinical community to develop more effective rehabilitation protocols maximizing sensorimotor function recovery in people with SCI. PMID:27293901

  12. Cellular dissection of the spinal cord motor column by BAC transgenesis and gene trapping in zebrafish.

    PubMed

    Asakawa, Kazuhide; Abe, Gembu; Kawakami, Koichi

    2013-01-01

    Bacterial artificial chromosome (BAC) transgenesis and gene/enhancer trapping are effective approaches for identification of genetically defined neuronal populations in the central nervous system (CNS). Here, we applied these techniques to zebrafish (Danio rerio) in order to obtain insights into the cellular architecture of the axial motor column in vertebrates. First, by using the BAC for the Mnx class homeodomain protein gene mnr2b/mnx2b, we established the mnGFF7 transgenic line expressing the Gal4FF transcriptional activator in a large part of the motor column. Single cell labeling of Gal4FF-expressing cells in the mnGFF7 line enabled a detailed investigation of the morphological characteristics of individual spinal motoneurons, as well as the overall organization of the motor column in a spinal segment. Secondly, from a large-scale gene trap screen, we identified transgenic lines that marked discrete subpopulations of spinal motoneurons with Gal4FF. Molecular characterization of these lines led to the identification of the ADAMTS3 gene, which encodes an evolutionarily conserved ADAMTS family of peptidases and is dynamically expressed in the ventral spinal cord. The transgenic fish established here, along with the identified gene, should facilitate an understanding of the cellular and molecular architecture of the spinal cord motor column and its connection to muscles in vertebrates.

  13. Memantine elicits spinal blockades of motor function, proprioception, and nociception in rats.

    PubMed

    Chen, Yu-Wen; Chiu, Chong-Chi; Liu, Kuo-Sheng; Hung, Ching-Hsia; Wang, Jhi-Joung

    2015-12-01

    Although memantine blocks sodium currents and produces local skin anesthesia, spinal anesthesia with memantine is unknown. The purpose of the study was to evaluate the local anesthetic effect of memantine in spinal anesthesia and its comparison with a widely used local anesthetic lidocaine. After intrathecally injecting the rats with five doses of each drug, the dose-response curves of memantine and lidocaine were constructed. The potencies of the drugs and durations of spinal anesthetic effects on motor function, proprioception, and nociception were compared with those of lidocaine. We showed that memantine produced dose-dependent spinal blockades in motor function, proprioception, and nociception. On a 50% effective dose (ED50 ) basis, the rank of potency was lidocaine greater than memantine (P < 0.05 for the differences). At the equipotent doses (ED25 , ED50 , ED75 ), the block duration produced by memantine was longer than that produced by lidocaine (P < 0.05 for the differences). Memantine, but not lidocaine, displayed more sensory/nociceptive block than motor block. The preclinical data demonstrated that memantine is less potent than lidocaine, whereas memantine produces longer duration of spinal anesthesia than lidocaine. Memantine shows a more sensory-selective action over motor blockade. PMID:26301611

  14. Memantine elicits spinal blockades of motor function, proprioception, and nociception in rats.

    PubMed

    Chen, Yu-Wen; Chiu, Chong-Chi; Liu, Kuo-Sheng; Hung, Ching-Hsia; Wang, Jhi-Joung

    2015-12-01

    Although memantine blocks sodium currents and produces local skin anesthesia, spinal anesthesia with memantine is unknown. The purpose of the study was to evaluate the local anesthetic effect of memantine in spinal anesthesia and its comparison with a widely used local anesthetic lidocaine. After intrathecally injecting the rats with five doses of each drug, the dose-response curves of memantine and lidocaine were constructed. The potencies of the drugs and durations of spinal anesthetic effects on motor function, proprioception, and nociception were compared with those of lidocaine. We showed that memantine produced dose-dependent spinal blockades in motor function, proprioception, and nociception. On a 50% effective dose (ED50 ) basis, the rank of potency was lidocaine greater than memantine (P < 0.05 for the differences). At the equipotent doses (ED25 , ED50 , ED75 ), the block duration produced by memantine was longer than that produced by lidocaine (P < 0.05 for the differences). Memantine, but not lidocaine, displayed more sensory/nociceptive block than motor block. The preclinical data demonstrated that memantine is less potent than lidocaine, whereas memantine produces longer duration of spinal anesthesia than lidocaine. Memantine shows a more sensory-selective action over motor blockade.

  15. [Spinal circuit motor plasticity mechanisms in long-term sports activity adaptation].

    PubMed

    Andriianova, E Iu; Lanskaia, O V

    2014-01-01

    Man interacts with the environment through motor activities getting considerable sensor information from numerous internal and external sources. There is significant evidence of I-a afferents sensor information being critical in initiating of functional and morphological transformations in the periods of both development and maturation of cortex and spinal cord. Ia fibers ability to transmit sensor information, generated by muscle and motor activities, causes plastic changes in the central nervous system, enabling man to acquire new skills and movements and develop them. Therefore, understanding of activity-dependent neural plasticity mechanisms is of great importance in developing methods to perfect motor function, for example, in doing sports. This article presents the results of investigation of activity-dependent changes in spinal cord circuits in athletes. There are new data of cervical and lumbosacral motor spinal system plasticity as a result of various longterm sports activities. It is shown, in particular, that, in comparison with non-athletes, in the spinal cord of ski-racers and basketball-players the representation area of upper and lower extremities muscles alpha-motorneurons with high reflex excitability is extended. Moreover,.the direction of the extension was specified by the upper segments activity. Besides, the volume of some revealed signs of cervical and lumbosacral spinal cord plasticity in the ski-racers, involved into moderate cyclic activity, was higher than that in the basketball-players, whose movements are more various.

  16. Spinal motor neuron migration and the significance of topographic organization in the nervous system.

    PubMed

    Kania, Artur

    2014-01-01

    The nervous system displays a high degree of topographic organisation such that neuronal soma position is closely correlated to axonal trajectory. One example of such order is the myotopic organisation of the motor system where spinal motor neuron position parallels that of target muscles. This chapter will discuss the molecular mechanisms underlying motor neuron soma positioning, which include transcriptional control of Reelin signaling and cadherin expression. As the same transcription factors have been shown to control motor axon innervation of target muscles, a simple mechanism of topographic organisation specification is becoming evident raising the question of how coordinating soma position with axon trajectory might be important for nervous system wiring and its function.

  17. An Optogenetic Demonstration of Motor Modularity in the Mammalian Spinal Cord

    PubMed Central

    Caggiano, Vittorio; Cheung, Vincent C. K.; Bizzi, Emilio

    2016-01-01

    Motor modules are neural entities hypothesized to be building blocks of movement construction. How motor modules are underpinned by neural circuits has remained obscured. As a first step towards dissecting these circuits, we optogenetically evoked motor outputs from the lumbosacral spinal cord of two strains of transgenic mice – the Chat, with channelrhodopsin (ChR2) expressed in motoneurons, and the Thy1, expressed in putatively excitatory neurons. Motor output was represented as a spatial field of isometric ankle force. We found that Thy1 force fields were more complex and diverse in structure than Chat fields: the Thy1 fields comprised mostly non-parallel vectors while the Chat fields, mostly parallel vectors. In both, most fields elicited by co-stimulation of two laser beams were well explained by linear combination of the separately-evoked fields. We interpreted the Thy1 force fields as representations of spinal motor modules. Our comparison of the Chat and Thy1 fields allowed us to conclude, with reasonable certainty, that the structure of neuromotor modules originates from excitatory spinal interneurons. Our results not only demonstrate, for the first time using optogenetics, how the spinal modules follow linearity in their combinations, but also provide a reference against which future optogenetic studies of modularity can be compared. PMID:27734925

  18. Intermittent Hypoxia-Induced Spinal Inflammation Impairs Respiratory Motor Plasticity by a Spinal p38 MAP Kinase-Dependent Mechanism.

    PubMed

    Huxtable, Adrianne G; Smith, Stephanie M C; Peterson, Timothy J; Watters, Jyoti J; Mitchell, Gordon S

    2015-04-29

    Inflammation is characteristic of most clinical disorders that challenge the neural control of breathing. Since inflammation modulates neuroplasticity, we studied the impact of inflammation caused by prolonged intermittent hypoxia on an important form of respiratory plasticity, acute intermittent hypoxia (three, 5 min hypoxic episodes, 5 min normoxic intervals) induced phrenic long-term facilitation (pLTF). Because chronic intermittent hypoxia elicits neuroinflammation and pLTF is undermined by lipopolysaccharide-induced systemic inflammation, we hypothesized that one night of intermittent hypoxia (IH-1) elicits spinal inflammation, thereby impairing pLTF by a p38 MAP kinase-dependent mechanism. pLTF and spinal inflammation were assessed in anesthetized rats pretreated with IH-1 (2 min hypoxia, 2 min normoxia; 8 h) or sham normoxia and allowed 16 h for recovery. IH-1 (1) transiently increased IL-6 (1.5 ± 0.2-fold; p = 0.02) and inducible nitric oxide synthase (iNOS) (2.4 ± 0.4-fold; p = 0.01) mRNA in cervical spinal homogenates, (2) elicited a sustained increase in IL-1β mRNA (2.4 ± 0.2-fold; p < 0.001) in isolated cervical spinal microglia, and (3) abolished pLTF (-1 ± 5% vs 56 ± 10% in controls; p < 0.001). pLTF was restored after IH-1 by systemic NSAID administration (ketoprofen; 55 ± 9%; p < 0.001) or spinal p38 MAP kinase inhibition (58 ± 2%; p < 0.001). IH-1 increased phosphorylated (activated) p38 MAP kinase immunofluorescence in identified phrenic motoneurons and adjacent microglia. In conclusion, IH-1 elicits spinal inflammation and impairs pLTF by a spinal p38 MAP kinase-dependent mechanism. By targeting inflammation, we may develop strategies to manipulate respiratory motor plasticity for therapeutic advantage when the respiratory control system is compromised (e.g., sleep apnea, apnea of prematurity, spinal injury, or motor neuron disease).

  19. Regenerating motor bridge axons refine connections and synapse on lumbar motoneurons to bypass chronic spinal cord injury.

    PubMed

    Campos, Lucas W; Chakrabarty, Samit; Haque, Raqeeb; Martin, John H

    2008-02-10

    To restore motor control after spinal cord injury requires reconnecting the brain with spinal motor circuits below the lesion. A bridge around the injury is an important alternative to promoting axon regeneration through the injury. Previously, we reported a novel motor bridge in rats. The thirteenth thoracic nerve was detached from the muscle it innervates and the cut end implanted caudally into the lumbar gray matter where motor bridge axons regenerate. In this study, we first determined that regenerating bridge axons project to spinal motor circuits. Stable projections were present in ventral motor laminae of the cord, including putative synapses directly on motoneurons, 2 months after insertion in the intact cord. At this time, earlier-forming dorsal horn projections were mostly eliminated. Regenerating axons were effective in evoking leg motor activity as early as 2 weeks. We next determined that bridge axons could regenerate caudal to a chronic injury. We hemisected the spinal cord at L2 and inserted the bridge nerve 1 month later at L5 and found ventral laminae projections similar to those in intact animals, including onto motoneurons directly. Finally, we determined that the bridge circuit could be activated by neural pathways rostral to its origin. For spinally hemisected animals, we electrically stimulated the rostral spinal cord and recorded evoked potentials from the bridge and, in turn, motor responses in the sciatic nerve. Our findings suggests that bridge motoneurons could be used by descending motor pathways as premotor interneurons to transmit neural signals to bypass a chronic spinal injury.

  20. Cannabidiol-treated rats exhibited higher motor score after cryogenic spinal cord injury.

    PubMed

    Kwiatkoski, Marcelo; Guimarães, Francisco Silveira; Del-Bel, Elaine

    2012-04-01

    Cannabidiol (CBD), a non-psychoactive constituent of cannabis, has been reported to induce neuroprotective effects in several experimental models of brain injury. We aimed at investigating whether this drug could also improve locomotor recovery of rats submitted to spinal cord cryoinjury. Rats were distributed into five experimental groups. Animals were submitted to laminectomy in vertebral segment T10 followed or not by application of liquid nitrogen for 5 s into the spinal cord at the same level to cause cryoinjury. The animals received injections of vehicle or CBD (20 mg/kg) immediately before, 3 h after and daily for 6 days after surgery. The Basso, Beattie, and Bresnahan motor evaluation test was used to assess motor function post-lesion one day before surgery and on the first, third, and seventh postoperative days. The extent of injury was evaluated by hematoxylin-eosin histology and FosB expression. Cryogenic lesion of the spinal cord resulted in a significant motor deficit. Cannabidiol-treated rats exhibited a higher Basso, Beattie, and Bresnahan locomotor score at the end of the first week after spinal cord injury: lesion + vehicle, day 1: zero, day 7: four, and lesion + Cannabidiol 20 mg/kg, day 1: zero, day 7: seven. Moreover, at this moment there was a significant reduction in the extent of tissue injury and FosB expression in the ventral horn of the spinal cord. The present study confirmed that application of liquid nitrogen to the spinal cord induces reproducible and quantifiable spinal cord injury associated with locomotor function impairments. Cannabidiol improved locomotor functional recovery and reduced injury extent, suggesting that it could be useful in the treatment of spinal cord lesions.

  1. Spinal motor and sensory neurons are androgen targets in an acrobatic bird.

    PubMed

    Fuxjager, Matthew J; Schultz, J Douglas; Barske, Julia; Feng, Ni Y; Fusani, Leonida; Mirzatoni, Anahid; Day, Lainy B; Hau, Michaela; Schlinger, Barney A

    2012-08-01

    Sex steroids affect the motivation to court mates, but less is known about how they influence motor movements associated with courtship behavior. Steroidal control of motor function may be especially important for species in which courtship requires superior strength, stamina, and neuromuscular coordination. Here we use the golden-collared manakin (Manacus vitellinus) to examine whether the neuromuscular circuitry that controls motoric aspects of courtship activity is sensitive to androgens. Males of this tropical species attract mates by rapidly jumping among branches in a courtship arena and using their wings to produce loud wing snaps. Testosterone activates this display via the androgen receptor (AR), and past work reveals that manakins injected with radio-labeled T ((3)H-T) accumulate radioactivity in the spinal cord. Thus, we used quantitative PCR to measure AR, estrogen receptor-α (ER-α) subtype, and aromatase (AROM) mRNA in spinal cords of male and female manakins and zebra finches. Expression of AR, but not ER-α or aromatase, was higher throughout the manakin spinal cord compared with the zebra finch. Next, we tested whether AR-expressing skeletal muscles are innervated by motor and sensory neurons that also express AR. To do this, we backfilled spinal neurons by injecting fluorescent tracers into select AR-sensitive wing and leg muscles of wild caught male and female manakins. We then removed these spinal cords and measured AR expression with in situ hybridization. Both sexes showed abundant AR mRNA in the cervical and lumbosacral spinal enlargements as well as in dorsal root ganglia attached to these enlargements. Together our findings suggest that androgens act widely on peripheral motor and sensory circuits in golden-collared manakins to influence wing snapping displays. PMID:22635677

  2. Spinal motor neurons are regenerated after mechanical lesion and genetic ablation in larval zebrafish

    PubMed Central

    Ohnmacht, Jochen; Yang, Yujie; Maurer, Gianna W.; Barreiro-Iglesias, Antón; Tsarouchas, Themistoklis M.; Wehner, Daniel; Sieger, Dirk; Becker, Catherina G.; Becker, Thomas

    2016-01-01

    ABSTRACT In adult zebrafish, relatively quiescent progenitor cells show lesion-induced generation of motor neurons. Developmental motor neuron generation from the spinal motor neuron progenitor domain (pMN) sharply declines at 48 hours post-fertilisation (hpf). After that, mostly oligodendrocytes are generated from the same domain. We demonstrate here that within 48 h of a spinal lesion or specific genetic ablation of motor neurons at 72 hpf, the pMN domain reverts to motor neuron generation at the expense of oligodendrogenesis. By contrast, generation of dorsal Pax2-positive interneurons was not altered. Larval motor neuron regeneration can be boosted by dopaminergic drugs, similar to adult regeneration. We use larval lesions to show that pharmacological suppression of the cellular response of the innate immune system inhibits motor neuron regeneration. Hence, we have established a rapid larval regeneration paradigm. Either mechanical lesions or motor neuron ablation is sufficient to reveal a high degree of developmental flexibility of pMN progenitor cells. In addition, we show an important influence of the immune system on motor neuron regeneration from these progenitor cells. PMID:26965370

  3. Competition with Primary Sensory Afferents Drives Remodeling of Corticospinal Axons in Mature Spinal Motor Circuits

    PubMed Central

    Jiang, Yu-Qiu; Zaaimi, Boubker

    2016-01-01

    Injury to the mature motor system drives significant spontaneous axonal sprouting instead of axon regeneration. Knowing the circuit-level determinants of axonal sprouting is important for repairing motor circuits after injury to achieve functional rehabilitation. Competitive interactions are known to shape corticospinal tract axon outgrowth and withdrawal during development. Whether and how competition contributes to reorganization of mature spinal motor circuits is unclear. To study this question, we examined plastic changes in corticospinal axons in response to two complementary proprioceptive afferent manipulations: (1) enhancing proprioceptive afferents activity by electrical stimulation; or (2) diminishing their input by dorsal rootlet rhizotomy. Experiments were conducted in adult rats. Electrical stimulation produced proprioceptive afferent sprouting that was accompanied by significant corticospinal axon withdrawal and a decrease in corticospinal connections on cholinergic interneurons in the medial intermediate zone and C boutons on motoneurons. In contrast, dorsal rootlet rhizotomy led to a significant increase in corticospinal connections, including those on cholinergic interneurons; C bouton density increased correspondingly. Motor cortex-evoked muscle potentials showed parallel changes to those of corticospinal axons, suggesting that reciprocal corticospinal axon changes are functional. Using the two complementary models, we showed that competitive interactions between proprioceptive and corticospinal axons are an important determinant in the organization of mature corticospinal axons and spinal motor circuits. The activity- and synaptic space-dependent properties of the competition enables prediction of the remodeling of spared corticospinal connection and spinal motor circuits after injury and informs the target-specific control of corticospinal connections to promote functional recovery. SIGNIFICANCE STATEMENT Neuroplasticity is limited in maturity

  4. Histological and Functional Benefit Following Transplantation of Motor Neuron Progenitors to the Injured Rat Spinal Cord

    PubMed Central

    Wyatt, Tanya; Yin, Hong Zhen; Poole, Aleksandra J.; Weiss, John H.; Gardener, Matthew J.; Dijkstra, Sipke; Fischer, David F.; Keirstead, Hans S.

    2010-01-01

    Background Motor neuron loss is characteristic of cervical spinal cord injury (SCI) and contributes to functional deficit. Methodology/Principal Findings In order to investigate the amenability of the injured adult spinal cord to motor neuron differentiation, we transplanted spinal cord injured animals with a high purity population of human motor neuron progenitors (hMNP) derived from human embryonic stem cells (hESCs). In vitro, hMNPs displayed characteristic motor neuron-specific markers, a typical electrophysiological profile, functionally innervated human or rodent muscle, and secreted physiologically active growth factors that caused neurite branching and neuronal survival. hMNP transplantation into cervical SCI sites in adult rats resulted in suppression of intracellular signaling pathways associated with SCI pathogenesis, which correlated with greater endogenous neuronal survival and neurite branching. These neurotrophic effects were accompanied by significantly enhanced performance on all parameters of the balance beam task, as compared to controls. Interestingly, hMNP transplantation resulted in survival, differentiation, and site-specific integration of hMNPs distal to the SCI site within ventral horns, but hMNPs near the SCI site reverted to a neuronal progenitor state, suggesting an environmental deficiency for neuronal maturation associated with SCI. Conclusions/Significance These findings underscore the barriers imposed on neuronal differentiation of transplanted cells by the gliogenic nature of the injured spinal cord, and the physiological relevance of transplant-derived neurotrophic support to functional recovery. PMID:20686613

  5. Optical stimulation for restoration of motor function following spinal cord injury

    PubMed Central

    Mallory, Grant W.; Grahn, Peter J.; Hachmann, Jan T.; Lujan, J. Luis; Lee, Kendall H.

    2015-01-01

    Spinal cord injury (SCI) can be defined as a loss of communication between the brain and the body due to disrupted pathways within the spinal cord. While many promising molecular strategies have emerged to reduce secondary injury and promote axonal regrowth, there is still no effective cure and recovery of function remains limited. Functional electrical stimulation (FES) represents a strategy developed to restore motor function without the need for regenerating severed spinal pathways. Despite its technological success, however, FES has not been widely integrated into the lives of spinal cord injury survivors. In this review, we briefly discuss the limitations of existing FES technologies. Additionally, we discuss how optogenetics, a rapidly evolving technique used primarily to investigate select neuronal populations within the brain, may eventually be used to replace FES as a form of therapy for functional restoration following SCI. PMID:25659246

  6. Spinal atypical protein kinase C activity is necessary to stabilize inactivity-induced phrenic motor facilitation.

    PubMed

    Strey, Kristi A; Nichols, Nicole L; Baertsch, Nathan A; Broytman, Oleg; Baker-Herman, Tracy L

    2012-11-14

    The neural network controlling breathing must establish rhythmic motor output at a level adequate to sustain life. Reduced respiratory neural activity elicits a novel form of plasticity in circuits driving the diaphragm known as inactivity-induced phrenic motor facilitation (iPMF), a rebound increase in phrenic inspiratory output observed once respiratory neural drive is restored. The mechanisms underlying iPMF are unknown. Here, we demonstrate in anesthetized rats that spinal mechanisms give rise to iPMF and that iPMF consists of at least two mechanistically distinct phases: (1) an early, labile phase that requires atypical PKC (PKCζ and/or PKCι/λ) activity to transition to a (2) late, stable phase. Early (but not late) iPMF is associated with increased interactions between PKCζ/ι and the scaffolding protein ZIP (PKCζ-interacting protein)/p62 in spinal regions associated with the phrenic motor pool. Although PKCζ/ι activity is necessary for iPMF, spinal atypical PKC activity is not necessary for phrenic long-term facilitation (pLTF) following acute intermittent hypoxia, an activity-independent form of spinal respiratory plasticity. Thus, while iPMF and pLTF both manifest as prolonged increases in phrenic burst amplitude, they arise from distinct spinal cellular pathways. Our data are consistent with the hypotheses that (1) local mechanisms sense and respond to reduced respiratory-related activity in the phrenic motor pool and (2) inactivity-induced increases in phrenic inspiratory output require local PKCζ/ι activity to stabilize into a long-lasting iPMF. Although the physiological role of iPMF is unknown, we suspect that iPMF represents a compensatory mechanism, assuring adequate motor output in a physiological system in which prolonged inactivity ends life. PMID:23152633

  7. Interactive virtual feedback improves gait motor imagery after spinal cord injury: An exploratory study

    PubMed Central

    Roosink, Meyke; Robitaille, Nicolas; Jackson, Philip L.; Bouyer, Laurent J.; Mercier, Catherine

    2016-01-01

    Purpose: Motor imagery can improve motor function and reduce pain. This is relevant to individuals with spinal cord injury (SCI) in whom motor dysfunction and neuropathic pain are prevalent. However, therapy efficacy could be dependent on motor imagery ability, and a clear understanding of how motor imagery might be facilitated is currently lacking. Thus, the aim of the present study was to assess the immediate effects of interactive virtual feedback on motor imagery performance after SCI. Methods: Nine individuals with a traumatic SCI participated in the experiment. Motor imagery tasks consisted of forward (i.e. simpler) and backward (i.e. more complex) walking while receiving interactive versus static virtual feedback. Motor imagery performance (vividness, effort and speed), neuropathic pain intensity and feasibility (immersion, distraction, side-effects) were assessed. Results: During interactive feedback trials, motor imagery vividness and speed were significantly higher and effort was significantly lower as compared static feedback trials. No change in neuropathic pain was observed. Adverse effects were minor, and immersion was reported to be good. Conclusions: This exploratory study showed that interactive virtual walking was feasible and facilitated motor imagery performance. The response to motor imagery interventions after SCI might be improved by using interactive virtual feedback. PMID:26890097

  8. Effect of oscillating electrical field stimulation on motor function recovery and myelin regeneration after spinal cord injury in rats.

    PubMed

    Tian, Da-Sheng; Jing, Jue-Hua; Qian, Jun; Chen, Lei; Zhu, Bin

    2016-05-01

    [Purpose] The aim of this study was to evaluate the effect of oscillating electrical field stimulation on motor function recovery and myelin regeneration in rats with spinal cord injury. [Subjects and Methods] A rat model of spinal cord injury was constructed by using the Allen weight-drop method. These rats were randomly divided into normal, spinal cord injury, and spinal cord injury + oscillating electrical field stimulation groups. The experimental group received the intervention with oscillating electrical field stimulation, and the control group received the intervention with an electrical field stimulator without oscillating electrical field stimulation. Each group was then randomly divided into seven subgroups according to observation time (1, 2, 4, 6, 8, 10, and 12 weeks). Basso-Beattie-Bresnahan score and inclined plate test score evaluation, motor evoked potential detection, and histological observation were performed. [Results] In the first 2 weeks of oscillating electrical field stimulation, the oscillating electrical field stimulation and inclined plate test scores of spinal cord injury group and spinal cord injury + oscillating electrical field stimulation group were not significantly different. In the fourth week, the scores of the spinal cord injury group were significantly lower than those of the spinal cord injury + oscillating electrical field stimulation group. The motor evoked potential incubation period in the spinal cord injury + oscillating electrical field stimulation group at the various time points was shorter than that in the spinal cord injury group. In the sixth week, the relative area of myelin in the spinal cord injury + oscillating electrical field stimulation group was evidently larger than that in the spinal cord injury group. [Conclusion] Oscillating electrical field stimulation could effectively improve spinal cord conduction function and promote motor function recovery in rats with spinal cord injury, as well as promote myelin

  9. Effect of oscillating electrical field stimulation on motor function recovery and myelin regeneration after spinal cord injury in rats.

    PubMed

    Tian, Da-Sheng; Jing, Jue-Hua; Qian, Jun; Chen, Lei; Zhu, Bin

    2016-05-01

    [Purpose] The aim of this study was to evaluate the effect of oscillating electrical field stimulation on motor function recovery and myelin regeneration in rats with spinal cord injury. [Subjects and Methods] A rat model of spinal cord injury was constructed by using the Allen weight-drop method. These rats were randomly divided into normal, spinal cord injury, and spinal cord injury + oscillating electrical field stimulation groups. The experimental group received the intervention with oscillating electrical field stimulation, and the control group received the intervention with an electrical field stimulator without oscillating electrical field stimulation. Each group was then randomly divided into seven subgroups according to observation time (1, 2, 4, 6, 8, 10, and 12 weeks). Basso-Beattie-Bresnahan score and inclined plate test score evaluation, motor evoked potential detection, and histological observation were performed. [Results] In the first 2 weeks of oscillating electrical field stimulation, the oscillating electrical field stimulation and inclined plate test scores of spinal cord injury group and spinal cord injury + oscillating electrical field stimulation group were not significantly different. In the fourth week, the scores of the spinal cord injury group were significantly lower than those of the spinal cord injury + oscillating electrical field stimulation group. The motor evoked potential incubation period in the spinal cord injury + oscillating electrical field stimulation group at the various time points was shorter than that in the spinal cord injury group. In the sixth week, the relative area of myelin in the spinal cord injury + oscillating electrical field stimulation group was evidently larger than that in the spinal cord injury group. [Conclusion] Oscillating electrical field stimulation could effectively improve spinal cord conduction function and promote motor function recovery in rats with spinal cord injury, as well as promote myelin

  10. Effect of oscillating electrical field stimulation on motor function recovery and myelin regeneration after spinal cord injury in rats

    PubMed Central

    Tian, Da-Sheng; Jing, Jue-Hua; Qian, Jun; Chen, Lei; Zhu, Bin

    2016-01-01

    [Purpose] The aim of this study was to evaluate the effect of oscillating electrical field stimulation on motor function recovery and myelin regeneration in rats with spinal cord injury. [Subjects and Methods] A rat model of spinal cord injury was constructed by using the Allen weight-drop method. These rats were randomly divided into normal, spinal cord injury, and spinal cord injury + oscillating electrical field stimulation groups. The experimental group received the intervention with oscillating electrical field stimulation, and the control group received the intervention with an electrical field stimulator without oscillating electrical field stimulation. Each group was then randomly divided into seven subgroups according to observation time (1, 2, 4, 6, 8, 10, and 12 weeks). Basso-Beattie-Bresnahan score and inclined plate test score evaluation, motor evoked potential detection, and histological observation were performed. [Results] In the first 2 weeks of oscillating electrical field stimulation, the oscillating electrical field stimulation and inclined plate test scores of spinal cord injury group and spinal cord injury + oscillating electrical field stimulation group were not significantly different. In the fourth week, the scores of the spinal cord injury group were significantly lower than those of the spinal cord injury + oscillating electrical field stimulation group. The motor evoked potential incubation period in the spinal cord injury + oscillating electrical field stimulation group at the various time points was shorter than that in the spinal cord injury group. In the sixth week, the relative area of myelin in the spinal cord injury + oscillating electrical field stimulation group was evidently larger than that in the spinal cord injury group. [Conclusion] Oscillating electrical field stimulation could effectively improve spinal cord conduction function and promote motor function recovery in rats with spinal cord injury, as well as promote myelin

  11. Evolution of EEG Motor Rhythms after Spinal Cord Injury: A Longitudinal Study

    PubMed Central

    López-Larraz, Eduardo; Montesano, Luis; Gil-Agudo, Ángel; Minguez, Javier; Oliviero, Antonio

    2015-01-01

    Spinal cord injury (SCI) does not only produce a lack of sensory and motor function caudal to the level of injury, but it also leads to a progressive brain reorganization. Chronic SCI patients attempting to move their affected limbs present a significant reduction of brain activation in the motor cortex, which has been linked to the deafferentation. The aim of this work is to study the evolution of the motor-related brain activity during the first months after SCI. Eighteen subacute SCI patients were recruited to participate in bi-weekly experimental sessions during at least two months. Their EEG was recorded to analyze the temporal evolution of the event-related desynchronization (ERD) over the motor cortex, both during motor attempt and motor imagery of their paralyzed hands. The results show that the α and β ERD evolution after SCI is negatively correlated with the clinical progression of the patients during the first months after the injury. This work provides the first longitudinal study of the event-related desynchronization during the subacute phase of spinal cord injury. Furthermore, our findings reveal a strong association between the ERD changes and the clinical evolution of the patients. These results help to better understand the brain transformation after SCI, which is important to characterize the neuroplasticity mechanisms involved after this lesion and may lead to new strategies for rehabilitation and motor restoration of these patients. PMID:26177457

  12. Evolution of EEG Motor Rhythms after Spinal Cord Injury: A Longitudinal Study.

    PubMed

    López-Larraz, Eduardo; Montesano, Luis; Gil-Agudo, Ángel; Minguez, Javier; Oliviero, Antonio

    2015-01-01

    Spinal cord injury (SCI) does not only produce a lack of sensory and motor function caudal to the level of injury, but it also leads to a progressive brain reorganization. Chronic SCI patients attempting to move their affected limbs present a significant reduction of brain activation in the motor cortex, which has been linked to the deafferentation. The aim of this work is to study the evolution of the motor-related brain activity during the first months after SCI. Eighteen subacute SCI patients were recruited to participate in bi-weekly experimental sessions during at least two months. Their EEG was recorded to analyze the temporal evolution of the event-related desynchronization (ERD) over the motor cortex, both during motor attempt and motor imagery of their paralyzed hands. The results show that the α and β ERD evolution after SCI is negatively correlated with the clinical progression of the patients during the first months after the injury. This work provides the first longitudinal study of the event-related desynchronization during the subacute phase of spinal cord injury. Furthermore, our findings reveal a strong association between the ERD changes and the clinical evolution of the patients. These results help to better understand the brain transformation after SCI, which is important to characterize the neuroplasticity mechanisms involved after this lesion and may lead to new strategies for rehabilitation and motor restoration of these patients. PMID:26177457

  13. Combined motor cortex and spinal cord neuromodulation promotes corticospinal system functional and structural plasticity and motor function after injury.

    PubMed

    Song, Weiguo; Amer, Alzahraa; Ryan, Daniel; Martin, John H

    2016-03-01

    An important strategy for promoting voluntary movements after motor system injury is to harness activity-dependent corticospinal tract (CST) plasticity. We combine forelimb motor cortex (M1) activation with co-activation of its cervical spinal targets in rats to promote CST sprouting and skilled limb movement after pyramidal tract lesion (PTX). We used a two-step experimental design in which we first established the optimal combined stimulation protocol in intact rats and then used the optimal protocol in injured animals to promote CST repair and motor recovery. M1 was activated epidurally using an electrical analog of intermittent theta burst stimulation (iTBS). The cervical spinal cord was co-activated by trans-spinal direct current stimulation (tsDCS) that was targeted to the cervical enlargement, simulated from finite element method. In intact rats, forelimb motor evoked potentials (MEPs) were strongly facilitated during iTBS and for 10 min after cessation of stimulation. Cathodal, not anodal, tsDCS alone facilitated MEPs and also produced a facilitatory aftereffect that peaked at 10 min. Combined iTBS and cathodal tsDCS (c-tsDCS) produced further MEP enhancement during stimulation, but without further aftereffect enhancement. Correlations between forelimb M1 local field potentials and forelimb electromyogram (EMG) during locomotion increased after electrical iTBS alone and further increased with combined stimulation (iTBS+c-tsDCS). This optimized combined stimulation was then used to promote function after PTX because it enhanced functional connections between M1 and spinal circuits and greater M1 engagement in muscle contraction than either stimulation alone. Daily application of combined M1 iTBS on the intact side and c-tsDCS after PTX (10 days, 27 min/day) significantly restored skilled movements during horizontal ladder walking. Stimulation produced a 5.4-fold increase in spared ipsilateral CST terminations. Combined neuromodulation achieves optimal motor

  14. Spinal 5-HT7 receptors induce phrenic motor facilitation via EPAC-mTORC1 signaling.

    PubMed

    Fields, D P; Springborn, S R; Mitchell, G S

    2015-09-01

    Spinal serotonin type 7 (5-HT7) receptors elicit complex effects on motor activity. Whereas 5-HT7 receptor activation gives rise to long-lasting phrenic motor facilitation (pMF), it also constrains 5-HT2 receptor-induced pMF via "cross-talk inhibition." We hypothesized that divergent cAMP-dependent signaling pathways give rise to these distinct 5-HT7 receptor actions. Specifically, we hypothesized that protein kinase A (PKA) mediates cross-talk inhibition of 5-HT2 receptor-induced pMF whereas 5-HT7 receptor-induced pMF results from exchange protein activated by cAMP (EPAC) signaling. Anesthetized, paralyzed, and ventilated rats receiving intrathecal (C4) 5-HT7 receptor agonist (AS-19) injections expressed pMF for >90 min, an effect abolished by pretreatment with a selective EPAC inhibitor (ESI-05) but not a selective PKA inhibitor (KT-5720). Furthermore, intrathecal injections of a selective EPAC activator (8-pCPT-2'-Me-cAMP) were sufficient to elicit pMF. Finally, spinal mammalian target of rapamycin complex-1 (mTORC1) inhibition via intrathecal rapamycin abolished 5-HT7 receptor- and EPAC-induced pMF, demonstrating that spinal 5-HT7 receptors elicit pMF by an EPAC-mTORC1 signaling pathway. Thus 5-HT7 receptors elicit and constrain spinal phrenic motor plasticity via distinct signaling mechanisms that diverge at cAMP (EPAC vs. PKA). Selective manipulation of these molecules may enable refined regulation of serotonin-dependent spinal motor plasticity for therapeutic advantage. PMID:26269554

  15. Spinal 5-HT7 receptors induce phrenic motor facilitation via EPAC-mTORC1 signaling

    PubMed Central

    Fields, D. P.; Springborn, S. R.

    2015-01-01

    Spinal serotonin type 7 (5-HT7) receptors elicit complex effects on motor activity. Whereas 5-HT7 receptor activation gives rise to long-lasting phrenic motor facilitation (pMF), it also constrains 5-HT2 receptor-induced pMF via “cross-talk inhibition.” We hypothesized that divergent cAMP-dependent signaling pathways give rise to these distinct 5-HT7 receptor actions. Specifically, we hypothesized that protein kinase A (PKA) mediates cross-talk inhibition of 5-HT2 receptor-induced pMF whereas 5-HT7 receptor-induced pMF results from exchange protein activated by cAMP (EPAC) signaling. Anesthetized, paralyzed, and ventilated rats receiving intrathecal (C4) 5-HT7 receptor agonist (AS-19) injections expressed pMF for >90 min, an effect abolished by pretreatment with a selective EPAC inhibitor (ESI-05) but not a selective PKA inhibitor (KT-5720). Furthermore, intrathecal injections of a selective EPAC activator (8-pCPT-2′-Me-cAMP) were sufficient to elicit pMF. Finally, spinal mammalian target of rapamycin complex-1 (mTORC1) inhibition via intrathecal rapamycin abolished 5-HT7 receptor- and EPAC-induced pMF, demonstrating that spinal 5-HT7 receptors elicit pMF by an EPAC-mTORC1 signaling pathway. Thus 5-HT7 receptors elicit and constrain spinal phrenic motor plasticity via distinct signaling mechanisms that diverge at cAMP (EPAC vs. PKA). Selective manipulation of these molecules may enable refined regulation of serotonin-dependent spinal motor plasticity for therapeutic advantage. PMID:26269554

  16. Effect of percutaneous stimulation at different spinal levels on the activation of sensory and motor roots.

    PubMed

    Roy, François D; Gibson, Grady; Stein, Richard B

    2012-11-01

    Percutaneous spinal stimulation is a promising new technique for understanding human spinal reflexes and for evaluating the pathophysiology of motor roots. Previous studies have generally stimulated the T11/T12 or T12/L1 vertebral junctions, sites that overlie the lumbosacral enlargement. The present study sought to determine the best location for targeting sensory and motor roots during sitting. We used paired stimuli, 50 ms apart, to distinguish the contribution of the reflex and motor components which make up the root evoked potential. This assumed that post-stimulation attenuation, primarily through homosynaptic depression, would abolish the second potential if it was trans-synaptic in origin. Conversely, successive responses would be unchanged if motor roots were being stimulated. Here, we show that sensory root reflexes were optimally elicited with percutaneous stimulation over the L1-L3 vertebrae. However, the optimal position varied between subjects and depended on the target muscle being studied. A collision test showed that the reflex recorded in pre-tibial flexors was low in amplitude and was prone to crosstalk from neighbouring muscles. In contrast to the reflex response, direct motor root activation was optimal with stimulation over the more caudal L5-S1 vertebrae. The present results support the utility of paired stimulation for evaluating the topographical recruitment of sensory and motor roots to human leg muscles.

  17. Intraoperative monitoring during decompression of the spinal cord and spinal nerves using transcranial motor-evoked potentials: The law of twenty percent.

    PubMed

    Tanaka, Satoshi; Hirao, Jun; Oka, Hidehiro; Akimoto, Jiro; Takanashi, Junko; Yamada, Junichi

    2015-09-01

    Motor-evoked potential (MEP) monitoring was performed during 196 consecutive spinal (79 cervical and 117 lumbar) surgeries for the decompression of compressive spinal and spinal nerve diseases. MEP monitoring in spinal surgery has been considered sensitive to predict postoperative neurological recovery. In this series, transcranial stimulation consisted of trains of five pulses at a constant voltage (200-600 V). For the normalization of MEP, we recorded compound muscle action potentials (CMAP) after peripheral nerve stimulation, usually on the median nerve at the wrist 2 seconds before or after each transcranial stimulation of the motor area, for all operations. The sensitivity and specificity of MEP monitoring was 100% and 97.4%, respectively, or 96.9% with or without CMAP compensation (if the threshold of postoperative motor palsy was defined as 20% relative amplitude rate [RAR]). The mean RAR after CMAP normalization, of the most affected muscle in the patient group with excellent postoperative results (recovery rate of a Japan Orthopedic Association score of more than 50%) was significantly higher than that in the other groups (p=0.0224). All patients with an amplitude increase rate (AIR) with CMAP normalization of more than 20% achieved neurological recovery postoperatively. Our results suggest that if the RAR is more than 20%, postoperative motor palsy can be avoided in spinal surgery. If the AIR with normalization by CMAP after peripheral nerve stimulation is more than 20%, neurological recovery can be expected in spinal surgery. PMID:26142049

  18. Electrophysiological biomarkers of neuromodulatory strategies to recover motor function after spinal cord injury

    PubMed Central

    Gad, Parag; Roy, Roland R.; Choe, Jaehoon; Creagmile, Jack; Zhong, Hui; Gerasimenko, Yury

    2015-01-01

    The spinal cord contains the circuitry to control posture and locomotion after complete paralysis, and this circuitry can be enabled with epidural stimulation [electrical enabling motor control (eEmc)] and/or administration of pharmacological agents [pharmacological enabling motor control (fEmc)] when combined with motor training. We hypothesized that the characteristics of the spinally evoked potentials after chronic administration of both strychnine and quipazine under the influence of eEmc during standing and stepping can be used as biomarkers to predict successful motor performance. To test this hypothesis we trained rats to step bipedally for 7 wk after paralysis and characterized the motor potentials evoked in the soleus and tibialis anterior (TA) muscles with the rats in a non-weight-bearing position, standing and stepping. The middle responses (MRs) to spinally evoked stimuli were suppressed with either or both drugs when the rat was suspended, whereas the addition of either or both drugs resulted in an overall activation of the extensor muscles during stepping and/or standing and reduced the drag duration and cocontraction between the TA and soleus muscles during stepping. The administration of quipazine and strychnine in concert with eEmc and step training after injury resulted in larger-amplitude evoked potentials [MRs and late responses (LRs)] in flexors and extensors, with the LRs consisting of a more normal bursting pattern, i.e., randomly generated action potentials within the bursts. This pattern was linked to more successful standing and stepping. Thus it appears that selected features of the patterns of potentials evoked in specific muscles with stimulation can serve as effective biomarkers and predictors of motor performance. PMID:25695648

  19. IPLEX Administration Improves Motor Neuron Survival and Ameliorates Motor Functions in a Severe Mouse Model of Spinal Muscular Atrophy

    PubMed Central

    Murdocca, Michela; Malgieri, Arianna; Luchetti, Andrea; Saieva, Luciano; Dobrowolny, Gabriella; de Leonibus, Elvira; Filareto, Antonio; Quitadamo, Maria Chiara; Novelli, Giuseppe; Musarò, Antonio; Sangiuolo, Federica

    2012-01-01

    Spinal muscular atrophy (SMA) is an inherited neurodegenerative disorder and the first genetic cause of death in childhood. SMA is caused by low levels of survival motor neuron (SMN) protein that induce selective loss of α-motor neurons (MNs) in the spinal cord, resulting in progressive muscle atrophy and consequent respiratory failure. To date, no effective treatment is available to counteract the course of the disease. Among the different therapeutic strategies with potential clinical applications, the evaluation of trophic and/or protective agents able to antagonize MNs degeneration represents an attractive opportunity to develop valid therapies. Here we investigated the effects of IPLEX (recombinant human insulinlike growth factor 1 [rhIGF-1] complexed with recombinant human IGF-1 binding protein 3 [rhIGFBP-3]) on a severe mouse model of SMA. Interestingly, molecular and biochemical analyses of IGF-1 carried out in SMA mice before drug administration revealed marked reductions of IGF-1 circulating levels and hepatic mRNA expression. In this study, we found that perinatal administration of IPLEX, even if does not influence survival and body weight of mice, results in reduced degeneration of MNs, increased muscle fiber size and in amelioration of motor functions in SMA mice. Additionally, we show that phenotypic changes observed are not SMN-dependent, since no significant SMN modification was addressed in treated mice. Collectively, our data indicate IPLEX as a good therapeutic candidate to hinder the progression of the neurodegenerative process in SMA. PMID:22669476

  20. Motor primitives and synergies in spinal cord and after injury– the current state of play

    PubMed Central

    Giszter, Simon F.; Hart, Corey B.

    2013-01-01

    Modular pattern generator elements, also known as burst synergies or motor primitives, have become a useful and important way of describing motor behavior, albeit controversial. It is suggested that these synergy elements may comprise part of the pattern shaping layers of a McCrea/Rybak two layer pattern generator, as well as being used in other ways in spinal cord. The data supporting modular synergies ranges across species including man and encompasses motor pattern analyses and neural recordings. Recently, synergy persistence and changes following clinical trauma have been presented. These new data underscore the importance of understanding the modular structure of motor behaviors and the underlying circuitry in order to best provide principled therapies and to understand phenomena reported in the clinic. We discuss the evidence and different viewpoints on modularity, the neural underpinnings identified thus far, and possible critical issues for the future of this area. PMID:23531009

  1. Motor Neuron Diseases Accompanying Spinal Stenosis: A Case Study.

    PubMed

    Shin, HyeonJu; Park, Sun Kyung; HaeJin, Suh; Choi, Yun Suk

    2016-03-01

    A 75-year-old man, who was healthy, visited the hospital because of shooting pain and numbness in both lower limbs (right > left). The patient had an L4/5 moderate right foraminal stenosis and right subarticular disc protrusion and received a lumbar epidural block. The patient experienced severe weakness in the right lower limb after 2 days. Lumbar and cervical magnetic resonance images were taken and electromyography and a nerve conduction study were performed to arrive at the diagnosis of a motor neuron disease. The patient expired 4 months later with respiratory failure due to motor neuron disease. This case suggests that any abnormal neurological symptoms that occur after an epidural block should be examined thoroughly via testing and consultations to identify the cause of the symptoms. PMID:27008301

  2. Motor Neuron Diseases Accompanying Spinal Stenosis: A Case Study.

    PubMed

    Shin, HyeonJu; Park, Sun Kyung; HaeJin, Suh; Choi, Yun Suk

    2016-03-01

    A 75-year-old man, who was healthy, visited the hospital because of shooting pain and numbness in both lower limbs (right > left). The patient had an L4/5 moderate right foraminal stenosis and right subarticular disc protrusion and received a lumbar epidural block. The patient experienced severe weakness in the right lower limb after 2 days. Lumbar and cervical magnetic resonance images were taken and electromyography and a nerve conduction study were performed to arrive at the diagnosis of a motor neuron disease. The patient expired 4 months later with respiratory failure due to motor neuron disease. This case suggests that any abnormal neurological symptoms that occur after an epidural block should be examined thoroughly via testing and consultations to identify the cause of the symptoms.

  3. Prediction of functional outcome by motor capability after spinal cord injury.

    PubMed

    Lazar, R B; Yarkony, G M; Ortolano, D; Heinemann, A W; Perlow, E; Lovell, L; Meyer, P R

    1989-11-01

    The relationship between early motor status and functional outcome after spinal cord injury (SCI) was evaluated prospectively in 52 quadriplegic and 26 paraplegic patients. Motor status was measured within 72 hours of injury and quantified with the Motor Index Score (MIS). Functional status was evaluated with the Modified Barthel Index (MBI). A senior physical therapist completed the MIS and the MBI when each patient was admitted to the spinal cord intensive care unit and every 30 days during rehabilitation. Early motor function was correlated with average daily improvement in functional status including self-care and mobility (p = .001). The initial MIS strongly correlated with functional status of quadriplegics at admission (p = .001), at 60 days, and at rehabilitation discharge (p = .001). In paraplegics, the overall MBI at admission, after 60 days of rehabilitation, and at discharge was not correlated with early motor function. However, the MIS correlated significantly with the MBI self-care subscore at 60 days and at discharge (p = .01), but not with the mobility subscore. The initial MIS was also significantly correlated to functional status at discharge in patients with complete lesions (p = .001), but was not related to functional status at discharge in patients with incomplete lesions. The MIS appears to be a useful tool in predicting function during rehabilitation, although individual differences in ambulation, particularly for patients with paraplegia, limit the predictive utility of this index. PMID:2818153

  4. Specific Deficit in Implicit Motor Sequence Learning following Spinal Cord Injury

    PubMed Central

    Bloch, Ayala; Tamir, Dror; Vakil, Eli; Zeilig, Gabi

    2016-01-01

    Background Physical and psychosocial rehabilitation following spinal cord injury (SCI) leans heavily on learning and practicing new skills. However, despite research relating motor sequence learning to spinal cord activity and clinical observations of impeded skill-learning after SCI, implicit procedural learning following spinal cord damage has not been examined. Objective To test the hypothesis that spinal cord injury (SCI) in the absence of concomitant brain injury is associated with a specific implicit motor sequence learning deficit that cannot be explained by depression or impairments in other cognitive measures. Methods Ten participants with SCI in T1-T11, unharmed upper limb motor and sensory functioning, and no concomitant brain injury were compared to ten matched control participants on measures derived from the serial reaction time (SRT) task, which was used to assess implicit motor sequence learning. Explicit generation of the SRT sequence, depression, and additional measures of learning, memory, and intelligence were included to explore the source and specificity of potential learning deficits. Results There was no between-group difference in baseline reaction time, indicating that potential differences between the learning curves of the two groups could not be attributed to an overall reduction in response speed in the SCI group. Unlike controls, the SCI group showed no decline in reaction time over the first six blocks of the SRT task and no advantage for the initially presented sequence over the novel interference sequence. Meanwhile, no group differences were found in explicit learning, depression, or any additional cognitive measures. Conclusions The dissociation between impaired implicit learning and intact declarative memory represents novel empirical evidence of a specific implicit procedural learning deficit following SCI, with broad implications for rehabilitation and adjustment. PMID:27355834

  5. Impairment of spinal motor neurons in spinocerebellar ataxia type 1-knock-in mice.

    PubMed

    Takechi, Yasuhiko; Mieda, Tokue; Iizuka, Akira; Toya, Syutaro; Suto, Nana; Takagishi, Kenji; Nakazato, Yoichi; Nakamura, Kazuhiro; Hirai, Hirokazu

    2013-02-22

    Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of polyglutamine repeats in the Ataxin-1 protein. An accumulating body of cerebellar, histological and behavioral analyses has proven that SCA1-knock-in mice (in which the endogenous Atxn1 gene is replaced with mutant Atxn1 that has abnormally expanded 154 CAG repeats) work as a good tool, which resembles the central nervous system pathology of SCA1 patients. However, the peripheral nervous system pathology of the model mice has not been studied despite the fact that the clinical manifestation is also characterized by peripheral involvement. We show here that spinal motor neurons are degenerated in SCA1-knock-in mice. Histologically, some spinal motor neurons of the SCA1-knock-in mice have polyglutamine aggregates in their nuclei and also thinner and demyelinated axons. Electrophysiological examinations of the mice showed slower nerve conduction velocities in spinal motor neurons and lower amplitudes of muscle action potential, compared to wild-type mice. Consistently, the mice displayed decrease in rearing number and total rearing time. These results suggest that the knock-in mice serve as a definite model that reproduces peripheral involvement and are therefore useful for research on the peripheral nervous system pathology in SCA1 patients.

  6. Spinal 5-HT7 receptor activation induces long-lasting phrenic motor facilitation

    PubMed Central

    Hoffman, M S; Mitchell, G S

    2011-01-01

    Abstract Acute intermittent hypoxia elicits a form of serotonin-dependent respiratory plasticity known as phrenic long term facilitation (pLTF). Episodic spinal serotonin-2 (5-HT2) receptor activation on or near phrenic motor neurons is necessary for pLTF. A hallmark of pLTF is the requirement for serotonin-dependent synthesis of brain-derived neurotrophic factor (BDNF), and activation of its high affinity receptor, TrkB. Activation of spinal Gs protein-coupled adenosine 2A receptors (GsPCRs) elicits a unique form of long-lasting phrenic motor facilitation (PMF), but via unique mechanisms (BDNF independent TrkB trans-activation). We hypothesized that other GsPCRs elicit PMF, specifically serotonin-7 (5-HT7) receptors, which are expressed in phrenic motor neurons. Cervical spinal (C4) injections of a selective 5-HT7 receptor agonist, AS-19 (10 μm, 5 μl; 3 × 5 min), in anaesthetized, vagotomized and ventilated male Sprague–Dawley rats elicited long-lasting PMF (>120 min), an effect prevented by pretreatment with a 5-HT7 receptor antagonist (SB 269970; 5 mm, 7 μl). GsPCR activation ‘trans-activates’ TrkB by increasing synthesis of an immature TrkB isoform. Spinal injection of a TrkB inhibitor (k252a) and siRNAs that prevent TrkB (but not BDNF) mRNA translation both blocked 5-HT7 agonist-induced PMF, confirming a requirement for TrkB synthesis and activity. k252a affected late PMF (≥90 min) only. Spinal inhibition of the PI3K/AKT pathway blocked 5-HT7 agonist-induced PMF, whereas MEK/ERK inhibition delayed, but did not block, PMF. An understanding of signalling mechanisms giving rise to PMF may guide development of novel therapeutic strategies to treat ventilatory control disorders associated with respiratory insufficiency, such as spinal injury and motor neuron disease. PMID:21242254

  7. Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy.

    PubMed

    Naryshkin, Nikolai A; Weetall, Marla; Dakka, Amal; Narasimhan, Jana; Zhao, Xin; Feng, Zhihua; Ling, Karen K Y; Karp, Gary M; Qi, Hongyan; Woll, Matthew G; Chen, Guangming; Zhang, Nanjing; Gabbeta, Vijayalakshmi; Vazirani, Priya; Bhattacharyya, Anuradha; Furia, Bansri; Risher, Nicole; Sheedy, Josephine; Kong, Ronald; Ma, Jiyuan; Turpoff, Anthony; Lee, Chang-Sun; Zhang, Xiaoyan; Moon, Young-Choon; Trifillis, Panayiota; Welch, Ellen M; Colacino, Joseph M; Babiak, John; Almstead, Neil G; Peltz, Stuart W; Eng, Loren A; Chen, Karen S; Mull, Jesse L; Lynes, Maureen S; Rubin, Lee L; Fontoura, Paulo; Santarelli, Luca; Haehnke, Daniel; McCarthy, Kathleen D; Schmucki, Roland; Ebeling, Martin; Sivaramakrishnan, Manaswini; Ko, Chien-Ping; Paushkin, Sergey V; Ratni, Hasane; Gerlach, Irene; Ghosh, Anirvan; Metzger, Friedrich

    2014-08-01

    Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality. Through chemical screening and optimization, we identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to Δ7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA.

  8. Comparison of commonly used retrograde tracers in rat spinal motor neurons.

    PubMed

    Yu, You-Lai; Li, Hai-Yan; Zhang, Pei-Xun; Yin, Xiao-Feng; Han, Na; Kou, Yu-Hui; Jiang, Bao-Guo

    2015-10-01

    The purpose of this study was to investigate the effect of four fluorescent dyes, True Blue (TB), Fluoro-Gold (FG), Fluoro-Ruby (FR), and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI), in retrograde tracing of rat spinal motor neurons. We transected the muscle branch of the rat femoral nerve and applied each tracer to the proximal stump in single labeling experiments, or combinations of tracers (FG-DiI and TB-DiI) in double labeling experiments. In the single labeling experiments, significantly fewer labeled motor neurons were observed after FR labeling than after TB, FG, or DiI, 3 days after tracer application. By 1 week, there were no significant differences in the number of labeled neurons between the four groups. In the double-labeling experiment, the number of double-labeled neurons in the FG-DiI group was not significantly different from that in the TB-DiI group 1 week after tracer application. Our findings indicate that TB, FG, and DiI have similar labeling efficacies in the retrograde labeling of spinal motor neurons in the rat femoral nerve when used alone. Furthermore, combinations of DiI and TB or FG are similarly effective. Therefore, of the dyes studied, TB, FG and DiI, and combinations of DiI with TB or FG, are the most suitable for retrograde labeling studies of motor neurons in the rat femoral nerve. PMID:26692873

  9. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease?

    PubMed

    Shababi, Monir; Lorson, Christian L; Rudnik-Schöneborn, Sabine S

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder that is the leading genetic cause of infantile death. SMA is characterized by loss of motor neurons in the ventral horn of the spinal cord, leading to weakness and muscle atrophy. SMA occurs as a result of homozygous deletion or mutations in Survival Motor Neuron-1 (SMN1). Loss of SMN1 leads to a dramatic reduction in SMN protein, which is essential for motor neuron survival. SMA disease severity ranges from extremely severe to a relatively mild adult onset form of proximal muscle atrophy. Severe SMA patients typically die mostly within months or a few years as a consequence of respiratory insufficiency and bulbar paralysis. SMA is widely known as a motor neuron disease; however, there are numerous clinical reports indicating the involvement of additional peripheral organs contributing to the complete picture of the disease in severe cases. In this review, we have compiled clinical and experimental reports that demonstrate the association between the loss of SMN and peripheral organ deficiency and malfunction. Whether defective peripheral organs are a consequence of neuronal damage/muscle atrophy or a direct result of SMN loss will be discussed.

  10. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease?

    PubMed Central

    Shababi, Monir; Lorson, Christian L; Rudnik-Schöneborn, Sabine S

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder that is the leading genetic cause of infantile death. SMA is characterized by loss of motor neurons in the ventral horn of the spinal cord, leading to weakness and muscle atrophy. SMA occurs as a result of homozygous deletion or mutations in Survival Motor Neuron-1 (SMN1). Loss of SMN1 leads to a dramatic reduction in SMN protein, which is essential for motor neuron survival. SMA disease severity ranges from extremely severe to a relatively mild adult onset form of proximal muscle atrophy. Severe SMA patients typically die mostly within months or a few years as a consequence of respiratory insufficiency and bulbar paralysis. SMA is widely known as a motor neuron disease; however, there are numerous clinical reports indicating the involvement of additional peripheral organs contributing to the complete picture of the disease in severe cases. In this review, we have compiled clinical and experimental reports that demonstrate the association between the loss of SMN and peripheral organ deficiency and malfunction. Whether defective peripheral organs are a consequence of neuronal damage/muscle atrophy or a direct result of SMN loss will be discussed. PMID:23876144

  11. One day of motor training with amphetamine impairs motor recovery following spinal cord injury.

    PubMed

    Wong, Jamie K; Steward, Oswald

    2012-02-01

    It has previously been reported that a single dose of amphetamine paired with training on a beam walking task can enhance locomotor recovery following brain injury (Feeney et al., 1982). Here, we investigated whether this same drug/training regimen could enhance functional recovery following either thoracic (T9) or cervical (C5) spinal cord injury. Different groups of female Sprague-Dawley rats were trained on a beam walking task, and in a straight alley for assessment of hindlimb locomotor recovery using the BBB locomotor scale. For rats that received C5 hemisections, forelimb grip strength was assessed using a grip strength meter. Three separate experiments assessed the consequences of training rats on the beam walking task 24 h following a thoracic lateral hemisection with administration of either amphetamine or saline. Beginning 1 h following drug administration, rats either received additional testing/retraining on the beam hourly for 6 h, or they were returned to their home cages without further testing/retraining. Rats with thoracic spinal cord injuries that received amphetamine in conjunction with testing/retraining on the beam at 1 day post injury (DPI) exhibited significantly impaired recovery on the beam walking task and BBB. Rats with cervical spinal cord injuries that received training with amphetamine also exhibited significant impairments in beam walking and locomotion, as well as impairments in gripping and reaching abilities. Even when administered at 14 DPI, the drug/training regimen significantly impaired reaching ability in cervical spinal cord injured rats. Impairments were not seen in rats that received amphetamine without training. Histological analyses revealed that rats that received training with amphetamine had significantly larger lesions than saline controls. These data indicate that an amphetamine/training regimen that improves recovery after cortical injury has the opposite effect of impairing recovery following spinal cord injury

  12. Protective effect of rosemary on acrylamide motor neurotoxicity in spinal cord of rat offspring: postnatal follow-up study

    PubMed Central

    Al-Gholam, Marwa A.; El-Mehi, Abeer E.; El-Barbary, Abd El-Moneum; Fokar, Ahmed Zo El

    2016-01-01

    The direct interactive effects of rosemary and acrylamide on the development of motor neurons in the spinal cord remains unknown. Our goal is to confirm the protective effects of rosemary against motor neuronal degeneration induced by acrylamide in the developing postnatal rat spinal cord using a postnatal rat model. We assigned the offspring of treated female rats into control, rosemary; acrylamide group; and recovery groups. This work depended on clinical, histopathological, morphometrically, immunohistochemical and genetic methods. In the acrylamide group, we observed oxidation, motor neuron degeneration, apoptosis, myelin degeneration, neurofilament reduction, reactive gliosis. Whoever, concomitant rosemary intake and withdrawal of acrylamide modulate these effects. These findings proof that dietary rosemary can directly protect motor neuron against acrylamide toxicity in the mammalian developing spinal cord. PMID:27051566

  13. Protective effect of rosemary on acrylamide motor neurotoxicity in spinal cord of rat offspring: postnatal follow-up study.

    PubMed

    Al-Gholam, Marwa A; Nooh, Hanaa Zakaria; El-Mehi, Abeer E; El-Barbary, Abd El-Moneum; Fokar, Ahmed Zo El

    2016-03-01

    The direct interactive effects of rosemary and acrylamide on the development of motor neurons in the spinal cord remains unknown. Our goal is to confirm the protective effects of rosemary against motor neuronal degeneration induced by acrylamide in the developing postnatal rat spinal cord using a postnatal rat model. We assigned the offspring of treated female rats into control, rosemary; acrylamide group; and recovery groups. This work depended on clinical, histopathological, morphometrically, immunohistochemical and genetic methods. In the acrylamide group, we observed oxidation, motor neuron degeneration, apoptosis, myelin degeneration, neurofilament reduction, reactive gliosis. Whoever, concomitant rosemary intake and withdrawal of acrylamide modulate these effects. These findings proof that dietary rosemary can directly protect motor neuron against acrylamide toxicity in the mammalian developing spinal cord. PMID:27051566

  14. Protective effect of rosemary on acrylamide motor neurotoxicity in spinal cord of rat offspring: postnatal follow-up study.

    PubMed

    Al-Gholam, Marwa A; Nooh, Hanaa Zakaria; El-Mehi, Abeer E; El-Barbary, Abd El-Moneum; Fokar, Ahmed Zo El

    2016-03-01

    The direct interactive effects of rosemary and acrylamide on the development of motor neurons in the spinal cord remains unknown. Our goal is to confirm the protective effects of rosemary against motor neuronal degeneration induced by acrylamide in the developing postnatal rat spinal cord using a postnatal rat model. We assigned the offspring of treated female rats into control, rosemary; acrylamide group; and recovery groups. This work depended on clinical, histopathological, morphometrically, immunohistochemical and genetic methods. In the acrylamide group, we observed oxidation, motor neuron degeneration, apoptosis, myelin degeneration, neurofilament reduction, reactive gliosis. Whoever, concomitant rosemary intake and withdrawal of acrylamide modulate these effects. These findings proof that dietary rosemary can directly protect motor neuron against acrylamide toxicity in the mammalian developing spinal cord.

  15. Is Spinal Muscular Atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

    PubMed Central

    Simone, Chiara; Ramirez, Agnese; Bucchia, Monica; Rinchetti, Paola; Rideout, Hardy; Papadimitriou, Dimitra; Re, Diane B.; Corti, Stefania

    2016-01-01

    Spinal Muscular Atrophy (SMA) is a genetic neurological disease that causes infant mortality; no effective therapies are currently available. SMA is due to homozygous mutations and/or deletions in the Survival Motor Neuron 1 (SMN1) gene and subsequent reduction of the SMN protein, leading to the death of motor neurons. However, there is increasing evidence that in addition to motor neurons, other cell types are contributing to SMA pathology. In this review, we will discuss the involvement of non-motor neuronal cells, located both inside and outside the central nervous system, in disease onset and progression. These contribution of non-motor neuronal cells to disease pathogenesis has important therapeutic implications: in fact, even if SMN restoration in motor neurons is needed, it has been shown that optimal phenotypic amelioration in animal models of SMA requires a more widespread SMN correction. It will be crucial to take this evidence into account before clinical translation of the novel therapeutic approaches that are currently under development. PMID:26681261

  16. ALS disrupts spinal motor neuron maturation and aging pathways within gene co-expression networks.

    PubMed

    Ho, Ritchie; Sances, Samuel; Gowing, Genevieve; Amoroso, Mackenzie Weygandt; O'Rourke, Jacqueline G; Sahabian, Anais; Wichterle, Hynek; Baloh, Robert H; Sareen, Dhruv; Svendsen, Clive N

    2016-09-01

    Modeling amyotrophic lateral sclerosis (ALS) with human induced pluripotent stem cells (iPSCs) aims to reenact embryogenesis, maturation and aging of spinal motor neurons (spMNs) in vitro. As the maturity of spMNs grown in vitro compared to spMNs in vivo remains largely unaddressed, it is unclear to what extent this in vitro system captures critical aspects of spMN development and molecular signatures associated with ALS. Here, we compared transcriptomes among iPSC-derived spMNs, fetal spinal tissues and adult spinal tissues. This approach produced a maturation scale revealing that iPSC-derived spMNs were more similar to fetal spinal tissue than to adult spMNs. Additionally, we resolved gene networks and pathways associated with spMN maturation and aging. These networks enriched for pathogenic familial ALS genetic variants and were disrupted in sporadic ALS spMNs. Altogether, our findings suggest that developing strategies to further mature and age iPSC-derived spMNs will provide more effective iPSC models of ALS pathology. PMID:27428653

  17. Angiogenic microspheres promote neural regeneration and motor function recovery after spinal cord injury in rats

    PubMed Central

    Yu, Shukui; Yao, Shenglian; Wen, Yujun; Wang, Ying; Wang, Hao; Xu, Qunyuan

    2016-01-01

    This study examined sustained co-delivery of vascular endothelial growth factor (VEGF), angiopoietin-1 and basic fibroblast growth factor (bFGF) encapsulated in angiogenic microspheres. These spheres were delivered to sites of spinal cord contusion injury in rats, and their ability to induce vessel formation, neural regeneration and improve hindlimb motor function was assessed. At 2–8 weeks after spinal cord injury, ELISA-determined levels of VEGF, angiopoietin-1, and bFGF were significantly higher in spinal cord tissues in rats that received angiogenic microspheres than in those that received empty microspheres. Sites of injury in animals that received angiogenic microspheres also contained greater numbers of isolectin B4-binding vessels and cells positive for nestin or β III-tubulin (P < 0.01), significantly more NF-positive and serotonergic fibers, and more MBP-positive mature oligodendrocytes. Animals receiving angiogenic microspheres also suffered significantly less loss of white matter volume. At 10 weeks after injury, open field tests showed that animals that received angiogenic microspheres scored significantly higher on the Basso-Beattie-Bresnahan scale than control animals (P < 0.01). Our results suggest that biodegradable, biocompatible PLGA microspheres can release angiogenic factors in a sustained fashion into sites of spinal cord injury and markedly stimulate angiogenesis and neurogenesis, accelerating recovery of neurologic function. PMID:27641997

  18. Angiogenic microspheres promote neural regeneration and motor function recovery after spinal cord injury in rats.

    PubMed

    Yu, Shukui; Yao, Shenglian; Wen, Yujun; Wang, Ying; Wang, Hao; Xu, Qunyuan

    2016-01-01

    This study examined sustained co-delivery of vascular endothelial growth factor (VEGF), angiopoietin-1 and basic fibroblast growth factor (bFGF) encapsulated in angiogenic microspheres. These spheres were delivered to sites of spinal cord contusion injury in rats, and their ability to induce vessel formation, neural regeneration and improve hindlimb motor function was assessed. At 2-8 weeks after spinal cord injury, ELISA-determined levels of VEGF, angiopoietin-1, and bFGF were significantly higher in spinal cord tissues in rats that received angiogenic microspheres than in those that received empty microspheres. Sites of injury in animals that received angiogenic microspheres also contained greater numbers of isolectin B4-binding vessels and cells positive for nestin or β III-tubulin (P < 0.01), significantly more NF-positive and serotonergic fibers, and more MBP-positive mature oligodendrocytes. Animals receiving angiogenic microspheres also suffered significantly less loss of white matter volume. At 10 weeks after injury, open field tests showed that animals that received angiogenic microspheres scored significantly higher on the Basso-Beattie-Bresnahan scale than control animals (P < 0.01). Our results suggest that biodegradable, biocompatible PLGA microspheres can release angiogenic factors in a sustained fashion into sites of spinal cord injury and markedly stimulate angiogenesis and neurogenesis, accelerating recovery of neurologic function. PMID:27641997

  19. Crosstalk between p38, Hsp25 and Akt in spinal motor neurons after sciatic nerve injury

    NASA Technical Reports Server (NTRS)

    Murashov, A. K.; Ul Haq, I.; Hill, C.; Park, E.; Smith, M.; Wang, X.; Wang, X.; Goldberg, D. J.; Wolgemuth, D. J.

    2001-01-01

    The p38 stress-activated protein kinase pathway is involved in regulation of phosphorylation of Hsp25, which in turn regulates actin filament dynamic in non-neuronal cells. We report that p38, Hsp25 and Akt signaling pathways were specifically activated in spinal motor neurons after sciatic nerve axotomy. The activation of the p38 kinase was required for induction of Hsp25 expression. Furthermore, Hsp25 formed a complex with Akt, a member of PI-3 kinase pathway that prevents neuronal cell death. Together, our observations implicate Hsp25 as a central player in a complex system of signaling that may both promote regeneration of nerve fibers and prevent neuronal cell death in the injured spinal cord.

  20. Identification of a spinal circuit for light touch and fine motor control

    PubMed Central

    Bourane, Steeve; Grossmann, Katja S.; Britz, Olivier; Dalet, Antoine; Del Barrio, Marta Garcia; Stam, Floor J.; Garcia-Campmany, Lidia; Koch, Stephanie; Goulding, Martyn

    2015-01-01

    Sensory circuits in the dorsal spinal cord integrate and transmit multiple cutaneous sensory modalities including the sense of light touch. Here we identify a population of excitatory interneurons (INs) in the dorsal horn that are important for transmitting innocuous light touch sensation. These neurons express the ROR alpha (RORα) nuclear orphan receptor and are selectively innervated by cutaneous low threshold mechanoreceptors (LTMs). Targeted removal of RORα INs in the dorsal spinal cord leads a marked reduction in behavioral responsiveness to light touch without affecting responses to noxious and itch stimuli. RORα IN-deficient mice also display a selective deficit in corrective foot movements. This phenotype, together with our demonstration that the RORα INs are innervated by corticospinal and vestibulospinal projection neurons, argues that the RORα INs direct corrective reflex movements by integrating touch information with descending motor commands from the cortex and cerebellum. PMID:25635458

  1. A hybrid electrical/chemical circuit in the spinal cord generates a transient embryonic motor behavior.

    PubMed

    Knogler, Laura D; Ryan, Joel; Saint-Amant, Louis; Drapeau, Pierre

    2014-07-16

    Spontaneous network activity is a highly stereotyped early feature of developing circuits throughout the nervous system, including in the spinal cord. Spinal locomotor circuits produce a series of behaviors during development before locomotion that reflect the continual integration of spinal neurons into a functional network, but how the circuitry is reconfigured is not understood. The first behavior of the zebrafish embryo (spontaneous coiling) is mediated by an electrical circuit that subsequently generates mature locomotion (swimming) as chemical neurotransmission develops. We describe here a new spontaneous behavior, double coiling, that consists of two alternating contractions of the tail in rapid succession. Double coiling was glutamate-dependent and required descending hindbrain excitation, similar to but preceding swimming, making it a discrete intermediary developmental behavior. At the cellular level, motoneurons had a distinctive glutamate-dependent activity pattern that correlated with double coiling. Two glutamatergic interneurons, CoPAs and CiDs, had different activity profiles during this novel behavior. CoPA neurons failed to show changes in activity patterns during the period in which double coiling appears, whereas CiD neurons developed a glutamate-dependent activity pattern that correlated with double coiling and they innervated motoneurons at that time. Additionally, double coils were modified after pharmacological reduction of glycinergic neurotransmission such that embryos produced three or more rapidly alternating coils. We propose that double coiling behavior represents an important transition of the motor network from an electrically coupled spinal cord circuit that produces simple periodic coils to a spinal network driven by descending chemical neurotransmission, which generates more complex behaviors.

  2. Effect of hyperbaric oxygen on MMP9/2 expression and motor function in rats with spinal cord injury

    PubMed Central

    Hou, Ying-Nuo; Ding, Wen-Yuan; Shen, Yong; Yang, Da-Long; Wang, Lin-Feng; Zhang, Peng

    2015-01-01

    To study the effect of hyperbaric oxygen intervention on the microenvironment of nerve regeneration after spinal cord injury modeling and to explore the possible mechanism of nerve regeneration and functional recovery in rats with spinal cord injury. In 98 adult female SD rats, 90 successful models were obtained, which were divided into sham group, spinal cord injury group and hyperbaric oxygen group using randomized block method, 30/group. Spinal cord injury rat model was established in accordance with the modified Allen method. Motor function was assessed at the time points of before modeling, one day, three days, one week, two weeks, three weeks and four weeks after modeling respectively by BBB rating, inclined plane test and improved Tarlov score. At 3 days after modeling, apoptosis of neuronal cells in spinal cord injury region in experimental group was detected by TUNEL method; gene and protein expression of MMP9/2 in spinal cord injury and surrounding tissues was detected by RT-PCR and Western blot assay. At 4 weeks after modeling, histopathological morphological changes in spinal cord injury were observed by HE staining; fluorogold retrograde tracing was used to observe the regeneration and distribution of spinal cord nerve fibers and axon regeneration was observed by TEM. The three motor function scores in hyperbaric oxygen group at each time point after two weeks of treatment were significantly increased compared with spinal cord injury group (P < 0.05). At 3 d after modeling, apoptosis index in hyperbaric oxygen group were significantly lower than those in spinal cord injury group (P < 0.05). At 72 h after modeling, compared with spinal cord injury group, MMP9/2 gene and protein expression in hyperbaric oxygen group was significantly lower (P < 0.05). At four weeks after modeling, fluorogold positive nerve fibers were the most sham group, followed by hyperbaric oxygen group and spinal cord injury group in order; the differences among the groups were

  3. Effect of hyperbaric oxygen on MMP9/2 expression and motor function in rats with spinal cord injury.

    PubMed

    Hou, Ying-Nuo; Ding, Wen-Yuan; Shen, Yong; Yang, Da-Long; Wang, Lin-Feng; Zhang, Peng

    2015-01-01

    To study the effect of hyperbaric oxygen intervention on the microenvironment of nerve regeneration after spinal cord injury modeling and to explore the possible mechanism of nerve regeneration and functional recovery in rats with spinal cord injury. In 98 adult female SD rats, 90 successful models were obtained, which were divided into sham group, spinal cord injury group and hyperbaric oxygen group using randomized block method, 30/group. Spinal cord injury rat model was established in accordance with the modified Allen method. Motor function was assessed at the time points of before modeling, one day, three days, one week, two weeks, three weeks and four weeks after modeling respectively by BBB rating, inclined plane test and improved Tarlov score. At 3 days after modeling, apoptosis of neuronal cells in spinal cord injury region in experimental group was detected by TUNEL method; gene and protein expression of MMP9/2 in spinal cord injury and surrounding tissues was detected by RT-PCR and Western blot assay. At 4 weeks after modeling, histopathological morphological changes in spinal cord injury were observed by HE staining; fluorogold retrograde tracing was used to observe the regeneration and distribution of spinal cord nerve fibers and axon regeneration was observed by TEM. The three motor function scores in hyperbaric oxygen group at each time point after two weeks of treatment were significantly increased compared with spinal cord injury group (P < 0.05). At 3 d after modeling, apoptosis index in hyperbaric oxygen group were significantly lower than those in spinal cord injury group (P < 0.05). At 72 h after modeling, compared with spinal cord injury group, MMP9/2 gene and protein expression in hyperbaric oxygen group was significantly lower (P < 0.05). At four weeks after modeling, fluorogold positive nerve fibers were the most sham group, followed by hyperbaric oxygen group and spinal cord injury group in order; the differences among the groups were

  4. Effect of hyperbaric oxygen on MMP9/2 expression and motor function in rats with spinal cord injury.

    PubMed

    Hou, Ying-Nuo; Ding, Wen-Yuan; Shen, Yong; Yang, Da-Long; Wang, Lin-Feng; Zhang, Peng

    2015-01-01

    To study the effect of hyperbaric oxygen intervention on the microenvironment of nerve regeneration after spinal cord injury modeling and to explore the possible mechanism of nerve regeneration and functional recovery in rats with spinal cord injury. In 98 adult female SD rats, 90 successful models were obtained, which were divided into sham group, spinal cord injury group and hyperbaric oxygen group using randomized block method, 30/group. Spinal cord injury rat model was established in accordance with the modified Allen method. Motor function was assessed at the time points of before modeling, one day, three days, one week, two weeks, three weeks and four weeks after modeling respectively by BBB rating, inclined plane test and improved Tarlov score. At 3 days after modeling, apoptosis of neuronal cells in spinal cord injury region in experimental group was detected by TUNEL method; gene and protein expression of MMP9/2 in spinal cord injury and surrounding tissues was detected by RT-PCR and Western blot assay. At 4 weeks after modeling, histopathological morphological changes in spinal cord injury were observed by HE staining; fluorogold retrograde tracing was used to observe the regeneration and distribution of spinal cord nerve fibers and axon regeneration was observed by TEM. The three motor function scores in hyperbaric oxygen group at each time point after two weeks of treatment were significantly increased compared with spinal cord injury group (P < 0.05). At 3 d after modeling, apoptosis index in hyperbaric oxygen group were significantly lower than those in spinal cord injury group (P < 0.05). At 72 h after modeling, compared with spinal cord injury group, MMP9/2 gene and protein expression in hyperbaric oxygen group was significantly lower (P < 0.05). At four weeks after modeling, fluorogold positive nerve fibers were the most sham group, followed by hyperbaric oxygen group and spinal cord injury group in order; the differences among the groups were

  5. Comparison of commonly used retrograde tracers in rat spinal motor neurons

    PubMed Central

    Yu, You-lai; Li, Hai-yan; Zhang, Pei-xun; Yin, Xiao-feng; Han, Na; Kou, Yu-hui; Jiang, Bao-guo

    2015-01-01

    The purpose of this study was to investigate the effect of four fluorescent dyes, True Blue (TB), Fluoro-Gold (FG), Fluoro-Ruby (FR), and 1,1’-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI), in retrograde tracing of rat spinal motor neurons. We transected the muscle branch of the rat femoral nerve and applied each tracer to the proximal stump in single labeling experiments, or combinations of tracers (FG-DiI and TB-DiI) in double labeling experiments. In the single labeling experiments, significantly fewer labeled motor neurons were observed after FR labeling than after TB, FG, or DiI, 3 days after tracer application. By 1 week, there were no significant differences in the number of labeled neurons between the four groups. In the double-labeling experiment, the number of double-labeled neurons in the FG-DiI group was not significantly different from that in the TB-DiI group 1 week after tracer application. Our findings indicate that TB, FG, and DiI have similar labeling efficacies in the retrograde labeling of spinal motor neurons in the rat femoral nerve when used alone. Furthermore, combinations of DiI and TB or FG are similarly effective. Therefore, of the dyes studied, TB, FG and DiI, and combinations of DiI with TB or FG, are the most suitable for retrograde labeling studies of motor neurons in the rat femoral nerve. PMID:26692873

  6. Motor command for precision grip in the macaque monkey can be mediated by spinal interneurons.

    PubMed

    Alstermark, B; Pettersson, L G; Nishimura, Y; Yoshino-Saito, K; Tsuboi, F; Takahashi, M; Isa, T

    2011-07-01

    In motor control, the general view is still that spinal interneurons mainly contribute to reflexes and automatic movements. The question raised here is whether spinal interneurons can mediate the cortical command for independent finger movements, like a precision grip between the thumb and index finger in the macaque monkey, or if this function depends exclusively on a direct corticomotoneuronal pathway. This study is a followup of a previous report (Sasaki et al. J Neurophysiol 92: 3142-3147, 2004) in which we trained macaque monkeys to pick a small piece of sweet potato from a cylinder by a precision grip between the index finger and thumb. We have now isolated one spinal interneuronal system, the C3-C4 propriospinal interneurons with projection to hand and arm motoneurons. In the previous study, the lateral corticospinal tract (CST) was interrupted in C4/C5 (input intact to the C3-C4 propriospinal interneurons), and in this study, the CST was interrupted in C2 (input abolished). The precision grip could be performed within the first 15 days after a CST lesion in C4/C5 but not in C2. We conclude that C3-C4 propriospinal interneurons also can carry the command for precision grip. PMID:21511706

  7. Motor Vehicle Crash–Related Injury Causation Scenarios for Spinal Injuries in Restrained Children and Adolescents

    PubMed Central

    ZONFRILLO, MARK R.; LOCEY, CAITLIN M.; SCARFONE, STEVEN R.; ARBOGAST, KRISTY B.

    2016-01-01

    Objective Motor vehicle crash (MVC)-related spinal injuries result in significant morbidity and mortality in children. The objective was to identify MVC-related injury causation scenarios for spinal injuries in restrained children. Methods This was a case series of occupants in MVCs from the Crash Injury Research and Engineering Network (CIREN) data set. Occupants aged 0–17 years old with at least one Abbreviated Injury Scale (AIS) 2+ severity spinal injury in vehicles model year 1990+ that did not experience a rollover were included. Unrestrained occupants, those not using the shoulder portion of the belt restraint, and those with child restraint gross misuse were excluded. Occupants with preexisting comorbidities contributing to spinal injury and occupants with limited injury information were also excluded. A multidisciplinary team retrospectively reviewed each case to determine injury causation scenarios (ICSs). Crash conditions, occupant and restraint characteristics, and injuries were qualitatively summarized. Results Fifty-nine cases met the study inclusion criteria and 17 were excluded. The 42 occupants included sustained 97 distinct AIS 2+ spinal injuries (27 cervical, 22 thoracic, and 48 lumbar; 80 AIS-2, 15 AIS-3, 1 AIS-5, and 1 AIS-6), with fracture as the most common injury type (80%). Spinal-injured occupants were most frequently in passenger cars (64%), and crash direction was most often frontal (62%). Mean delta-V was 51.3 km/h ± 19.4 km/h. The average occupant age was 12.4 ± 5.3 years old, and 48% were 16- to 17-year-olds. Thirty-six percent were right front passengers and 26% were drivers. Most occupants were lap and shoulder belt restrained (88%). Non-spinal AIS 2+ injuries included those of the lower extremity and pelvis (n = 56), head (n = 43), abdomen (n = 39), and thorax (n = 36). Spinal injury causation was typically due to flexion or lateral bending over the lap and or shoulder belt or child restraint harness, compression by occupant

  8. Cervical spinal demyelination with ethidium bromide impairs respiratory (phrenic) activity and forelimb motor behavior in rats.

    PubMed

    Nichols, N L; Punzo, A M; Duncan, I D; Mitchell, G S; Johnson, R A

    2013-01-15

    Although respiratory complications are a major cause of morbidity/mortality in many neural injuries or diseases, little is known concerning mechanisms whereby deficient myelin impairs breathing, or how patients compensate for such changes. Here, we tested the hypothesis that respiratory and forelimb motor functions are impaired in a rat model of focal dorsolateral spinal demyelination (ethidium bromide, EB). Ventilation, phrenic nerve activity and horizontal ladder walking were performed 7-14 days post-C2 injection of EB or vehicle (SHAM). EB caused dorsolateral demyelination at C2-C3 followed by significant spontaneous remyelination at 14 days post-EB. Although ventilation did not differ between groups, ipsilateral integrated phrenic nerve burst amplitude was significantly reduced versus SHAM during chemoreceptor activation at 7 days post-EB but recovered by 14 days. The ratio of ipsi- to contralateral phrenic nerve amplitude correlated with cross-sectional lesion area. This ratio was significantly reduced 7 days post-EB versus SHAM during baseline conditions, and versus SHAM and 14-day groups during chemoreceptor activation. Limb function ipsilateral to EB was impaired 7 days post-EB and partially recovered by 14 days post-EB. EB provides a reversible model of focal, spinal demyelination, and may be a useful model to study mechanisms of functional impairment and recovery via motor plasticity, or the efficacy of new therapeutic interventions to reduce severity or duration of disease. PMID:23159317

  9. Six-Minute Walk Test demonstrates motor fatigue in spinal muscular atrophy

    PubMed Central

    Montes, J.; McDermott, M. P.; Martens, W. B.; Dunaway, S.; Glanzman, A. M.; Riley, S.; Quigley, J.; Montgomery, M. J.; Sproule, D.; Tawil, R.; Chung, W. K.; Darras, B. T.; De Vivo, D. C.; Kaufmann, P.; Finkel, R. S.

    2010-01-01

    Background: In spinal muscular atrophy (SMA), weakness, decreased endurance, and fatigue limit mobility. Scales have been developed to measure function across the wide spectrum of disease severity. However, these scales typically are observer dependent, and scores are based on sums across Likert-scaled items. The Six-Minute Walk Test (6MWT) is an objective, easily administered, and standardized evaluation of functional exercise capacity that has been proven reliable in other neurologic disorders and in children. Methods: To study the performance of the 6MWT in SMA, 18 ambulatory participants were evaluated in a cross-sectional study. Clinical measures were 6MWT, 10-m walk/run, Hammersmith Functional Motor Scale–Expanded (HFMSE), forced vital capacity, and handheld dynamometry. Associations between the 6MWT total distance and other outcomes were analyzed using Spearman correlation coefficients. A paired t test was used to compare the mean distance walked in the first and sixth minutes. Results: The 6MWT was associated with the HFMSE score (r = 0.83, p < 0.0001), 10-m walk/run (r = −0.87, p < 0.0001), and knee flexor strength (r = 0.62, p = 0.01). Gait velocity decreased during successive minutes in nearly all participants. The average first minute distance (57.5 m) was significantly more than the sixth minute distance (48 m) (p = 0.0003). Conclusion: The Six-Minute Walk Test (6MWT) can be safely performed in ambulatory patients with spinal muscular atrophy (SMA), correlates with established outcome measures, and is sensitive to fatigue-related changes. The 6MWT is a promising candidate outcome measure for clinical trials in ambulatory subjects with SMA. GLOSSARY FVC = forced vital capacity; HFMSE = Hammersmith Functional Motor Scale–Expanded; HHD = handheld dynamometry; 6MWT = Six-Minute Walk Test; SMA = spinal muscular atrophy. PMID:20211907

  10. Reduced functional recovery by delaying motor training after spinal cord injury.

    PubMed

    Norrie, B A; Nevett-Duchcherer, J M; Gorassini, M A

    2005-07-01

    The purpose of this study was to examine if a delay in rehabilitative motor training after spinal cord injury affects functional motor recovery. We studied a skilled motor task in which rats traversed a raised horizontal ladder and we quantified errors in accurate stepping, i.e., foot slips between rungs. After lesions to the dorsal quadrant of the thoracic (T8) spinal cord that aimed to unilaterally sever the corticospinal and rubrospinal tracts, rats were re-trained to walk across the ladder, either immediately after injury or after a 3-mo delay. Before training, the error rate in accurate stepping of the affected hindlimb was similar in the immediately (69.4 +/- 5.3%) and delay (62.7 +/- 4.1%; means +/- SE)-trained animals (not significantly different), suggesting that accurate stepping did not improve spontaneously if rats were not exposed to the ladder. After a 3-wk course of training (30 runs across the ladder per day, 5 day/wk), improvements in accurate stepping performance were greater if training was implemented immediately after injury. On average, immediately trained animals improved stepping performance by 61.5 +/- 28.2%, whereas the delay trained group improved by only 34.9 +/- 28.8% (significantly different). The degree of damage to the corticospinal and rubrospinal tracts was very similar in the two groups of animals, indicating that differences in lesion size did not contribute to the differences in performance improvement. Animals with large lesions to the corticospinal and rubrospinal tracts (>70%) displayed poor recovery from training (especially for delay-trained animals), suggesting that these two pathways were important in mediating improvements in accurate stepping. In addition, recovery of stepping-like reflexes appeared not to contribute to the recovery of accurate stepping given that the time course of reflex recovery was not related to the time course of recovery of accurate stepping. We conclude that training of a skilled motor task that

  11. Spinal Muscular Atrophy Patient iPSC-Derived Motor Neurons Have Reduced Expression of Proteins Important in Neuronal Development

    PubMed Central

    Fuller, Heidi R.; Mandefro, Berhan; Shirran, Sally L.; Gross, Andrew R.; Kaus, Anjoscha S.; Botting, Catherine H.; Morris, Glenn E.; Sareen, Dhruv

    2016-01-01

    Spinal muscular atrophy (SMA) is an inherited neuromuscular disease primarily characterized by degeneration of spinal motor neurons, and caused by reduced levels of the SMN protein. Previous studies to understand the proteomic consequences of reduced SMN have mostly utilized patient fibroblasts and animal models. We have derived human motor neurons from type I SMA and healthy controls by creating their induced pluripotent stem cells (iPSCs). Quantitative mass spectrometry of these cells revealed increased expression of 63 proteins in control motor neurons compared to respective fibroblasts, whereas 30 proteins were increased in SMA motor neurons vs. their fibroblasts. Notably, UBA1 was significantly decreased in SMA motor neurons, supporting evidence for ubiquitin pathway defects. Subcellular distribution of UBA1 was predominantly cytoplasmic in SMA motor neurons in contrast to nuclear in control motor neurons; suggestive of neurodevelopmental abnormalities. Many of the proteins that were decreased in SMA motor neurons, including beta III-tubulin and UCHL1, were associated with neurodevelopment and differentiation. These neuron-specific consequences of SMN depletion were not evident in fibroblasts, highlighting the importance of iPSC technology. The proteomic profiles identified here provide a useful resource to explore the molecular consequences of reduced SMN in motor neurons, and for the identification of novel biomarker and therapeutic targets for SMA. PMID:26793058

  12. Inducing Chronic Excitotoxicity in the Mouse Spinal Cord to Investigate Lower Motor Neuron Degeneration

    PubMed Central

    Blizzard, Catherine A.; Lee, K. M.; Dickson, Tracey C.

    2016-01-01

    We report the methodology for the chronic delivery of an excitotoxin to the mouse spinal cord via surgically implanted osmotic mini-pumps. Previous studies have investigated the effect of chronic application of excitotoxins in the rat, however there has been little translation of this model to the mouse. Using mice that express yellow fluorescent protein (YFP), motor neuron and neuromuscular junction alterations can be investigate following targeted, long-term (28 days) exposure to the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor excitotoxin, kainic acid. By targeting the L3-4 region of the lumbar spinal cord, with insertion of an intrathecal catheter into the subarachnoid space at L5, chronic application of the kainic acid results in slow excitotoxic death in the anterior ventral horn, with a significant (P < 0.05) reduction in the number of SMI-32 immunopositive neurons present after 28 days infusion. Use of the Thy1-YFP mice provides unrivaled visualization of the neuromuscular junction and enables the resultant distal degeneration in skeletal muscle to be observed. Both neuromuscular junction retraction at the gastrocnemius muscle and axonal fragmentation in the sciatic nerve were observed after chronic infusion of kainic acid for 28 days. Lower motor neuron, and distal neuromuscular junction, degeneration are pathological hallmarks of the devastating neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). This mouse model will be advantageous for increasing our understanding of how the pathophysiological phenomena associated with this disease can lead to lower motor neuron loss and distal pathology, as well as providing a robust in vivo platform to test therapeutic interventions directed at excitotoxic mechanisms. PMID:26973454

  13. AMPA Receptor Phosphorylation and Synaptic Colocalization on Motor Neurons Drive Maladaptive Plasticity below Complete Spinal Cord Injury

    PubMed Central

    Stuck, Ellen D.; Irvine, Karen-Amanda; Bresnahan, Jacqueline C.

    2015-01-01

    Abstract Clinical spinal cord injury (SCI) is accompanied by comorbid peripheral injury in 47% of patients. Human and animal modeling data have shown that painful peripheral injuries undermine long-term recovery of locomotion through unknown mechanisms. Peripheral nociceptive stimuli induce maladaptive synaptic plasticity in dorsal horn sensory systems through AMPA receptor (AMPAR) phosphorylation and trafficking to synapses. Here we test whether ventral horn motor neurons in rats demonstrate similar experience-dependent maladaptive plasticity below a complete SCI in vivo. Quantitative biochemistry demonstrated that intermittent nociceptive stimulation (INS) rapidly and selectively increases AMPAR subunit GluA1 serine 831 phosphorylation and localization to synapses in the injured spinal cord, while reducing synaptic GluA2. These changes predict motor dysfunction in the absence of cell death signaling, suggesting an opportunity for therapeutic reversal. Automated confocal time-course analysis of lumbar ventral horn motor neurons confirmed a time-dependent increase in synaptic GluA1 with concurrent decrease in synaptic GluA2. Optical fractionation of neuronal plasma membranes revealed GluA2 removal from extrasynaptic sites on motor neurons early after INS followed by removal from synapses 2 h later. As GluA2-lacking AMPARs are canonical calcium-permeable AMPARs (CP-AMPARs), their stimulus- and time-dependent insertion provides a therapeutic target for limiting calcium-dependent dynamic maladaptive plasticity after SCI. Confirming this, a selective CP-AMPAR antagonist protected against INS-induced maladaptive spinal plasticity, restoring adaptive motor responses on a sensorimotor spinal training task. These findings highlight the critical involvement of AMPARs in experience-dependent spinal cord plasticity after injury and provide a pharmacologically targetable synaptic mechanism by which early postinjury experience shapes motor plasticity. PMID:26668821

  14. AMPA Receptor Phosphorylation and Synaptic Colocalization on Motor Neurons Drive Maladaptive Plasticity below Complete Spinal Cord Injury.

    PubMed

    Huie, J Russell; Stuck, Ellen D; Lee, Kuan H; Irvine, Karen-Amanda; Beattie, Michael S; Bresnahan, Jacqueline C; Grau, James W; Ferguson, Adam R

    2015-01-01

    Clinical spinal cord injury (SCI) is accompanied by comorbid peripheral injury in 47% of patients. Human and animal modeling data have shown that painful peripheral injuries undermine long-term recovery of locomotion through unknown mechanisms. Peripheral nociceptive stimuli induce maladaptive synaptic plasticity in dorsal horn sensory systems through AMPA receptor (AMPAR) phosphorylation and trafficking to synapses. Here we test whether ventral horn motor neurons in rats demonstrate similar experience-dependent maladaptive plasticity below a complete SCI in vivo. Quantitative biochemistry demonstrated that intermittent nociceptive stimulation (INS) rapidly and selectively increases AMPAR subunit GluA1 serine 831 phosphorylation and localization to synapses in the injured spinal cord, while reducing synaptic GluA2. These changes predict motor dysfunction in the absence of cell death signaling, suggesting an opportunity for therapeutic reversal. Automated confocal time-course analysis of lumbar ventral horn motor neurons confirmed a time-dependent increase in synaptic GluA1 with concurrent decrease in synaptic GluA2. Optical fractionation of neuronal plasma membranes revealed GluA2 removal from extrasynaptic sites on motor neurons early after INS followed by removal from synapses 2 h later. As GluA2-lacking AMPARs are canonical calcium-permeable AMPARs (CP-AMPARs), their stimulus- and time-dependent insertion provides a therapeutic target for limiting calcium-dependent dynamic maladaptive plasticity after SCI. Confirming this, a selective CP-AMPAR antagonist protected against INS-induced maladaptive spinal plasticity, restoring adaptive motor responses on a sensorimotor spinal training task. These findings highlight the critical involvement of AMPARs in experience-dependent spinal cord plasticity after injury and provide a pharmacologically targetable synaptic mechanism by which early postinjury experience shapes motor plasticity.

  15. Alterations in multidimensional motor unit number index of hand muscles after incomplete cervical spinal cord injury.

    PubMed

    Li, Le; Li, Xiaoyan; Liu, Jie; Zhou, Ping

    2015-01-01

    The objective of this study was to apply a novel multidimensional motor unit number index (MD-MUNIX) technique to examine hand muscles in patients with incomplete cervical spinal cord injury (SCI). The MD-MUNIX was estimated from the compound muscle action potential (CMAP) and different levels of surface interference pattern electromyogram (EMG) at multiple directions of voluntary isometric muscle contraction. The MD-MUNIX was applied in the first dorsal interosseous (FDI), thenar and hypothenar muscles of SCI (n = 12) and healthy control (n = 12) subjects. The results showed that the SCI subjects had significantly smaller CMAP and MD-MUNIX in all the three examined muscles, compared to those derived from the healthy control subjects. The multidimensional motor unit size index (MD-MUSIX) demonstrated significantly larger values for the FDI and hypothenar muscles in SCI subjects than those from healthy control subjects, whereas the MD-MUSIX enlargement was marginally significant for the thenar muscles. The findings from the MD-MUNIX analyses provide an evidence of motor unit loss in hand muscles of cervical SCI patients, contributing to hand function deterioration. PMID:26005410

  16. Generating Diverse Spinal Motor Neuron Subtypes from Human Pluripotent Stem Cells

    PubMed Central

    Patani, Rickie

    2016-01-01

    Resolving the mechanisms underlying human neuronal diversification remains a major challenge in developmental and applied neurobiology. Motor neurons (MNs) represent a diverse pool of neuronal subtypes exhibiting differential vulnerability in different human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). The ability to predictably manipulate MN subtype lineage restriction from human pluripotent stem cells (PSCs) will form the essential basis to establishing accurate, clinically relevant in vitro disease models. I first overview motor neuron developmental biology to provide some context for reviewing recent studies interrogating pathways that influence the generation of MN diversity. I conclude that motor neurogenesis from PSCs provides a powerful reductionist model system to gain insight into the developmental logic of MN subtype diversification and serves more broadly as a leading exemplar of potential strategies to resolve the molecular basis of neuronal subclass differentiation within the nervous system. These studies will in turn permit greater mechanistic understanding of differential MN subtype vulnerability using in vitro human disease models. PMID:26823667

  17. Characterization of recovered walking patterns and motor control after contusive spinal cord injury in rats

    PubMed Central

    Hansen, Christopher N; Linklater, William; Santiago, Raquel; Fisher, Lesley C; Moran, Stephanie; Buford, John A; Michele Basso, D

    2012-01-01

    Currently, complete recovery is unattainable for most individuals with spinal cord injury (SCI). Instead, recovery is typically accompanied by persistent sensory and motor deficits. Restoration of preinjury function will likely depend on improving plasticity and integration of these impaired systems. Eccentric muscle actions require precise integration of sensorimotor signals and are predominant during the yield (E2) phase of locomotion. Motor neuron activation and control during eccentric contractions is impaired across a number of central nervous system (CNS) disorders, but remains unexamined after SCI. Therefore, we characterized locomotor recovery after contusive SCI using hindlimb (HL) kinematics and electromyographic (EMG) recordings with specific consideration of eccentric phases of treadmill (TM) walking. Deficits in E2 and a caudal shift of locomotor subphases persisted throughout the 3-week recovery period. EMG records showed notable deficits in the semitendinosus (ST) during yield. Unlike other HL muscles, recruitment of ST changed with recovery. At 7 days, the typical dual-burst pattern of ST was lost and the second burst (ST2) was indistinct. By 21 days, the dual-burst pattern returned, but latencies remained impaired. We show that ST2 burst duration is highly predictive of open field Basso, Beattie, Bresnahan (BBB) scores. Moreover, we found that simple changes in locomotor specificity which enhance eccentric actions result in new motor patterns after SCI. Our findings identify a caudal shift in stepping kinematics, irregularities in E2, and aberrant ST2 bursting as markers of incomplete recovery. These residual impairments may provide opportunities for targeted rehabilitation. PMID:23139900

  18. Synergistic integration of Netrin and ephrin axon guidance signals by spinal motor neurons

    PubMed Central

    Poliak, Sebastian; Morales, Daniel; Croteau, Louis-Philippe; Krawchuk, Dayana; Palmesino, Elena; Morton, Susan; Cloutier, Jean-François; Charron, Frederic; Dalva, Matthew B; Ackerman, Susan L; Kao, Tzu-Jen; Kania, Artur

    2015-01-01

    During neural circuit assembly, axonal growth cones are exposed to multiple guidance signals at trajectory choice points. While axonal responses to individual guidance cues have been extensively studied, less is known about responses to combination of signals and underlying molecular mechanisms. Here, we studied the convergence of signals directing trajectory selection of spinal motor axons entering the limb. We first demonstrate that Netrin-1 attracts and repels distinct motor axon populations, according to their expression of Netrin receptors. Quantitative in vitro assays demonstrate that motor axons synergistically integrate both attractive or repulsive Netrin-1 signals together with repulsive ephrin signals. Our investigations of the mechanism of ephrin-B2 and Netrin-1 integration demonstrate that the Netrin receptor Unc5c and the ephrin receptor EphB2 can form a complex in a ligand-dependent manner and that Netrin–ephrin synergistic growth cones responses involve the potentiation of Src family kinase signaling, a common effector of both pathways. DOI: http://dx.doi.org/10.7554/eLife.10841.001 PMID:26633881

  19. Different phase delays of peripheral input to primate motor cortex and spinal cord promote cancellation at physiological tremor frequencies.

    PubMed

    Koželj, Saša; Baker, Stuart N

    2014-05-01

    Neurons in the spinal cord and motor cortex (M1) are partially phase-locked to cycles of physiological tremor, but with opposite phases. Convergence of spinal and cortical activity onto motoneurons may thus produce phase cancellation and a reduction in tremor amplitude. The mechanisms underlying this phase difference are unknown. We investigated coherence between spinal and M1 activity with sensory input. In two anesthetized monkeys, we electrically stimulated the medial, ulnar, deep radial, and superficial radial nerves; stimuli were timed as independent Poisson processes (rate 10 Hz). Single units were recorded from M1 (147 cells) or cervical spinal cord (61 cells). Ninety M1 cells were antidromically identified as pyramidal tract neurons (PTNs); M1 neurons were additionally classified according to M1 subdivision (rostral/caudal, M1r/c). Spike-stimulus coherence analysis revealed significant coupling over a broad range of frequencies, with the strongest coherence at <50 Hz. Delays implied by the slope of the coherence phase-frequency relationship were greater than the response onset latency, reflecting the importance of late response components for the transmission of oscillatory inputs. The spike-stimulus coherence phase over the 6-13 Hz physiological tremor band differed significantly between M1 and spinal cells (phase differences relative to the cord of 2.72 ± 0.29 and 1.72 ± 0.37 radians for PTNs from M1c and M1r, respectively). We conclude that different phases of the response to peripheral input could partially underlie antiphase M1 and spinal cord activity during motor behavior. The coordinated action of spinal and cortical feedback will act to reduce tremulous oscillations, possibly improving the overall stability and precision of motor control.

  20. eGFP expression under the Uchl1 promoter labels corticospinal motor neurons and a subpopulation of degeneration resistant spinal motor neurons in ALS mouse models

    NASA Astrophysics Data System (ADS)

    Yasvoina, Marina V.

    Current understanding of basic cellular and molecular mechanisms for motor neuron vulnerability during motor neuron disease initiation and progression is incomplete. The complex cytoarchitecture and cellular heterogeneity of the cortex and spinal cord greatly impedes our ability to visualize, isolate, and study specific neuron populations in both healthy and diseased states. We generated a novel reporter line, the Uchl1-eGFP mouse, in which cortical and spinal components of motor neuron circuitry are genetically labeled with eGFP under the Uchl1 promoter. A series of cellular and anatomical analyses combined with retrograde labeling, molecular marker expression, and electrophysiology were employed to determine identity of eGFP expressing cells in the motor cortex and the spinal cord of novel Uchl1-eGFP reporter mice. We conclude that eGFP is expressed in corticospinal motor neurons (CSMN) in the motor cortex and a subset of S-type alpha and gamma spinal motor neurons (SMN) in the spinal cord. hSOD1G93A and Alsin-/- mice, mouse models for amyotrophic lateral sclerosis (ALS), were bred to Uchl1-eGFP reporter mouse line to investigate the pathophysiology and underlying mechanisms of CSMN degeneration in vivo. Evidence suggests early and progressive degeneration of CSMN and SMN in the hSOD1G93A transgenic mice. We show an early increase of autophagosome formation in the apical dendrites of vulnerable CSMN in hSOD1G93A-UeGFP mice, which is localized to the apical dendrites. In addition, labeling S-type alpha and gamma SMN in the hSOD1G93A-UeGFP mice provide a unique opportunity to study basis of their resistance to degeneration. Mice lacking alsin show moderate clinical phenotype and mild CSMN axon degeneration in the spinal cord, which suggests vulnerability of CSMN. Therefore, we investigated the CSMN cellular and axon defects in aged Alsin-/- mice bred to Uchl1-eGFP reporter mouse line. We show that while CSMN are preserved and lack signs of degeneration, CSMN axons

  1. Motor Alterations Induced by Chronic 4-Aminopyridine Infusion in the Spinal Cord In vivo: Role of Glutamate and GABA Receptors

    PubMed Central

    Lazo-Gómez, Rafael; Tapia, Ricardo

    2016-01-01

    Motor neuron (MN) degeneration is the pathological hallmark of MN diseases, a group of neurodegenerative disorders clinically manifested as muscle fasciculations and hyperreflexia, followed by paralysis, respiratory failure, and death. Ample evidence supports a role of glutamate-mediated excitotoxicity in motor death. In previous work we showed that stimulation of glutamate release from nerve endings by perfusion of the K+-channel blocker 4-aminopyridine (4-AP) in the rat hippocampus induces seizures and neurodegeneration, and that AMPA infusion in the spinal cord produces paralysis and MN death. On these bases, in this work we have tested the effect of the chronic infusion of 4-AP in the spinal cord, using implanted osmotic minipumps, on motor activity and on MN survival, and the mechanisms underlying this effect. 4-AP produced muscle fasciculations and motor deficits assessed in two motor tests, which start 2–3 h after the implant, which ameliorated spontaneously within 6–7 days, but no neurodegeneration. These effects were prevented by both AMPA and NMDA receptors blockers. The role of GABAA receptors was also explored, and we found that chronic infusion of bicuculline induced moderate MN degeneration and enhanced the hyperexcitation produced by 4-AP. Unexpectedly, the GABAAR agonist muscimol also induced motor deficits and failed to prevent the MN death induced by AMPA. We conclude that motor alterations induced by chronic 4-AP infusion in the spinal cord in vivo is due to ionotropic glutamate receptor overactivation and that blockade of GABAergic neurotransmission induces MN death under chronic conditions. These results shed light on the role of glutamatergic and GABAergic neurotransmission in the regulation of MN excitability in the spinal cord. PMID:27242406

  2. Transgenic mice ectopically expressing HOXA5 in the dorsal spinal cord show structural defects of the cervical spinal cord along with sensory and motor defects of the forelimb.

    PubMed

    Krieger, Karin E; Abbott, Matthew A; Joksimovic, Milan; Lueth, Paul A; Sonea, Ioana M; Jeannotte, Lucie; Tuggle, Christopher K

    2004-06-21

    Mutation of murine Hoxa5 has shown that HOXA5 controls lung, gastrointestinal tract and vertebrae development. Hoxa5 is also expressed in the spinal cord, yet no central nervous system phenotype has been described in Hoxa5 knockouts. To identify the role of Hoxa5 in spinal cord development, we developed transgenic mice that express HOXA5 in the dorsal spinal cord in the brachial region. Using HOXA5-specific antibodies, we show this expression pattern is ectopic as the endogenous protein is expressed only in the ventral spinal cord at this anterio-posterior level. This transgenic line (Hoxa5SV2) also displays forelimb-specific motor and sensory defects. Hoxa5SV2 transgenic mice cannot support their body weight in a forelimb hang, and forelimb strength is decreased. However, Rotarod performance was not impaired in Hoxa5SV2 mice. Hoxa5SV2 mice also show a delayed forelimb response to noxious heat, although hindlimb response time was normal. Administration of an analgesic significantly reduced the hang test defect and decreased the transgene effect on forelimb strength, indicating that pain pathways may be affected. The morphology of transgenic cervical (but not lumbar) spinal cord is highly aberrant. Nissl staining indicates superficial laminae of the dorsal horn are severely disrupted. The distribution of cells and axons immunoreactive for substance P, neurokinin-B, and their primary receptors were aberrant only in transgenic cervical spinal cord. Further, we see increased levels of apoptosis in transgenic spinal cord at embryonic day 13.5. Our evidence suggests apoptosis due to HOXA5 misexpression is a major cause of loss of superficial lamina cells in Hoxa5SV2 mice. PMID:15158076

  3. Collateral development and spinal motor reorganization after nerve injury and repair

    PubMed Central

    Yu, Youlai; Zhang, Peixun; Han, Na; Kou, Yuhui; Yin, Xiaofeng; Jiang, Baoguo

    2016-01-01

    Functional recovery is often unsatisfactory after severe extended nerve defects or proximal nerve trunks injuries repaired by traditional repair methods, as the long regeneration distance for the regenerated axons to reinnervate their original target end-organs. The proximal nerve stump can regenerate with many collaterals that reinnervate the distal stump after peripheral nerve injury, it may be possible to use nearby fewer nerve fibers to repair more nerve fibers at the distal end to shorten the regenerating distance. In this study, the proximal peroneal nerve was used to repair both the distal peroneal and tibial nerve. The number and location of motor neurons in spinal cord as well as functional and morphological recovery were assessed at 2 months, 4 months and 8 months after nerve repair, respectively. Projections from the intact peroneal and tibial nerves were also studied in normal animals. The changes of motor neurons were assessed using the retrograde neurotracers FG and DiI to backlabel motor neurons that regenerate axons into two different pathways. To evaluate the functional recovery, the muscle forces and sciatic function index were examined. The muscles and myelinated axons were assessed using electrophysiology and histology. The results showed that all labeled motor neurons after nerve repair were always confined within the normal peroneal nerve pool and nearly all the distribution of motor neurons labeled via distal different nerves was disorganized as compared to normal group. However, there was a significant decline in the number of double labeled motor neurons and an obvious improvement with respect to the functional and morphological recovery between 2 and 8 months. In addition, the tibial/peroneal motor neuron number ratio at different times was 2.11±0.05, 2.13±0.08, 2.09±0.12, respectively, and was close to normal group (2.21±0.09). Quantitative analysis showed no significant morphological differences between myelinated nerve fibers

  4. Fictive rhythmic motor patterns produced by the tail spinal cord in salamanders.

    PubMed

    Charrier, V; Cabelguen, J-M

    2013-01-01

    Most investigations into the role of the body axis in vertebrate locomotion have focused on the trunk, although in most tetrapods, the tail also plays an active role. In salamanders, the tail contributes to propulsion during swimming and to dynamic balance and maneuverability during terrestrial locomotion. The aim of the present study was to obtain information concerning the neural mechanisms that produce tail muscle contractions during locomotion in the salamander Pleurodeles waltlii. We recorded the ventral root activities in in vitro spinal cord preparations in which locomotor-like activity was induced via bath application of N-methyl-d-aspartate (20μM) and d-serine (10μM). Recordings showed that the tail spinal cord is capable of producing propagated waves of motor activity that alternate between the left and right sides. Lesion experiments further revealed that the tail rhythmogenic network is composed of a double chain of identical hemisegmental oscillators. Finally, using spinal cord preparations bathed in a chamber partitioned into two pools, we revealed efficient short-distance coupling between the trunk and tail networks. Together, our results demonstrate the existence of a pattern generator for rhythmic tail movements in the salamander and show that the global architecture of the tail network is similar to that previously proposed for the mid-trunk locomotor network in the salamander. Our findings further support the view that salamanders can control their trunk and tail independently during stepping movements. The relevance of our results in relation to the generation of tail muscle contractions in freely moving salamanders is discussed.

  5. Direct-trauma model of posttraumatic syringomyelia with a computer-controlled motorized spinal cord impactor.

    PubMed

    Wong, Johnny H Y; Song, Xin; Hemley, Sarah J; Bilston, Lynne E; Cheng, Shaokoon; Stoodley, Marcus A

    2016-05-01

    OBJECTIVE The pathogenesis of posttraumatic syringomyelia remains enigmatic and is not adequately explained by current theories. Experimental investigations require a reproducible animal model that replicates the human condition. Current animal models are imperfect because of their low reliability, severe neurological deficits, or dissimilar mechanism of injury. The objective of this study was to develop a reproducible rodent model of posttraumatic syringomyelia using a spinal cord impactor that produces an injury that more closely mimics the human condition and does not produce severe neurological deficits. METHODS The study consisted of 2 parts. Seventy animals were studied overall: 20 in Experiment 1 and 48 in Experiment 2 after two rats with severe deficits were killed early. Experiment 1 aimed to determine the optimal force setting for inducing a cystic cavity without neurological deficits using a computer-controlled motorized spinal cord impactor. Twenty animals received an impact that ranged from 50 to 150 kDyn. Using the optimal force for producing an initial cyst determined from Experiment 1, Experiment 2 aimed to compare the progression of cavities in animals with and those without arachnoiditis induced by kaolin. Forty-eight animals were killed at 1, 3, 6, or 12 weeks after syrinx induction. Measurements of cavity size and maximum anteroposterior and lateral diameters were evaluated using light microscopy. RESULTS In Experiment 1, cavities were present in 95% of the animals. The duration of limb weakness and spinal cord cavity size correlated with the delivered force. The optimal force chosen for Experiment 2 was 75 kDyn. In Experiment 2, cavities occurred in 92% of the animals. Animals in the kaolin groups developed larger cavities and more vacuolations and enlarged perivascular spaces than those in the nonkaolin groups. CONCLUSIONS This impact model reliably produces cavities that resemble human posttraumatic syringomyelia and is suitable for further

  6. Deletions of the survival motor neuron gene in unaffected siblings of patients with spinal muscular atrophy

    SciTech Connect

    Cobben, J.M.; Steege, G. van der; Grootscholten, P.

    1995-10-01

    DNA studies in 103 spinal muscular atrophy (SMA) patients from The Netherlands revealed homozygosity for a survival motor neuron (SMN) deletion in 96 (93%) of 103. Neuronal apoptosis inhibitory protein deletions were found in 38 (37%) of 103 and occurred most frequently in SMA type 1. SMN deletions have not yet been described to occur in healthy subjects. In this study, however, four unaffected sibs from two SMA families showed homozygosity for SMN deletions. Homozygosity for an SMN deletion in unaffected persons seems to be very rare. Therefore, demonstration of a homozygous SMN deletion in a clinically presumed SMA patient should be considered as a confirmation of the diagnosis, whether or not SMN is in fact the causal gene for SMA. 19 refs., 2 figs.

  7. A modern neuroscience approach to chronic spinal pain: combining pain neuroscience education with cognition-targeted motor control training.

    PubMed

    Nijs, Jo; Meeus, Mira; Cagnie, Barbara; Roussel, Nathalie A; Dolphens, Mieke; Van Oosterwijck, Jessica; Danneels, Lieven

    2014-05-01

    Chronic spinal pain (CSP) is a severely disabling disorder, including nontraumatic chronic low back and neck pain, failed back surgery, and chronic whiplash-associated disorders. Much of the current therapy is focused on input mechanisms (treating peripheral elements such as muscles and joints) and output mechanisms (addressing motor control), while there is less attention to processing (central) mechanisms. In addition to the compelling evidence for impaired motor control of spinal muscles in patients with CSP, there is increasing evidence that central mechanisms (ie, hyperexcitability of the central nervous system and brain abnormalities) play a role in CSP. Hence, treatments for CSP should address not only peripheral dysfunctions but also the brain. Therefore, a modern neuroscience approach, comprising therapeutic pain neuroscience education followed by cognition-targeted motor control training, is proposed. This perspective article explains why and how such an approach to CSP can be applied in physical therapist practice.

  8. Trunk robot rehabilitation training with active stepping reorganizes and enriches trunk motor cortex representations in spinal transected rats.

    PubMed

    Oza, Chintan S; Giszter, Simon F

    2015-05-01

    Trunk motor control is crucial for postural stability and propulsion after low thoracic spinal cord injury (SCI) in animals and humans. Robotic rehabilitation aimed at trunk shows promise in SCI animal models and patients. However, little is known about the effect of SCI and robot rehabilitation of trunk on cortical motor representations. We previously showed reorganization of trunk motor cortex after adult SCI. Non-stepping training also exacerbated some SCI-driven plastic changes. Here we examine effects of robot rehabilitation that promotes recovery of hindlimb weight support functions on trunk motor cortex representations. Adult rats spinal transected as neonates (NTX rats) at the T9/10 level significantly improve function with our robot rehabilitation paradigm, whereas treadmill-only trained do not. We used intracortical microstimulation to map motor cortex in two NTX groups: (1) treadmill trained (control group); and (2) robot-assisted treadmill trained (improved function group). We found significant robot rehabilitation-driven changes in motor cortex: (1) caudal trunk motor areas expanded; (2) trunk coactivation at cortex sites increased; (3) richness of trunk cortex motor representations, as examined by cumulative entropy and mutual information for different trunk representations, increased; (4) trunk motor representations in the cortex moved toward more normal topography; and (5) trunk and forelimb motor representations that SCI-driven plasticity and compensations had caused to overlap were segregated. We conclude that effective robot rehabilitation training induces significant reorganization of trunk motor cortex and partially reverses some plastic changes that may be adaptive in non-stepping paraplegia after SCI.

  9. Trunk Robot Rehabilitation Training with Active Stepping Reorganizes and Enriches Trunk Motor Cortex Representations in Spinal Transected Rats

    PubMed Central

    Oza, Chintan S.

    2015-01-01

    Trunk motor control is crucial for postural stability and propulsion after low thoracic spinal cord injury (SCI) in animals and humans. Robotic rehabilitation aimed at trunk shows promise in SCI animal models and patients. However, little is known about the effect of SCI and robot rehabilitation of trunk on cortical motor representations. We previously showed reorganization of trunk motor cortex after adult SCI. Non-stepping training also exacerbated some SCI-driven plastic changes. Here we examine effects of robot rehabilitation that promotes recovery of hindlimb weight support functions on trunk motor cortex representations. Adult rats spinal transected as neonates (NTX rats) at the T9/10 level significantly improve function with our robot rehabilitation paradigm, whereas treadmill-only trained do not. We used intracortical microstimulation to map motor cortex in two NTX groups: (1) treadmill trained (control group); and (2) robot-assisted treadmill trained (improved function group). We found significant robot rehabilitation-driven changes in motor cortex: (1) caudal trunk motor areas expanded; (2) trunk coactivation at cortex sites increased; (3) richness of trunk cortex motor representations, as examined by cumulative entropy and mutual information for different trunk representations, increased; (4) trunk motor representations in the cortex moved toward more normal topography; and (5) trunk and forelimb motor representations that SCI-driven plasticity and compensations had caused to overlap were segregated. We conclude that effective robot rehabilitation training induces significant reorganization of trunk motor cortex and partially reverses some plastic changes that may be adaptive in non-stepping paraplegia after SCI. PMID:25948267

  10. Ethanol withdrawal hyper-responsiveness mediated by NMDA receptors in spinal cord motor neurons

    PubMed Central

    Li, Hui-Fang; Kendig, Joan J

    2003-01-01

    Following ethanol (EtOH) exposure, population excitatory postsynaptic potentials (pEPSPs) in isolated spinal cord increase to a level above control (withdrawal hyper-responsiveness). The present studies were designed to characterize this phenomenon and in particular to test the hypothesis that protein kinases mediate withdrawal. Patch-clamp studies were carried out in motor neurons in rat spinal cord slices. Currents were evoked by brief pulses of glutamate, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or N-methyl-D-aspartic acid (NMDA). Of 15 EtOH-sensitive neurons in which currents were evoked by glutamate, four (27%) displayed withdrawal hyper-responsiveness in the washout period. Mean current area after washout was 129.6±5% of control. When currents were evoked by AMPA, two of 10 neurons (20%) displayed withdrawal hyper-responsiveness, with a mean current area 122±8% of control on washout. Of a group of 11 neurons in which currents were evoked by NMDA, nine (82%) displayed withdrawal hyper-responsiveness. Mean increase in current area at the end of the washout period was to 133±6% of control (n=9, P<0.001). When NMDA applications were stopped durithe period of EtOH exposure, mean area of NMDA-evoked responses on washout was only 98.0±5% of control (n=6, P>0.05). The tyrosine kinase inhibitor genistein (10–20 μM) blocked withdrawal hyper-responsiveness. Of six EtOH-sensitive neurons, the mean NMDA-evoked current area after washout was 89±6% of control, P>0.05. The protein kinase A (PKA) inhibitor Rp-cAMP (20–500 μM) did not block withdrawal hyper-responsiveness. On washout, the mean NMDA-evoked current area was 124±6% of control (n=5, P<0.05). Two broad-spectrum specific protein kinase C (PKC) inhibitors, GF-109203X (0.3 μM) and chelerythrine chloride (0.5–2 nM), blocked withdrawal hyper-responsiveness. Responses on washout were 108±7%, n=5 and 88±4%, n=4 of control, respectively, P>0.05. NMDA activation during EtOH exposure

  11. Motor imagery reinforces brain compensation of reach-to-grasp movement after cervical spinal cord injury

    PubMed Central

    Mateo, Sébastien; Di Rienzo, Franck; Bergeron, Vance; Guillot, Aymeric; Collet, Christian; Rode, Gilles

    2015-01-01

    Individuals with cervical spinal cord injury (SCI) that causes tetraplegia are challenged with dramatic sensorimotor deficits. However, certain rehabilitation techniques may significantly enhance their autonomy by restoring reach-to-grasp movements. Among others, evidence of motor imagery (MI) benefits for neurological rehabilitation of upper limb movements is growing. This literature review addresses MI effectiveness during reach-to-grasp rehabilitation after tetraplegia. Among articles from MEDLINE published between 1966 and 2015, we selected ten studies including 34 participants with C4 to C7 tetraplegia and 22 healthy controls published during the last 15 years. We found that MI of possible non-paralyzed movements improved reach-to-grasp performance by: (i) increasing both tenodesis grasp capabilities and muscle strength; (ii) decreasing movement time (MT), and trajectory variability; and (iii) reducing the abnormally increased brain activity. MI can also strengthen motor commands by potentiating recruitment and synchronization of motoneurons, which leads to improved recovery. These improvements reflect brain adaptations induced by MI. Furthermore, MI can be used to control brain-computer interfaces (BCI) that successfully restore grasp capabilities. These results highlight the growing interest for MI and its potential to recover functional grasping in individuals with tetraplegia, and motivate the need for further studies to substantiate it. PMID:26441568

  12. Contact-mediated inhibition between oligodendrocyte progenitor cells and motor exit point glia establishes the spinal cord transition zone.

    PubMed

    Smith, Cody J; Morris, Angela D; Welsh, Taylor G; Kucenas, Sarah

    2014-09-01

    Rapid conduction of action potentials along motor axons requires that oligodendrocytes and Schwann cells myelinate distinct central and peripheral nervous system (CNS and PNS) domains along the same axon. Despite the importance of this arrangement for nervous system function, the mechanisms that establish and maintain this precise glial segregation at the motor exit point (MEP) transition zone are unknown. Using in vivo time-lapse imaging in zebrafish, we observed that prior to myelination, oligodendrocyte progenitor cells (OPCs) extend processes into the periphery via the MEP and immediately upon contact with spinal motor root glia retract back into the spinal cord. Characterization of the peripheral cell responsible for repelling OPC processes revealed that it was a novel, CNS-derived population of glia we propose calling MEP glia. Ablation of MEP glia resulted in the absence of myelinating glia along spinal motor root axons and an immediate breach of the MEP by OPCs. Taken together, our results identify a novel population of CNS-derived peripheral glia located at the MEP that selectively restrict the migration of OPCs into the periphery via contact-mediated inhibition.

  13. In vitro reactive nitrating species toxicity in dissociated spinal motor neurons from NFL (-/-) and hNFL (+/+) transgenic mice.

    PubMed

    Strong, Michael; Sopper, Maggie; He, Bei Ping

    2003-06-01

    We utilized fetal spinal motor neurons isolated from either NFL (-/-) or hNFL (+/+) transgenic mice to determine whether the loss of the low molecular weight neurofilament protein (NFL) places spinal motor neurons at a greater risk for cell death triggered by reactive nitrating species (RNS). After 21 days in serum-free, antibiotic-free medium, both the NFL (-/-) and hNFL (+/+) motor neurons developed neurofilamentous aggregates. Cultures were then exposed to nitric oxide(100 microM NOC 5, 100 microM NOC 12, or 2 mM sodium nitroprusside) or to peroxynitrite (250 mM SIN-1) forvarying intervals. NFL (-/-) cultures demonstrated extensive numbers of apoptotic neurons within six hours and complete cell loss by 24 hours in response to NOC 5 and NOC 12. In contrast, apoptosis was only observed in the motor neurons derived from control (C57bl/6) or hNLF (+/+) mice at 24 hours. In response to 2 mM sodium nitroprusside, necrosis was induced in all cells within 60 minutes. In response to 250 mM SIN-1, both C57bl/6 and hNFL (+/+) cells survived to six hours with only minimal evidence of degeneration while NFL (-/-) motor neurons were necrotic by 60 minutes. These observations suggest that NFL deficient motor neurons are at an enhanced risk of cell death mediated by RNS.

  14. Small Molecule Suppressors of Drosophila Kinesin Deficiency Rescue Motor Axon Development in a Zebrafish Model of Spinal Muscular Atrophy

    PubMed Central

    Gassman, Andrew; Hao, Le T.; Bhoite, Leena; Bradford, Chad L.; Chien, Chi-Bin; Beattie, Christine E.; Manfredi, John P.

    2013-01-01

    Proximal spinal muscular atrophy (SMA) is the most common inherited motor neuropathy and the leading hereditary cause of infant mortality. Currently there is no effective treatment for the disease, reflecting a need for pharmacologic interventions that restore performance of dysfunctional motor neurons or suppress the consequences of their dysfunction. In a series of assays relevant to motor neuron biology, we explored the activities of a collection of tetrahydroindoles that were reported to alter the metabolism of amyloid precursor protein (APP). In Drosophila larvae the compounds suppressed aberrant larval locomotion due to mutations in the Khc and Klc genes, which respectively encode the heavy and light chains of kinesin-1. A representative compound of this class also suppressed the appearance of axonal swellings (alternatively termed axonal spheroids or neuritic beads) in the segmental nerves of the kinesin-deficient Drosophila larvae. Given the importance of kinesin-dependent transport for extension and maintenance of axons and their growth cones, three members of the class were tested for neurotrophic effects on isolated rat spinal motor neurons. Each compound stimulated neurite outgrowth. In addition, consistent with SMA being an axonopathy of motor neurons, the three axonotrophic compounds rescued motor axon development in a zebrafish model of SMA. The results introduce a collection of small molecules as pharmacologic suppressors of SMA-associated phenotypes and nominate specific members of the collection for development as candidate SMA therapeutics. More generally, the results reinforce the perception of SMA as an axonopathy and suggest novel approaches to treating the disease. PMID:24023935

  15. Coordinated motor activity in simulated spinal networks emerges from simple biologically plausible rules of connectivity.

    PubMed

    Dale, Nicholas

    2003-01-01

    The spinal motor circuits of the Xenopus embryo have been simulated in a 400-neuron network. To explore the consequences of differing patterns of synaptic connectivity within the network for the generation of the motor rhythm, a system of biologically plausible rules was devised to control synapse formation by three parameters. Each neuron had an intrinsic probability of synapse formation (P(soma), specified by a space constant lambda) that was a monotonically decreasing function of its soma location in the rostro-caudal axis of the simulated network. The neurons had rostral and caudal going axons of specified length (L(axon)) associated with a probability of synapse formation (P(axon)). The final probability of synapse formation was the product of P(soma) and P(axon). Realistic coordinated activity only occurred when L(axon) and the probabilities of interconnection were sufficiently high. Increasing the values of the three network parameters reduced the burst duration, cycle period, and rostro-caudal delay and increased the reliability with which the network functioned as measured by the coefficient of variance of these parameters. Whereas both L(axon) and P(axon) had powerful and consistent effects on network output, the effects of lambda on burst duration and rostro-caudal delay were more variable and depended on the values of the other two parameters. This network model can reproduce the rostro-caudal coordination of swimming without using coupled oscillator theory. The changes in network connectivity and resulting changes in activity explored by the model mimic the development of the motor pattern for swimming in the real embryo.

  16. Non-aggregating tau phosphorylation by cyclin-dependent kinase 5 contributes to motor neuron degeneration in spinal muscular atrophy.

    PubMed

    Miller, Nimrod; Feng, Zhihua; Edens, Brittany M; Yang, Ben; Shi, Han; Sze, Christie C; Hong, Benjamin Taige; Su, Susan C; Cantu, Jorge A; Topczewski, Jacek; Crawford, Thomas O; Ko, Chien-Ping; Sumner, Charlotte J; Ma, Long; Ma, Yong-Chao

    2015-04-15

    Mechanisms underlying motor neuron degeneration in spinal muscular atrophy (SMA), the leading inherited cause of infant mortality, remain largely unknown. Many studies have established the importance of hyperphosphorylation of the microtubule-associated protein tau in various neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. However, tau phosphorylation in SMA pathogenesis has yet to be investigated. Here we show that tau phosphorylation on serine 202 (S202) and threonine 205 (T205) is increased significantly in SMA motor neurons using two SMA mouse models and human SMA patient spinal cord samples. Interestingly, phosphorylated tau does not form aggregates in motor neurons or neuromuscular junctions (NMJs), even at late stages of SMA disease, distinguishing it from other tauopathies. Hyperphosphorylation of tau on S202 and T205 is mediated by cyclin-dependent kinase 5 (Cdk5) in SMA disease condition, because tau phosphorylation at these sites is significantly reduced in Cdk5 knock-out mice; genetic knock-out of Cdk5 activating subunit p35 in an SMA mouse model also leads to reduced tau phosphorylation on S202 and T205 in the SMA;p35(-/-) compound mutant mice. In addition, expression of the phosphorylation-deficient tauS202A,T205A mutant alleviates motor neuron defects in a zebrafish SMA model in vivo and mouse motor neuron degeneration in culture, whereas expression of phosphorylation-mimetic tauS202E,T205E promotes motor neuron defects. More importantly, genetic knock-out of tau in SMA mice rescues synapse stripping on motor neurons, NMJ denervation, and motor neuron degeneration in vivo. Altogether, our findings suggest a novel mechanism for SMA pathogenesis in which hyperphosphorylation of non-aggregating tau by Cdk5 contributes to motor neuron degeneration.

  17. Non-Aggregating Tau Phosphorylation by Cyclin-Dependent Kinase 5 Contributes to Motor Neuron Degeneration in Spinal Muscular Atrophy

    PubMed Central

    Miller, Nimrod; Feng, Zhihua; Edens, Brittany M.; Yang, Ben; Shi, Han; Sze, Christie C.; Hong, Benjamin Taige; Su, Susan C.; Cantu, Jorge A.; Topczewski, Jacek; Crawford, Thomas O.; Ko, Chien-Ping; Sumner, Charlotte J.; Ma, Long

    2015-01-01

    Mechanisms underlying motor neuron degeneration in spinal muscular atrophy (SMA), the leading inherited cause of infant mortality, remain largely unknown. Many studies have established the importance of hyperphosphorylation of the microtubule-associated protein tau in various neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. However, tau phosphorylation in SMA pathogenesis has yet to be investigated. Here we show that tau phosphorylation on serine 202 (S202) and threonine 205 (T205) is increased significantly in SMA motor neurons using two SMA mouse models and human SMA patient spinal cord samples. Interestingly, phosphorylated tau does not form aggregates in motor neurons or neuromuscular junctions (NMJs), even at late stages of SMA disease, distinguishing it from other tauopathies. Hyperphosphorylation of tau on S202 and T205 is mediated by cyclin-dependent kinase 5 (Cdk5) in SMA disease condition, because tau phosphorylation at these sites is significantly reduced in Cdk5 knock-out mice; genetic knock-out of Cdk5 activating subunit p35 in an SMA mouse model also leads to reduced tau phosphorylation on S202 and T205 in the SMA;p35−/− compound mutant mice. In addition, expression of the phosphorylation-deficient tauS202A,T205A mutant alleviates motor neuron defects in a zebrafish SMA model in vivo and mouse motor neuron degeneration in culture, whereas expression of phosphorylation-mimetic tauS202E,T205E promotes motor neuron defects. More importantly, genetic knock-out of tau in SMA mice rescues synapse stripping on motor neurons, NMJ denervation, and motor neuron degeneration in vivo. Altogether, our findings suggest a novel mechanism for SMA pathogenesis in which hyperphosphorylation of non-aggregating tau by Cdk5 contributes to motor neuron degeneration. PMID:25878277

  18. Spinal Activation of the cAMP-PKA Pathway Induces Respiratory Motor Recovery Following High Cervical Spinal Cord Injury

    PubMed Central

    Kajana, S.; Goshgarian, H.G.

    2008-01-01

    The present study investigated the involvement of the adenosine 3’5’-cyclic monophosphate-dependent protein kinase A (cAMP-PKA) pathway in the activation of the crossed phrenic pathways after left C2 spinal cord hemisection. Experiments were conducted on left C2 spinal cord hemisected, anesthetized, vagotomized, pancuronium paralyzed, and artificially ventilated male Sprague-Dawley rats. One week post-injury, the ipsilateral phrenic nerve exhibited no respiratory-related activity indicating a functionally complete hemisection. Intrathecal spinal cord administration of the cAMP analog, 8-Br-cAMP at the level of the phrenic nucleus resulted in an enhancement of contralateral phrenic nerve output and a restoration of respiratory-related activity in the phrenic nerve ipsilateral to the hemisection. Furthermore, pretreatment with Rp-8-Br-cAMP, a PKA inhibitor, abolished the effects of 8-Br-cAMP. These results suggest that PKA activation is necessary for the cAMP-mediated respiratory recovery following high cervical spinal cord injury and that activation of intracellular signaling cascades may represent an important strategy for improving respiratory function after spinal cord injury. PMID:18656458

  19. Electromyographic identification of spinal oscillator patterns and recouplings in a patient with incomplete spinal cord lesion: oscillator formation training as a method to improve motor activities.

    PubMed

    Schalow, G; Blanc, Y; Jeltsch, W; Zäch, G A

    1996-08-01

    A patient with a strongly lesioned spinal cord, sub C5, relearned running, besides improving other movements, by an oscillator formation training (rhythmic, dynamic, stereotyped exercise). After 45 days of jumping on a springboard and other rhythm trainings, the patient was able to run 90 m in 41 s (7.9 km/h) (even 9.3 km/h 3 years after the lesion) besides marching (5.7 km/h), cycling, playing tennis and skiing. FF-type (alpha 1) (f = 8.3-11.4 Hz) and FR-type (alpha 2) (f = 6.7 Hz) motor unit firings were identified by electromyography (EMG) with surface electrodes by their oscillatory firing patterns in this patient. In EMG literature, the alpha 2-oscillatory firing is called "myokymic discharging". Alternating long and short oscillation periods were measured in FF-type motor units, with changing focus (change from long/short to short/long oscillation periods). The alternating mean period durations differed by approximately 10 ms. Transient synchronization of oscillatory firing FF-type motor units was observed with up to two phase relations per oscillation cycle. In recumbent position, the phase change in synchronization of two oscillatory firing motor units in the soleus muscle of one leg correlated with the change from alternating to symmetrical oscillatory firing of a third motor unit in the soleus muscle of the other leg. This measurement indicates that the alternating oscillatory firing of premotor neuronal networks is correlated with synchronization of oscillatory firing neuronal subnetworks, i.e., with coupling changes of oscillators, and is not due to reciprocal inhibition of half-centre oscillators as suggested by the change from alternating to symmetrical oscillatory firing. Coupling changes of oscillatory firing subnetworks to generate macroscopic (integrative) network functions are therefore a general organization form of the central nervous system (CNS), and are not related to rhythmic movements like walking or running only. It is proposed that

  20. Granulocyte-Colony Stimulating Factor (G-CSF) Improves Motor Recovery in the Rat Impactor Model for Spinal Cord Injury

    PubMed Central

    Dittgen, Tanjew; Pitzer, Claudia; Plaas, Christian; Kirsch, Friederike; Vogt, Gerhard; Laage, Rico; Schneider, Armin

    2012-01-01

    Granulocyte-colony stimulating factor (G-CSF) improves outcome after experimental SCI by counteracting apoptosis, and enhancing connectivity in the injured spinal cord. Previously we have employed the mouse hemisection SCI model and studied motor function after subcutaneous or transgenic delivery of the protein. To further broaden confidence in animal efficacy data we sought to determine efficacy in a different model and a different species. Here we investigated the effects of G-CSF in Wistar rats using the New York University Impactor. In this model, corroborating our previous data, rats treated subcutaneously with G-CSF over 2 weeks show significant improvement of motor function. PMID:22253813

  1. Role of energy metabolic deficits and oxidative stress in excitotoxic spinal motor neuron degeneration in vivo

    PubMed Central

    Santa-Cruz, Luz Diana; Tapia, Ricardo

    2014-01-01

    MN (motor neuron) death in amyotrophic lateral sclerosis may be mediated by glutamatergic excitotoxicity. Previously, our group showed that the microdialysis perfusion of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate) in the rat lumbar spinal cord induced MN death and permanent paralysis within 12 h after the experiment. Here, we studied the involvement of energy metabolic deficiencies and of oxidative stress in this MN degeneration, by testing the neuroprotective effect of various energy metabolic substrates and antioxidants. Pyruvate, lactate, β-hydroxybutyrate, α-ketobutyrate and creatine reduced MN loss by 50–65%, preserved motor function and completely prevented the paralysis. Ascorbate, glutathione and glutathione ethyl ester weakly protected against motor deficits and reduced MN death by only 30–40%. Reactive oxygen species formation and 3-nitrotyrosine immunoreactivity were studied 1.5–2 h after AMPA perfusion, during the initial MN degenerating process, and no changes were observed. We conclude that mitochondrial energy deficiency plays a crucial role in this excitotoxic spinal MN degeneration, whereas oxidative stress seems a less relevant mechanism. Interestingly, we observed a clear correlation between the alterations of motor function and the number of damaged MNs, suggesting that there is a threshold of about 50% in the number of healthy MNs necessary to preserve motor function. PMID:24524836

  2. Spinal cord organotypic slice cultures for the study of regenerating motor axon interactions with 3D scaffolds.

    PubMed

    Gerardo-Nava, Jose; Hodde, Dorothee; Katona, Istvan; Bozkurt, Ahmet; Grehl, Torsten; Steinbusch, Harry W M; Weis, Joachim; Brook, Gary A

    2014-05-01

    Numerous in-vitro techniques exist for investigating the influence of 3D substrate topography on sensory axon growth. However, simple and cost-effective methods for studying post-natal motor axon interactions with such substrates are lacking. Here, spinal cord organotypic slice cultures (OSC) from post-natal day 7-9 rat pups were presented with spinal nerve roots, or blocks of fibrin hydrogel or 3D microporous collagen scaffolds to investigate motor axon-substrate interactions. By 7-14 days, axons from motor neuronal pools extended into the explanted nerve roots, growing along Schwann cell processes and demonstrating a full range of axon-Schwann cell interactions, from simple ensheathment to concentric wrapping by Schwann cell processes and the formation of compact myelin within a basal lamina sheath. Extensive motor axon regeneration and all stages of axon-Schwann interactions were also supported within the longitudinally orientated microporous framework of the 3D collagen scaffold. In stark contrast, the simple fibrin hydrogel only supported axon growth and cell migration over its surface. The relative ease of demonstrating such motor axon regeneration through the microporous 3D framework by immunofluorescence, two-photon microscopy and transmission electron microscopy strongly supports the adoption of this technique for assaying the influence of substrate topography and functionalization in regenerative bioengineering.

  3. Sensory neurons do not induce motor neuron loss in a human stem cell model of spinal muscular atrophy.

    PubMed

    Schwab, Andrew J; Ebert, Allison D

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder leading to paralysis and early death due to reduced SMN protein. It is unclear why there is such a profound motor neuron loss, but recent evidence from fly and mouse studies indicate that cells comprising the whole sensory-motor circuit may contribute to motor neuron dysfunction and loss. Here, we used induced pluripotent stem cells derived from SMA patients to test whether sensory neurons directly contribute to motor neuron loss. We generated sensory neurons from SMA induced pluripotent stem cells and found no difference in neuron generation or survival, although there was a reduced calcium response to depolarizing stimuli. Using co-culture of SMA induced pluripotent stem cell derived sensory neurons with control induced pluripotent stem cell derived motor neurons, we found no significant reduction in motor neuron number or glutamate transporter boutons on motor neuron cell bodies or neurites. We conclude that SMA sensory neurons do not overtly contribute to motor neuron loss in this human stem cell system.

  4. Electroacupuncture promotes the recovery of motor neuron function in the anterior horn of the injured spinal cord

    PubMed Central

    Yang, Jian-hui; Lv, Jian-guo; Wang, Hui; Nie, Hui-yong

    2015-01-01

    Acupuncture has been shown to lessen the inflammatory reaction after acute spinal cord injury and reduce secondary injury. However, the mechanism of action remains unclear. In this study, a rat model of spinal cord injury was established by compressing the T8–9 segments using a modified Nystrom method. Twenty-four hours after injury, Zusanli (ST36), Xuanzhong (GB39), Futu (ST32) and Sanyinjiao (SP6) were stimulated with electroacupuncture. Rats with spinal cord injury alone were used as controls. At 2, 4 and 6 weeks after injury, acetylcholinesterase (AChE) activity at the site of injury, the number of medium and large neurons in the spinal cord anterior horn, glial cell line-derived neurotrophic factor (GDNF) mRNA expression, and Basso, Beattie and Bresnahan locomotor rating scale scores were greater in the electroacupuncture group compared with the control group. These results demonstrate that electroacupuncture increases AChE activity, up-regulates GDNF mRNA expression, and promotes the recovery of motor neuron function in the anterior horn after spinal cord injury. PMID:26889195

  5. Electroacupuncture promotes the recovery of motor neuron function in the anterior horn of the injured spinal cord.

    PubMed

    Yang, Jian-Hui; Lv, Jian-Guo; Wang, Hui; Nie, Hui-Yong

    2015-12-01

    Acupuncture has been shown to lessen the inflammatory reaction after acute spinal cord injury and reduce secondary injury. However, the mechanism of action remains unclear. In this study, a rat model of spinal cord injury was established by compressing the T8-9 segments using a modified Nystrom method. Twenty-four hours after injury, Zusanli (ST36), Xuanzhong (GB39), Futu (ST32) and Sanyinjiao (SP6) were stimulated with electroacupuncture. Rats with spinal cord injury alone were used as controls. At 2, 4 and 6 weeks after injury, acetylcholinesterase (AChE) activity at the site of injury, the number of medium and large neurons in the spinal cord anterior horn, glial cell line-derived neurotrophic factor (GDNF) mRNA expression, and Basso, Beattie and Bresnahan locomotor rating scale scores were greater in the electroacupuncture group compared with the control group. These results demonstrate that electroacupuncture increases AChE activity, up-regulates GDNF mRNA expression, and promotes the recovery of motor neuron function in the anterior horn after spinal cord injury. PMID:26889195

  6. Maternal Care Effects on the Development of a Sexually Dimorphic Motor System: The Role of Spinal Oxytocin

    PubMed Central

    Lenz, Kathryn M.; Sengelaub, Dale R.

    2010-01-01

    Maternal licking in rats affects the development of the spinal nucleus of the bulbocavernosus (SNB), a sexually dimorphic motor nucleus that controls penile reflexes involved with copulation. Reduced maternal licking results in decreased motoneuron number, size, and dendritic length in the adult SNB, as well as deficits in adult male copulatory behavior. Our previous findings that licking-like tactile stimulation influences SNB dendritic development and upregulates Fos expression in the lumbosacral spinal cord suggest that afferent signaling is changed by differences in maternal stimulation. Oxytocin afferents from the hypothalamus are a possible candidate, given previous research that has shown oxytocin is released following sensory stimulation, oxytocin modulates excitability in the spinal cord, and is a pro-erectile modulator of male sex behavior. In this experiment, we used immunofluorescence and immediate early gene analysis to assess whether licking-like tactile stimulation of the perineum activated parvocellular oxytocinergic neurons in the hypothalamus in neonates. We also used enzyme immunoassay to determine whether this same stroking stimulation produced an increase in spinal oxytocin levels. We found that stroking increased Fos immunolabeling in small oxytocin-positive cells in the paraventricular nucleus of the hypothalamus, in comparison to unstroked or handled control pups. In addition, sixty seconds of licking-like perineal stimulation produced a transient 89% increase in oxytocin levels in the lumbosacral spinal cord. Together, these results suggest that oxytocin afferent activity may contribute to the effects of early maternal care on the masculinization of the SNB and resultant male copulatory behavior. PMID:20688065

  7. p53 Regulates the neuronal intrinsic and extrinsic responses affecting the recovery of motor function following spinal cord injury.

    PubMed

    Floriddia, Elisa M; Rathore, Khizr I; Tedeschi, Andrea; Quadrato, Giorgia; Wuttke, Anja; Lueckmann, Jan-Matthis; Kigerl, Kristina A; Popovich, Phillip G; Di Giovanni, Simone

    2012-10-01

    Following spinal trauma, the limited physiological axonal sprouting that contributes to partial recovery of function is dependent upon the intrinsic properties of neurons as well as the inhibitory glial environment. The transcription factor p53 is involved in DNA repair, cell cycle, cell survival, and axonal outgrowth, suggesting p53 as key modifier of axonal and glial responses influencing functional recovery following spinal injury. Indeed, in a spinal cord dorsal hemisection injury model, we observed a significant impairment in locomotor recovery in p53(-/-) versus wild-type mice. p53(-/-) spinal cords showed an increased number of activated microglia/macrophages and a larger scar at the lesion site. Loss- and gain-of-function experiments suggested p53 as a direct regulator of microglia/macrophages proliferation. At the axonal level, p53(-/-) mice showed a more pronounced dieback of the corticospinal tract (CST) and a decreased sprouting capacity of both CST and spinal serotoninergic fibers. In vivo expression of p53 in the sensorimotor cortex rescued and enhanced the sprouting potential of the CST in p53(-/-) mice, while, similarly, p53 expression in p53(-/-) cultured cortical neurons rescued a defect in neurite outgrowth, suggesting a direct role for p53 in regulating the intrinsic sprouting ability of CNS neurons. In conclusion, we show that p53 plays an important regulatory role at both extrinsic and intrinsic levels affecting the recovery of motor function following spinal cord injury. Therefore, we propose p53 as a novel potential multilevel therapeutic target for spinal cord injury.

  8. Endolysosomal Deficits Augment Mitochondria Pathology in Spinal Motor Neurons of Asymptomatic fALS Mice

    PubMed Central

    Xie, Yuxiang; Zhou, Bing; Lin, Mei-Yao; Wang, Shiwei; Foust, Kevin D.; Sheng, Zu-Hang

    2015-01-01

    One pathological hallmark in ALS motor neurons (MNs) is axonal accumulation of damaged mitochondria. A fundamental question remains: does reduced degradation of those mitochondria by impaired autophagy-lysosomal system contribute to mitochondrial pathology? Here, we reveal MN-targeted progressive lysosomal deficits accompanied by impaired autophagic degradation beginning at asymptomatic stages in fALS-linked hSOD1G93A mice. Lysosomal deficits result in accumulation of autophagic vacuoles engulfing damaged mitochondria along MN axons. Live imaging of spinal MNs from the adult disease mice demonstrates impaired dynein-driven retrograde transport of late endosomes (LEs). Expressing dynein-adaptor snapin reverses transport defects by competing with hSOD1G93A for binding dynein, thus rescuing autophagy-lysosomal deficits, enhancing mitochondria turnover, improving MN survival, and ameliorating the disease phenotype in hSOD1G93A mice. Our study provides a new mechanistic link for hSOD1G93A-mediated impairment of LE transport to autophagy-lysosome deficits and mitochondria pathology. Understanding these early pathological events benefits development of new therapeutic interventions for fALS-linked MN degeneration. PMID:26182418

  9. Endolysosomal Deficits Augment Mitochondria Pathology in Spinal Motor Neurons of Asymptomatic fALS Mice.

    PubMed

    Xie, Yuxiang; Zhou, Bing; Lin, Mei-Yao; Wang, Shiwei; Foust, Kevin D; Sheng, Zu-Hang

    2015-07-15

    One pathological hallmark in ALS motor neurons (MNs) is axonal accumulation of damaged mitochondria. A fundamental question remains: does reduced degradation of those mitochondria by an impaired autophagy-lysosomal system contribute to mitochondrial pathology? We reveal MN-targeted progressive lysosomal deficits accompanied by impaired autophagic degradation beginning at asymptomatic stages in fALS-linked hSOD1(G93A) mice. Lysosomal deficits result in accumulation of autophagic vacuoles engulfing damaged mitochondria along MN axons. Live imaging of spinal MNs from the adult disease mice demonstrates impaired dynein-driven retrograde transport of late endosomes (LEs). Expressing dynein-adaptor snapin reverses transport defects by competing with hSOD1(G93A) for binding dynein, thus rescuing autophagy-lysosomal deficits, enhancing mitochondrial turnover, improving MN survival, and ameliorating the disease phenotype in hSOD1(G93A) mice. Our study provides a new mechanistic link for hSOD1(G93A)-mediated impairment of LE transport to autophagy-lysosomal deficits and mitochondrial pathology. Understanding these early pathological events benefits development of new therapeutic interventions for fALS-linked MN degeneration.

  10. The role of spinal GABAergic circuits in the control of phrenic nerve motor output

    PubMed Central

    Ghali, Michael G. Z.; Rogers, Robert F.

    2015-01-01

    While supraspinal mechanisms underlying respiratory pattern formation are well characterized, the contribution of spinal circuitry to the same remains poorly understood. In this study, we tested the hypothesis that intraspinal GABAergic circuits are involved in shaping phrenic motor output. To this end, we performed bilateral phrenic nerve recordings in anesthetized adult rats and observed neurogram changes in response to knocking down expression of both isoforms (65 and 67 kDa) of glutamate decarboxylase (GAD65/67) using microinjections of anti-GAD65/67 short-interference RNA (siRNA) in the phrenic nucleus. The number of GAD65/67-positive cells was drastically reduced on the side of siRNA microinjections, especially in the lateral aspects of Rexed's laminae VII and IX in the ventral horn of cervical segment C4, but not contralateral to microinjections. We hypothesize that intraspinal GABAergic control of phrenic output is primarily phasic, but also plays an important role in tonic regulation of phrenic discharge. Also, we identified respiration-modulated GABAergic interneurons (both inspiratory and expiratory) located slightly dorsal to the phrenic nucleus. Our data provide the first direct evidence for the existence of intraspinal GABAergic circuits contributing to the formation of phrenic output. The physiological role of local intraspinal inhibition, independent of descending direct bulbospinal control, is discussed. PMID:25833937

  11. Spinal NMDA receptor activation constrains inactivity-induced phrenic motor facilitation in Charles River Sprague-Dawley rats

    PubMed Central

    Streeter, K. A.

    2014-01-01

    Reduced spinal synaptic inputs to phrenic motor neurons elicit a unique form of spinal plasticity known as inactivity-induced phrenic motor facilitation (iPMF). iPMF requires tumor necrosis factor-α (TNF-α) and atypical protein kinase C (aPKC) activity within spinal segments containing the phrenic motor nucleus to stabilize early, transient increases in phrenic burst amplitude into long-lasting iPMF. Here we tested the hypothesis that spinal N-methyl-d-aspartate receptor (NMDAR) activation constrains long-lasting iPMF in some rat substrains. Phrenic motor output was recorded in anesthetized, ventilated Harlan (HSD) and Charles River (CRSD) Sprague-Dawley rats exposed to a 30-min central neural apnea. HSD rats expressed a robust, long-lasting (>60 min) increase in phrenic burst amplitude (i.e., long-lasting iPMF) when respiratory neural activity was restored. By contrast, CRSD rats expressed an attenuated, transient (∼15 min) iPMF. Spinal NMDAR inhibition with DL-2-amino-5-phosphonopentanoic acid (APV) before neural apnea or shortly (4 min) prior to the resumption of respiratory neural activity revealed long-lasting iPMF in CRSD rats that was phenotypically similar to that in HSD rats. By contrast, APV did not alter iPMF expression in HSD rats. Spinal TNF-α or aPKC inhibition impaired long-lasting iPMF enabled by NMDAR inhibition in CRSD rats, suggesting that similar mechanisms give rise to long-lasting iPMF in CRSD rats with NMDAR inhibition as those giving rise to long-lasting iPMF in HSD rats. These results suggest that NMDAR activation can impose constraints on TNF-α-induced aPKC activation after neural apnea, impairing stabilization of transient iPMF into long-lasting iPMF. These data may have important implications for understanding differential responses to reduced respiratory neural activity in a heterogeneous human population. PMID:25103979

  12. Degeneration of Phrenic Motor Neurons Induces Long-Term Diaphragm Deficits following Mid-Cervical Spinal Contusion in Mice

    PubMed Central

    Nicaise, Charles; Putatunda, Rajarshi; Hala, Tamara J.; Regan, Kathleen A.; Frank, David M.; Brion, Jean-Pierre; Leroy, Karelle; Pochet, Roland; Wright, Megan C.

    2012-01-01

    Abstract A primary cause of morbidity and mortality following cervical spinal cord injury (SCI) is respiratory compromise, regardless of the level of trauma. In particular, SCI at mid-cervical regions targets degeneration of both descending bulbospinal respiratory axons and cell bodies of phrenic motor neurons, resulting in deficits in the function of the diaphragm, the primary muscle of inspiration. Contusion-type trauma to the cervical spinal cord is one of the most common forms of human SCI; however, few studies have evaluated mid-cervical contusion in animal models or characterized consequent histopathological and functional effects of degeneration of phrenic motor neuron–diaphragm circuitry. We have generated a mouse model of cervical contusion SCI that unilaterally targets both C4 and C5 levels, the location of the phrenic motor neuron pool, and have examined histological and functional outcomes for up to 6 weeks post-injury. We report that phrenic motor neuron loss in cervical spinal cord, phrenic nerve axonal degeneration, and denervation at diaphragm neuromuscular junctions (NMJ) resulted in compromised ipsilateral diaphragm function, as demonstrated by persistent reduction in diaphragm compound muscle action potential amplitudes following phrenic nerve stimulation and abnormalities in spontaneous diaphragm electromyography (EMG) recordings. This injury paradigm is reproducible, does not require ventilatory assistance, and provides proof-of-principle that generation of unilateral cervical contusion is a feasible strategy for modeling diaphragmatic/respiratory deficits in mice. This study and its accompanying analyses pave the way for using transgenic mouse technology to explore the function of specific genes in the pathophysiology of phrenic motor neuron degeneration and respiratory dysfunction following cervical SCI. PMID:23176637

  13. Plasticity and alterations of trunk motor cortex following spinal cord injury and non-stepping robot and treadmill training.

    PubMed

    Oza, Chintan S; Giszter, Simon F

    2014-06-01

    Spinal cord injury (SCI) induces significant reorganization in the sensorimotor cortex. Trunk motor control is crucial for postural stability and propulsion after low thoracic SCI and several rehabilitative strategies are aimed at trunk stability and control. However little is known about the effect of SCI and rehabilitation training on trunk motor representations and their plasticity in the cortex. Here, we used intracortical microstimulation to examine the motor cortex representations of the trunk in relation to other representations in three groups of chronic adult complete low thoracic SCI rats: chronic untrained, treadmill trained (but 'non-stepping') and robot assisted treadmill trained (but 'non-stepping') and compared with a group of normal rats. Our results demonstrate extensive and significant reorganization of the trunk motor cortex after chronic adult SCI which includes (1) expansion and rostral displacement of trunk motor representations in the cortex, with the greatest significant increase observed for rostral (to injury) trunk, and slight but significant increase of motor representation for caudal (to injury) trunk at low thoracic levels in all spinalized rats; (2) significant changes in coactivation and the synergy representation (or map overlap) between different trunk muscles and between trunk and forelimb. No significant differences were observed between the groups of transected rats for the majority of the comparisons. However, (3) the treadmill and robot-treadmill trained groups of rats showed a further small but significant rostral migration of the trunk representations, beyond the shift caused by transection alone. We conclude that SCI induces a significant reorganization of the trunk motor cortex, which is not qualitatively altered by non-stepping treadmill training or non-stepping robot assisted treadmill training, but is shifted further from normal topography by the training. This shift may potentially make subsequent rehabilitation with

  14. Automatic classification of motor unit potentials in surface EMG recorded from thenar muscles paralyzed by spinal cord injury.

    PubMed

    Winslow, Jeffrey; Dididze, Marine; Thomas, Christine K

    2009-12-15

    Involuntary electromyographic (EMG) activity has only been analyzed in the paralyzed thenar muscles of spinal cord injured (SCI) subjects for several minutes. It is unknown if this motor unit activity is ongoing. Longer duration EMG recordings can investigate the biological significance of this activity. Since no software is currently capable of classifying 24h of EMG data at a single motor unit level, the goal of this research was to devise an algorithm that would automatically classify motor unit potentials by tracking the firing behavior of motor units over 24h. Two channels of thenar muscle surface EMG were recorded over 24h from seven SCI subjects with a chronic cervical level injury using a custom data logging device with custom software. The automatic motor unit classification algorithm developed here employed multiple passes through these 24-h EMG recordings to segment, cluster, form global templates and classify motor unit potentials, including superimposed potentials. The classification algorithm was able to track an average of 19 global classes in seven 24-h recordings with a mean (+/-SE) accuracy of 89.9% (+/-0.98%) and classify potentials from these individual motor units with a mean accuracy of 90.3% (+/-0.97%). The algorithm could analyze 24h of data in 2-3 weeks with minimal input from a person, while a human operator was estimated to take more than 2 years. This automatic method could be applied clinically to investigate the fasciculation potentials often found in motoneuron disorders such as amyotrophic lateral sclerosis.

  15. Defects in Neuromuscular Transmission May Underlie Motor Dysfunction in Spinal and Bulbar Muscular Atrophy

    PubMed Central

    Xu, Youfen; Halievski, Katherine; Henley, Casey; Atchison, William D.; Katsuno, Masahisa; Adachi, Hiroaki; Sobue, Gen; Breedlove, S. Marc

    2016-01-01

    Spinal and bulbar muscular atrophy (SBMA) in men is an androgen-dependent neuromuscular disease caused by expanded CAG repeats in the androgen receptor (AR). Whether muscle or motor neuron dysfunction or both underlies motor impairment in SBMA is unknown. Muscles of SBMA mice show significant contractile dysfunction, implicating them as a likely source of motor dysfunction, but whether disease also impairs neuromuscular transmission is an open question. Thus, we examined synaptic function in three well-studied SBMA mouse models—the AR97Q, knock-in (KI), and myogenic141 models—by recording in vitro miniature and evoked end-plate potentials (MEPPs and EPPs, respectively) intracellularly from adult muscle fibers. We found striking defects in neuromuscular transmission suggesting that toxic AR in SBMA impairs both presynaptic and postsynaptic mechanisms. Notably, SBMA causes neuromuscular synapses to become weak and muscles to become hyperexcitable in all three models. Presynaptic defects included deficits in quantal content, reduced size of the readily releasable pool, and impaired short-term facilitation. Postsynaptic defects included prolonged decay times for both MEPPs and EPPs, marked resistance to μ-conotoxin (a sodium channel blocker), and enhanced membrane excitability. Quantitative PCR revealed robust upregulation of mRNAs encoding neonatal isoforms of the AChR (γ-subunit) and the voltage-gated sodium channel (NaV1.5) in diseased adult muscles of all three models, consistent with the observed slowing of synaptic potentials and resistance to μ-conotoxin. These findings suggest that muscles of SBMA patients regress to an immature state that impairs neuromuscular function. SIGNIFICANCE STATEMENT We have discovered that SBMA is accompanied by marked defects in neuromuscular synaptic transmission involving both presynaptic and postsynaptic mechanisms. For three different mouse models, we find that diseased synapses are weak, having reduced quantal content

  16. Topographic maps of human motor cortex in normal and pathological conditions: mirror movements, amputations and spinal cord injuries.

    PubMed

    Cohen, L G; Bandinelli, S; Topka, H R; Fuhr, P; Roth, B J; Hallett, M

    1991-01-01

    We studied motor evoked potentials to transcranial magnetic stimulation in patients with unilateral upper limb amputations, complete T10-T12 spinal cord transection, and congenital mirror movements and in controls. Different muscles in the trunk and upper and lower extremities were evaluated at rest. In controls, muscles could be activated with stimulation of regions several centimeters wide. These areas overlapped extensively when muscles studied were from the same limb and shifted positions abruptly when muscles were from different limbs. Distal muscles were easier to activate than proximal muscles and normally evidenced exclusively a contralateral representation. Congenital defects in motor control in patients with mirror movements resulted in marked derangement of the map of outputs of distal hand muscles with enlarged and ipsilateral representations. Peripheral lesions, either acquired (amputations) or congenital (congenital absence of a limb), resulted in plastic reorganization of motor outputs targeting muscles immediately proximal to the stump. Central nervous system lesions (i.e., spinal cord injury producing paraplegia) also resulted in enlargement of the map of outputs targeting muscles proximal to the lesion. These results indicate that magnetic stimulation is a useful non-invasive tool for exploring plastic changes in human motor pathways following different types of injury.

  17. Targeted axonal import (TAxI) peptide delivers functional proteins into spinal cord motor neurons after peripheral administration.

    PubMed

    Sellers, Drew L; Bergen, Jamie M; Johnson, Russell N; Back, Heidi; Ravits, John M; Horner, Philip J; Pun, Suzie H

    2016-03-01

    A significant unmet need in treating neurodegenerative disease is effective methods for delivery of biologic drugs, such as peptides, proteins, or nucleic acids into the central nervous system (CNS). To date, there are no operative technologies for the delivery of macromolecular drugs to the CNS via peripheral administration routes. Using an in vivo phage-display screen, we identify a peptide, targeted axonal import (TAxI), that enriched recombinant bacteriophage accumulation and delivered protein cargo into spinal cord motor neurons after intramuscular injection. In animals with transected peripheral nerve roots, TAxI delivery into motor neurons after peripheral administration was inhibited, suggesting a retrograde axonal transport mechanism for delivery into the CNS. Notably, TAxI-Cre recombinase fusion proteins induced selective recombination and tdTomato-reporter expression in motor neurons after intramuscular injections. Furthermore, TAxI peptide was shown to label motor neurons in the human tissue. The demonstration of a nonviral-mediated delivery of functional proteins into the spinal cord establishes the clinical potential of this technology for minimally invasive administration of CNS-targeted therapeutics.

  18. Targeted axonal import (TAxI) peptide delivers functional proteins into spinal cord motor neurons after peripheral administration

    PubMed Central

    Sellers, Drew L.; Bergen, Jamie M.; Johnson, Russell N.; Back, Heidi; Ravits, John M.; Horner, Philip J.; Pun, Suzie H.

    2016-01-01

    A significant unmet need in treating neurodegenerative disease is effective methods for delivery of biologic drugs, such as peptides, proteins, or nucleic acids into the central nervous system (CNS). To date, there are no operative technologies for the delivery of macromolecular drugs to the CNS via peripheral administration routes. Using an in vivo phage-display screen, we identify a peptide, targeted axonal import (TAxI), that enriched recombinant bacteriophage accumulation and delivered protein cargo into spinal cord motor neurons after intramuscular injection. In animals with transected peripheral nerve roots, TAxI delivery into motor neurons after peripheral administration was inhibited, suggesting a retrograde axonal transport mechanism for delivery into the CNS. Notably, TAxI-Cre recombinase fusion proteins induced selective recombination and tdTomato-reporter expression in motor neurons after intramuscular injections. Furthermore, TAxI peptide was shown to label motor neurons in the human tissue. The demonstration of a nonviral-mediated delivery of functional proteins into the spinal cord establishes the clinical potential of this technology for minimally invasive administration of CNS-targeted therapeutics. PMID:26888285

  19. Effect of Locomotor Training on Motor Recovery and Walking Ability in Patients with Incomplete Spinal Cord Injury: A Case Series

    PubMed Central

    Anwer, Shahnawaz; Equebal, Ameed; Palekar, Tushar J; Nezamuddin, M; Neyaz, Osama; Alghadir, Ahmad

    2014-01-01

    [Purpose] The aim of this study was to describe the effect of locomotor training on a treadmill for three individuals who have an incomplete spinal cord injury (SCI). [Subjects and Methods] Three indivduals (2 males, 1 female) with incomplete paraplegia participated in this prospective case series. All subjects participated in locomotor training for a maximum of 20 minutes on a motorized treadmill without elevation at a comfortable walking speed three days a week for four weeks as an adjunct to a conventional physiotherapy program. The lower extremity strength and walking capabilities were used as the outcome measures of this study. Lower extremity strength was measured by lower extremity motor score (LEMS). Walking capability was assessed using the Walking Index for Spinal Cord Injury (WISCI II). [Results] An increase in lower extremity motor score and walking capabilities at the end of training program was found. [Conclusion] Gait training on a treadmill can enhance motor recovery and walking capabilities in subjects with incomplete SCI. Further research is needed to generalize these findings and to identify which patients might benefit from locomotor training. PMID:25013303

  20. High-resolution direct microstimulation mapping of spinal cord motor pathways during resection of an intramedullary tumor.

    PubMed

    Gandhi, Ravi; Curtis, Corinne M; Cohen-Gadol, Aaron A

    2015-02-01

    Despite the use of advanced microsurgical techniques, resection of intramedullary tumors may result in significant postoperative deficits because of the vicinity or invasion of important functional tracts. Intraoperative monitoring of somatosensory evoked potentials and transcranial electrical motor evoked potentials has been used previously to limit such complications. Electromyography offers an opportunity for the surgeon to map the eloquent tissue associated with the tumor using intraoperative motor fiber stimulation. Similar to the use of cortical simulation in the resection of supratentorial gliomas, this technique can potentially advance the safety of intramedullary spinal cord tumor resection. The authors describe the use of intraoperative motor fiber tract stimulation to map the corticospinal tracts associated with an intramedullary tumor. This technique led to protection of these tracts during resection of the tumor. PMID:25431960

  1. Identification of gangliosides recognized by IgG anti-GalNAc-GD1a antibodies in bovine spinal motor neurons and motor nerves.

    PubMed

    Yoshino, Hiide; Ariga, Toshio; Suzuki, Akemi; Yu, Robert K; Miyatake, Tadashi

    2008-08-28

    The presence of immunoglobulin G (IgG)-type antibodies to the ganglioside, N-acetylgalactosaminyl GD1a (GalNAc-GD1a), is closely associated with the pure motor type of Guillain-Barré syndrome (GBS). In the present study, we isolated disialogangliosides from the motor neurons and motor nerves of bovine spinal cords by DEAE-Sephadex column chromatography. The disialoganglioside fraction contained GD1a, GD2, GD1b, and three gangliosides, designated X1, X2 and X3. Serum from a patient with axonal GBS with IgG anti-GalNAc-GD1a antibody yielded positive immunostaining with X1, X2, and X3. When isolated by preparative thin-layer chromatography (TLC), X1 migrated at the same position as GalNAc-GD1a from Tay-Sachs brain, suggesting that X1 is GalNAc-GD1a containing N-acetylneuraminic acid (NeuAc). TLC of isolated X2 revealed that it migrated between GD1a and GD2. On the other hand, X3 had a migratory rate on TLC between and GD1b and GT1b. Since both X2 and X3 were recognized by IgG anti-GalNAc-GD1a antibody, the results suggest that X2 is a GalNAc-GD1a species containing a mixture containing a NeuAc-and an N-glycolylneuraminic acid (NeuGc) species, and X3 is a GalNAc-GD1a species with two NeuGc. This evidence indicating the specific localization of GalNAc-GD1a and its isomers in spinal motor neurons should be useful in elucidating the pathogenic role of IgG anti-GalNAc-GD1a antibody in pure motor-type GBS.

  2. Serotonin 2A and 2B receptor-induced phrenic motor facilitation: differential requirement for spinal NADPH oxidase activity

    PubMed Central

    MacFarlane, P.M.; Vinit, S.; Mitchell, G.S.

    2011-01-01

    Acute intermittent hypoxia (AIH) facilitates phrenic motor output by a mechanism that requires spinal serotonin (type 2) receptor activation, NADPH oxidase activity and formation of reactive oxygen species (ROS). Episodic spinal serotonin (5-HT) receptor activation alone, without changes in oxygenation, is sufficient to elicit NADPH oxidase-dependent phrenic motor facilitation (pMF). Here we investigated: 1) whether serotonin 2A and/or 2B (5-HT2a/b) receptors are expressed in identified phrenic motor neurons, and 2) which receptor subtype is capable of eliciting NADPH-oxidase-dependent pMF. In anesthetized, artificially ventilated adult rats, episodic C4 intrathecal injections (3 × 6µl injections, 5 min intervals) of a 5-HT2a (DOI) or 5-HT2b (BW723C86) receptor agonist elicited progressive and sustained increases in integrated phrenic nerve burst amplitude (i.e. pMF), an effect lasting at least 90 minutes post-injection for both receptor subtypes. 5-HT2a and 5-HT2b receptor agonist-induced pMF were both blocked by selective antagonists (ketanserin and SB206553, respectively), but not by antagonists to the other receptor subtype. Single injections of either agonist failed to elicit pMF, demonstrating a need for episodic receptor activation. Phrenic motor neurons retrogradely labeled with cholera toxin B fragment expressed both 5-HT2a and 5-HT2b receptors. Pre-treatment with NADPH oxidase inhibitors (apocynin and DPI) blocked 5-HT2b, but not 5-HT2a-induced pMF. Thus, multiple spinal type 2 serotonin receptors elicit pMF, but they act via distinct mechanisms that differ in their requirement for NADPH oxidase activity. PMID:21223996

  3. Neurogenic motor evoked potential changes after acute experimental spinal cord i njury.

    PubMed

    Shen, Qiang; Jia, Lianshun; Zhou, Xuhui

    2000-08-15

    OBJECTIVE: To better understand the characte ristics of the neurogenic motor evoked potential (NMEP) before and after acute s pinal cord injury. METHODS: We recorded and characterized the spinal cord NMEP fro m 48 normal rats and from 38 rats with spinal cord hemisection lesion. Spinal co rd NMEPs were elicited by applying a range of current intensities with bipolar m icroelectrode stimuli to the C4 cord segment and recording the responses from sc iatic nerves with bipolar microelectrodes placed in the neurilemma. RESULTS: The evoked potentials consisted of three stable and re producible negative and three positive peaks. The meanplus minusSD latencies of N1 were 2.89plus minus0.22 ms on the right side and 2.89plus minus0.24 ms on th e left side. The mean conduction velocity was 47.9 m/s. The meanplus minusSD am plitudes of N1 were 3.61plus minus2.10 muV on the right side and 3.83plus minus2.3 2 muV on the left side. The amplitudes of N1 were signific antly different among the eight stimulus intensity groups (right side: F=2.22, df=7201, P=0.03; left side: F=2.11, df=7206, P=0.04). The amplitude was largest when the stimulus intensity was 1.1-2.5 mA. The latencies of N1 were not si gnificantly different among the eight stimulus intensity groups (right side: F=0.40, df=7201, P=0.9; left side: F=1.20, df=7206, P=0.3. The amplitudes and latencies of N2, N3 were not significantly different among the eight stimulus intensity groups. There were no significant changes in latency and amplitude between the left and the right side nerve responses. Thirty-eight rats underwent T9 cord right side hemisection. Among them, 20 (53%), 30 (79%), and 32 (84%) rats could not be reco rded in corresponding to N1, N2, and N3, respectively, in the right-side sciati c nerves; and 13 (79%), 18 (47%), and 21 (55%), in corresponding to N1, N2, and N3 in the left-side sciatic nerves. The latency was significantly delayed on th e both right and left sides. The amplitude N1 was significantly

  4. Motor unit firing rates during spasms in thenar muscles of spinal cord injured subjects

    PubMed Central

    Zijdewind, Inge; Bakels, Rob; Thomas, Christine K.

    2014-01-01

    Involuntary contractions of paralyzed muscles (spasms) commonly disrupt daily activities and rehabilitation after human spinal cord injury (SCI). Our aim was to examine the recruitment, firing rate modulation, and derecruitment of motor units that underlie spasms of thenar muscles after cervical SCI. Intramuscular electromyographic activity (EMG), surface EMG, and force were recorded during thenar muscle spasms that occurred spontaneously or that were triggered by movement of a shoulder or leg. Most spasms were submaximal (mean: 39%, SD: 33 of the force evoked by median nerve stimulation at 50 Hz) with strong relationships between EMG and force (R2 > 0.69). Unit recruitment occurred over a wide force range (0.2–103% of 50 Hz force). Significant unit rate modulation occurred during spasms (frequency at 25% maximal force: 8.8 Hz, 3.3 SD; at maximal force: 16.1 Hz, 4.1 SD). Mean recruitment frequency (7.1 Hz, 3.2 SD) was significantly higher than derecruitment frequency (5.4 Hz, 2.4 SD). Coactive unit pairs that fired for more than 4 s showed high (R2 > 0.7, n = 4) or low (R2:0.3–0.7, n = 12) rate-rate correlations, and derecruitment reversals (21 pairs, 29%). Later recruited units had higher or lower maximal firing rates than lower threshold units. These discrepant data show that coactive motoneurons are drive both by common inputs and by synaptic inputs from different sources during muscle spasms. Further, thenar motoneurons can still fire at high rates in response to various peripheral inputs after SCI, supporting the idea that low maximal voluntary firing rates and forces in thenar muscles result from reduced descending drive. PMID:25452723

  5. Divergent Modulation of Clinical Measures of Volitional and Reflexive Motor Behaviors following Serotonergic Medications in Human Incomplete Spinal Cord Injury

    PubMed Central

    Thompson, Christopher K.

    2013-01-01

    Abstract Incomplete spinal cord injury (SCI) can result in profound impairments in volitional strength and reflex excitability, which contribute to loss of function. Human and animal models suggest that disruption of endogenous monoaminergic input, particularly serotonin (5-HT), from supraspinal centers contributes to this impaired motor function following SCI. In the present study, we investigated the effects of 5-HT medications on motor function in individuals with chronic (>1 year) SCI. Clinical measures of strength, spasticity/spasms, and walking ability were assessed in 12 individuals with chronic incomplete SCI following acute administration of either 8 mg cyproheptadine, a 5-HT antagonist, or 10 mg escitalopram, a selective 5-HT reuptake inhibitor (SSRI), in a double-blinded, randomized, crossover fashion. Results indicated that 5-HT medications modulated both volitional and reflexive behaviors with little change in walking performance; 5-HT antagonist medications depressed clinical measures of strength and spasticity/spasms, whereas SSRIs augmented both strength and spasticity/spasms. These changes are consistent with the dysregulation of 5-HT sensitive spinal neurons following SCI. This understanding may augment clinicians' awareness of the motor consequences of 5-HT medications. PMID:22994901

  6. Abbreviated exposure to hypoxia is sufficient to induce CNS dysmyelination, modulate spinal motor neuron composition, and impair motor development in neonatal mice.

    PubMed

    Watzlawik, Jens O; Kahoud, Robert J; O'Toole, Ryan J; White, Katherine A M; Ogden, Alyssa R; Painter, Meghan M; Wootla, Bharath; Papke, Louisa M; Denic, Aleksandar; Weimer, Jill M; Carey, William A; Rodriguez, Moses

    2015-01-01

    Neonatal white matter injury (nWMI) is an increasingly common cause of cerebral palsy that results predominantly from hypoxic injury to progenitor cells including those of the oligodendrocyte lineage. Existing mouse models of nWMI utilize prolonged periods of hypoxia during the neonatal period, require complex cross-fostering and exhibit poor growth and high mortality rates. Abnormal CNS myelin composition serves as the major explanation for persistent neuro-motor deficits. Here we developed a simplified model of nWMI with low mortality rates and improved growth without cross-fostering. Neonatal mice are exposed to low oxygen from postnatal day (P) 3 to P7, which roughly corresponds to the period of human brain development between gestational weeks 32 and 36. CNS hypomyelination is detectable for 2-3 weeks post injury and strongly correlates with levels of body and brain weight loss. Immediately following hypoxia treatment, cell death was evident in multiple brain regions, most notably in superficial and deep cortical layers as well as the subventricular zone progenitor compartment. PDGFαR, Nkx2.2, and Olig2 positive oligodendrocyte progenitor cell were significantly reduced until postnatal day 27. In addition to CNS dysmyelination we identified a novel pathological marker for adult hypoxic animals that strongly correlates with life-long neuro-motor deficits. Mice reared under hypoxia reveal an abnormal spinal neuron composition with increased small and medium diameter axons and decreased large diameter axons in thoracic lateral and anterior funiculi. Differences were particularly pronounced in white matter motor tracts left and right of the anterior median fissure. Our findings suggest that 4 days of exposure to hypoxia are sufficient to induce experimental nWMI in CD1 mice, thus providing a model to test new therapeutics. Pathological hallmarks of this model include early cell death, decreased OPCs and hypomyelination in early postnatal life, followed by

  7. Abbreviated Exposure to Hypoxia Is Sufficient to Induce CNS Dysmyelination, Modulate Spinal Motor Neuron Composition, and Impair Motor Development in Neonatal Mice

    PubMed Central

    Watzlawik, Jens O.; Kahoud, Robert J.; O’Toole, Ryan J.; White, Katherine A. M.; Ogden, Alyssa R.; Painter, Meghan M.; Wootla, Bharath; Papke, Louisa M.; Denic, Aleksandar; Weimer, Jill M.; Carey, William A.; Rodriguez, Moses

    2015-01-01

    Neonatal white matter injury (nWMI) is an increasingly common cause of cerebral palsy that results predominantly from hypoxic injury to progenitor cells including those of the oligodendrocyte lineage. Existing mouse models of nWMI utilize prolonged periods of hypoxia during the neonatal period, require complex cross-fostering and exhibit poor growth and high mortality rates. Abnormal CNS myelin composition serves as the major explanation for persistent neuro-motor deficits. Here we developed a simplified model of nWMI with low mortality rates and improved growth without cross-fostering. Neonatal mice are exposed to low oxygen from postnatal day (P) 3 to P7, which roughly corresponds to the period of human brain development between gestational weeks 32 and 36. CNS hypomyelination is detectable for 2–3 weeks post injury and strongly correlates with levels of body and brain weight loss. Immediately following hypoxia treatment, cell death was evident in multiple brain regions, most notably in superficial and deep cortical layers as well as the subventricular zone progenitor compartment. PDGFαR, Nkx2.2, and Olig2 positive oligodendrocyte progenitor cell were significantly reduced until postnatal day 27. In addition to CNS dysmyelination we identified a novel pathological marker for adult hypoxic animals that strongly correlates with life-long neuro-motor deficits. Mice reared under hypoxia reveal an abnormal spinal neuron composition with increased small and medium diameter axons and decreased large diameter axons in thoracic lateral and anterior funiculi. Differences were particularly pronounced in white matter motor tracts left and right of the anterior median fissure. Our findings suggest that 4 days of exposure to hypoxia are sufficient to induce experimental nWMI in CD1 mice, thus providing a model to test new therapeutics. Pathological hallmarks of this model include early cell death, decreased OPCs and hypomyelination in early postnatal life, followed by

  8. Course of motor recovery following ventrolateral spinal cord injury in the rat.

    PubMed

    Webb, Aubrey A; Muir, Gillian D

    2004-11-01

    The purpose of this study was to determine the importance of the pathways running in the ventrolateral spinal funiculus for overground locomotion in adult, freely behaving rats. Left-sided ventrolateral cervical spinal cord injury was performed in adult female Long-Evans rats. The behavioural abilities of these animals were analyzed at 2 days, and weekly for up to 5.5 weeks following spinal cord injury. Behavioural testing consisted of Von Frey filament testing, ladder walking, a paw usage task, and the assessment of ground reaction forces during unrestrained trotting. Animals with injury to the left ventrolateral cervical spinal cord did not develop enhanced sensitivity to pedal mechanical stimulation. At 2 days following injury, animals had impaired skilled locomotion as indicated by increased number of footslips during ladder walking. At 2 days, these animals also used both limbs together more often for support while rearing, while using the forelimb ipsilateral to the injury less than did uninjured animals. Ground reaction force determination revealed that animals tend to bear less weight on the forelimb and hindlimb ipsilateral to the spinal cord injury 2 days after injury. All animals recovered normal or near normal sensorimotor abilities although subtle asymmetries in ground reaction forces were detectable at 5.5 weeks following spinal cord injury. These results suggest that axons in the ventrolateral spinal funiculi contribute to limb movements during exploration and locomotion but their roles can be served by other pathways after ventrolateral spinal injury. PMID:15325779

  9. Distinct changes in cortical and spinal excitability following high-frequency repetitive TMS to the human motor cortex.

    PubMed

    Quartarone, Angelo; Bagnato, Sergio; Rizzo, Vincenzo; Morgante, Francesca; Sant'angelo, Antonio; Battaglia, Fortunato; Messina, Corrado; Siebner, Hartwig Roman; Girlanda, Paolo

    2005-02-01

    It has been shown that high-frequency repetitive transcranial magnetic stimulation (rTMS) to the human primary motor hand area (M1-HAND) can induce a lasting increase in corticospinal excitability. Here we recorded motor evoked potentials (MEPs) from the right first dorsal interosseus muscle to investigate how sub-threshold high-frequency rTMS to the M1-HAND modulates cortical and spinal excitability. In a first experiment, we gave 1500 stimuli of 5 Hz rTMS. At an intensity of 90% of active motor threshold, rTMS produced no effect on MEP amplitude at rest. Increasing the intensity to 90% of resting motor threshold (RMT), rTMS produced an increase in MEP amplitude. This facilitatory effect gradually built up during the course of rTMS, reaching significance after the administration of 900 stimuli. In a second experiment, MEPs were elicited during tonic contraction using weak anodal electrical or magnetic test stimuli. 1500 (but not 600) conditioning stimuli at 90% of RMT induced a facilitation of MEPs in the contracting FDI muscle. In a third experiment, 600 conditioning stimuli were given at 90% of RMT to the M1-HAND. Using two well-established conditioning-test paradigms, we found a decrease in short-latency intracortical inhibition (SICI), and a facilitation of the first peak of facilitatory I-waves interaction (SICF). There was no correlation between the relative changes in SICI and SICF. These results demonstrate that subthreshold 5 Hz rTMS can induce lasting changes in specific neuronal subpopulations in the human corticospinal motor system, depending on the intensity and duration of rTMS. Short 5 Hz rTMS (600 stimuli) at 90% of RMT can selectively shape the excitability of distinct intracortical circuits, whereas prolonged 5 Hz rTMS (> or =900 stimuli) provokes an overall increase in excitability of the corticospinal output system, including spinal motoneurones.

  10. Neuronal nitric oxide synthase inhibitor, 7-nitroindazole, delays motor dysfunction and spinal motoneuron degeneration in the wobbler mouse.

    PubMed

    Ikeda, K; Iwasaki, Y; Kinoshita, M

    1998-09-18

    Gene mutations of superoxide dismutase (SOD) have been discovered in familial amyotrophic lateral sclerosis (ALS). Neuronal nitric oxide synthase (NOS), endothelial NOS and 3-nitrotyrosine immunoreactivities are selectively increased in the spinal motoneurons of sporadic ALS. Other study suggests that 3-nitrotyrosine immunoreactivity is enhanced in the spinal motoneurons of sporadic and familial ALS patients. The hypothesis is postulated that increased production of radical species, such as superoxide and peroxynitrite, may cause motoneuron degeneration in ALS. There are increased amounts of nitric oxide and SOD hypoactivities in the brain and spinal cord of wobbler mice. NOS is also induced in the vacuolated spinal motoneurons or axons in this animal. Free radicals might contribute to the pathogenesis of wobbler mouse motoneuron disease. Lecithinized SOD treatment has retarded the progression of this disease. This evidence allowed us to determine whether NOS inhibitors delay progression of wobbler mouse motoneuron disease. After clinical diagnosis at age 3-4 weeks, wobbler mice were injected with intraperitoneal non-selective NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg), two doses of neuronal NOS inhibitor, 7-nitroindazole (5 or 50 mg/kg) or a vehicle solution, daily for 4 weeks in a blind fashion. In comparison with vehicle, 7-nitroindazole-treated mice potentiated grip strength and attenuated deformities in the forelimbs. 7-Nitroindazole treatment increased the biceps muscle weight, reduced denervation muscle atrophy, and suppressed degeneration of spinal motoneurons. To a lesser degree, L-NAME-treated mice displayed slowed progression of disease. The present studies indicate that neuronal NOS inhibitor may be a candidate for promising therapy in lower motoneuron disease or motor neuropathy. PMID:9804111

  11. Retinoid signaling and Neurogenin2 function are coupled for the specification of spinal motor neurons through a chromatin modifier CBP

    PubMed Central

    Lee, Seunghee; Lee, Bora; Lee, Jae W.; Lee, Soo-Kyung

    2009-01-01

    SUMMARY Extracellular signals and cell-intrinsic transcription factors cooperatively instruct generation of diverse neurons. However, little is known about how neural progenitors integrate both cues and orchestrate chromatin changes for neuronal specification. Here, we report that extrinsic signal retinoic acid (RA) and intrinsic transcription factor Neurogenin2 (Ngn2) collaboratively trigger transcriptionally active chromatin in spinal motor neuron genes during development. Retinoic acid receptor (RAR) binds Ngn2 and is thereby recruited to motor neuron genes targeted by Ngn2. RA then facilitates the recruitment of a histone acetyltransferase CBP to the Ngn2/RAR-complex, markedly inducing histone H3/H4-acetylation. Correspondingly, timely inactivation of CBP and its paralogue p300 results in profound defects in motor neuron specification and motor axonal projection, accompanied by significantly reduced histone H3-acetylation of the motor neuron enhancer. Our study uncovers the mechanism by which extrinsic RA-signal and intrinsic transcription factor Ngn2 cooperate for cell-fate specification through their synergistic activity to trigger transcriptionally active chromatin. PMID:19524524

  12. Morphological characteristics of motor neurons do not determine their relative susceptibility to degeneration in a mouse model of severe spinal muscular atrophy.

    PubMed

    Thomson, Sophie R; Nahon, Joya E; Mutsaers, Chantal A; Thomson, Derek; Hamilton, Gillian; Parson, Simon H; Gillingwater, Thomas H

    2012-01-01

    Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality, resulting primarily from the degeneration and loss of lower motor neurons. Studies using mouse models of SMA have revealed widespread heterogeneity in the susceptibility of individual motor neurons to neurodegeneration, but the underlying reasons remain unclear. Data from related motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), suggest that morphological properties of motor neurons may regulate susceptibility: in ALS larger motor units innervating fast-twitch muscles degenerate first. We therefore set out to determine whether intrinsic morphological characteristics of motor neurons influenced their relative vulnerability to SMA. Motor neuron vulnerability was mapped across 10 muscle groups in SMA mice. Neither the position of the muscle in the body, nor the fibre type of the muscle innervated, influenced susceptibility. Morphological properties of vulnerable and disease-resistant motor neurons were then determined from single motor units reconstructed in Thy.1-YFP-H mice. None of the parameters we investigated in healthy young adult mice - including motor unit size, motor unit arbor length, branching patterns, motor endplate size, developmental pruning and numbers of terminal Schwann cells at neuromuscular junctions - correlated with vulnerability. We conclude that morphological characteristics of motor neurons are not a major determinant of disease-susceptibility in SMA, in stark contrast to related forms of motor neuron disease such as ALS. This suggests that subtle molecular differences between motor neurons, or extrinsic factors arising from other cell types, are more likely to determine relative susceptibility in SMA.

  13. Beneficial effects of early environmental enrichment on motor development and spinal cord plasticity in a rat model of cerebral palsy.

    PubMed

    Marques, Marília Rossato; Stigger, Felipe; Segabinazi, Ethiane; Augustin, Otávio Américo; Barbosa, Sílvia; Piazza, Francele Valente; Achaval, Matilde; Marcuzzo, Simone

    2014-04-15

    Cerebral palsy (CP) results from nonprogressive lesions in the immature brain generating changes on the neuromuscular system. Environmental enrichment (EE) is a combination of stimuli that provides greater motivation and interest in novel movement exploration through the provision of various devices associated to enhanced social stimulation that would mimic the physiotherapy approach. The aim of this study was to verify whether EE is able to prevent the establishment of motor impairment in a CP rat model. The animals were divided in two groups: control animals (healthy) and animals submitted to a CP model. After this, the pups were exposed to two environments: enriched or standard, totaling four groups: Control group (without CP in a standard environment), CP group (CP model in a standard environment), EE group (without CP in an enriched environment) and CP-EE (CP model in an enriched environment). The experimental model was induced in pregnant Wistar rats by the association of maternal exposure to bacterial endotoxin, perinatal anoxia and sensorimotor restriction of the pups. The assessment of motor skills was held using the following tests: open field, rotarod, horizontal ladder, narrow suspended bar and stride length. The histological analysis evaluated the mean cross-sectional area (CSA) of the soleus muscle fibers, the mean CSA of motoneuronal somata and expression of synaptophysin in the ventral horn of the spinal cord. EE was able to prevent the motor deficits, however, it did not reverse the muscle atrophy observed in CP animals. Furthermore, there was an average increase in the mean area of motoneurons and an increase in the expression of synaptophysin in the ventral horn of the spinal cord of the CP-EE group in relation to CP animals reared in a standard environment. Hereupon, the stimulus increment provided by EE can prevent the onset of motor deficits and histological changes in a CP rat model.

  14. The sacral networks and neural pathways used to elicit lumbar motor rhythm in the rodent spinal cord.

    PubMed

    Cherniak, Meir; Etlin, Alex; Strauss, Ido; Anglister, Lili; Lev-Tov, Aharon

    2014-01-01

    Identification of neural networks and pathways involved in activation and modulation of spinal central pattern generators (CPGs) in the absence of the descending control from the brain is important for further understanding of neural control of movement and for developing innovative therapeutic approaches to improve the mobility of spinal cord injury patients. Activation of the hindlimb innervating segments by sacrocaudal (SC) afferent input and by specific application of neurochemicals to the sacral networks is feasible in the isolated spinal cord preparation of the newborn rat. Here we review our recent studies of sacral relay neurons with lumbar projections and evaluate their role in linking the sacral and thoracolumbar (TL) networks during different motor behaviors. Our major findings show that: (1) heterogeneous groups of dorsal, intermediate and ventral sacral-neurons with ventral and lateral ascending funicular projections mediate the activation of the locomotor CPGs through sacral sensory input; and (2) rhythmic excitation of lumbar flexor motoneurons, produced by bath application of alpha-1 adrenoceptor agonists to the sacral segments is mediated exclusively by ventral clusters of sacral-neurons with lumbar projections through the ventral funiculus.

  15. An ~140-kb deletion associated with feline spinal muscular atrophy implies an essential LIX1 function for motor neuron survival

    PubMed Central

    Fyfe, John C.; Menotti-Raymond, Marilyn; David, Victor A.; Brichta, Lars; Schäffer, Alejandro A.; Agarwala, Richa; Murphy, William J.; Wedemeyer, William J.; Gregory, Brittany L.; Buzzell, Bethany G.; Drummond, Meghan C.; Wirth, Brunhilde; O'Brien, Stephen J.

    2006-01-01

    The leading genetic cause of infant mortality is spinal muscular atrophy (SMA), a clinically and genetically heterogeneous group of disorders. Previously we described a domestic cat model of autosomal recessive, juvenile-onset SMA similar to human SMA type III. Here we report results of a whole-genome scan for linkage in the feline SMA pedigree using recently developed species-specific and comparative mapping resources. We identified a novel SMA gene candidate, LIX1, in an ~140-kb deletion on feline chromosome A1q in a region of conserved synteny to human chromosome 5q15. Though LIX1 function is unknown, the predicted secondary structure is compatible with a role in RNA metabolism. LIX1 expression is largely restricted to the central nervous system, primarily in spinal motor neurons, thus offering explanation of the tissue restriction of pathology in feline SMA. An exon sequence screen of 25 human SMA cases, not otherwise explicable by mutations at the SMN1 locus, failed to identify comparable LIX1 mutations. Nonetheless, a LIX1-associated etiology in feline SMA implicates a previously undetected mechanism of motor neuron maintenance and mandates consideration of LIX1 as a candidate gene in human SMA when SMN1 mutations are not found. PMID:16899656

  16. Muscle expression of mutant androgen receptor protein accounts for systemic and motor neuron disease phenotypes in Spinal & Bulbar Muscular Atrophy

    PubMed Central

    Cortes, Constanza J.; Ling, Shuo-Chien; Guo, Ling T.; Hung, Gene; Tsunemi, Taiji; Ly, Linda; Tokunaga, Seiya; Lopez, Edith; Sopher, Bryce L.; Bennett, C. Frank; Shelton, G. Diane; Cleveland, Don W.; La Spada, Albert R.

    2014-01-01

    X-linked spinal & bulbar muscular atrophy (SBMA) is characterized by adult-onset muscle weakness and lower motor neuron degeneration. SBMA is caused by CAG-polyglutamine (polyQ) repeat expansions in the androgen receptor (AR) gene. Pathological findings include motor neuron loss, with polyQ-AR accumulation in intranuclear inclusions. SBMA patients exhibit myopathic features, suggesting a role for muscle in disease pathogenesis. To determine the contribution of muscle, we developed a BAC mouse model featuring a floxed first exon to permit cell-type-specific excision of human AR121Q. BAC fxAR121 mice develop systemic and neuromuscular phenotypes, including shortened survival. After validating termination of AR121 expression and full rescue with ubiquitous Cre, we crossed BAC fxAR121 mice with Human Skeletal Actin-Cre mice. Muscle-specific excision prevented weight loss, motor phenotypes, muscle pathology, and motor neuronopathy, and dramatically extended survival. Our results reveal a crucial role for muscle expression of polyQ-AR in SBMA, and suggest muscle-directed therapies as effective treatments. PMID:24742458

  17. Lentiviral vectors carrying enhancer elements of Hb9 promoter drive selective transgene expression in mouse spinal cord motor neurons.

    PubMed

    Peviani, Marco; Kurosaki, Mami; Terao, Mineko; Lidonnici, Dario; Gensano, Francesco; Battaglia, Elisa; Tortarolo, Massimo; Piva, Roberto; Bendotti, Caterina

    2012-03-30

    Recombinant lentiviral vectors (rLVs) have emerged as versatile tools for gene delivery applications due to a number of favorable features, such as the possibility to maintain long-term transgene expression, the flexibility in the design of the expression cassettes and recent improvements in their biosafety profile. Since rLVs are able to infect multiple cell types including post-mitotic cells such as neurons and skeletal muscle cells, several studies have been exploring their application for the study and cure of neurodegenerative diseases. In particular, the introduction of rLVs carrying cell-type specific promoters could restrict the transgene expression either to neuronal or glial cells, thus helping to better dissect in vivo the role played by these cell populations in several neurodegenerative processes. In this study we developed rLVs carrying motor neuron specific regulatory sequences derived from the promoter of homeobox gene Hb9, and demonstrated that these constructs can represent a suitable platform for selective gene-targeting of murine spinal cord motor neurons, in vivo. This tool could be instrumental in the dissection of the molecular mechanisms involved in the selective degeneration of motor neurons occurring in Motor Neuron Diseases.

  18. Muscle expression of mutant androgen receptor accounts for systemic and motor neuron disease phenotypes in spinal and bulbar muscular atrophy.

    PubMed

    Cortes, Constanza J; Ling, Shuo-Chien; Guo, Ling T; Hung, Gene; Tsunemi, Taiji; Ly, Linda; Tokunaga, Seiya; Lopez, Edith; Sopher, Bryce L; Bennett, C Frank; Shelton, G Diane; Cleveland, Don W; La Spada, Albert R

    2014-04-16

    X-linked spinal and bulbar muscular atrophy (SBMA) is characterized by adult-onset muscle weakness and lower motor neuron degeneration. SBMA is caused by CAG-polyglutamine (polyQ) repeat expansions in the androgen receptor (AR) gene. Pathological findings include motor neuron loss, with polyQ-AR accumulation in intranuclear inclusions. SBMA patients exhibit myopathic features, suggesting a role for muscle in disease pathogenesis. To determine the contribution of muscle, we developed a BAC mouse model featuring a floxed first exon to permit cell-type-specific excision of human AR121Q. BAC fxAR121 mice develop systemic and neuromuscular phenotypes, including shortened survival. After validating termination of AR121 expression and full rescue with ubiquitous Cre, we crossed BAC fxAR121 mice with Human Skeletal Actin-Cre mice. Muscle-specific excision prevented weight loss, motor phenotypes, muscle pathology, and motor neuronopathy and dramatically extended survival. Our results reveal a crucial role for muscle expression of polyQ-AR in SBMA and suggest muscle-directed therapies as effective treatments.

  19. A Systematic Review of Experimental Strategies Aimed at Improving Motor Function after Acute and Chronic Spinal Cord Injury.

    PubMed

    Gomes-Osman, Joyce; Cortes, Mar; Guest, James; Pascual-Leone, Alvaro

    2016-03-01

    While various approaches have been proposed in clinical trials aimed at improving motor function after spinal cord injury in humans, there is still limited information regarding the scope, methodological quality, and evidence associated with single-intervention and multi-intervention approaches. A systematic review performed using the PubMed search engine and the key words "spinal cord injury motor recovery" identified 1973 records, of which 39 were selected (18 from the search records and 21 from reference list inspection). Study phase ( clinicaltrials.org criteria) and methodological quality (Cochrane criteria) were assessed. Studies included proposed a broad range of single-intervention (encompassing cell therapies, pharmacology, electrical stimulation, rehabilitation) (encompassing cell therapies, pharmacology, electrical stimulation, rehabilitation) and multi-intervention approaches (that combined more than one strategy). The highest evidence level was for Phase III studies supporting the role of multi-intervention approaches that contained a rehabilitation component. Quality appraisal revealed that the percentage of selected studies classified with high risk of bias by Cochrane criteria was as follows: random sequence generation = 64%; allocation concealment = 77%; blinding of participants and personnel = 69%; blinding of outcome assessment = 64%; attrition = 44%; selective reporting = 44%. The current literature contains a high proportion of studies with a limited ability to measure efficacy in a valid manner because of low methodological strength in all items of the Cochrane risk of bias assessment. Recommendations to decrease bias are discussed and include increased methodological rigor in the study design and recruitment of study participants, and the use of electrophysiological and imaging measures that can assess functional integrity of the spinal cord (and may be sufficiently sensitive to detect changes that occur in response to therapeutic

  20. Blends of rostral and caudal scratch reflex motor patterns elicited by simultaneous stimulation of two sites in the spinal turtle.

    PubMed

    Stein, P S; Camp, A W; Robertson, G A; Mortin, L I

    1986-08-01

    Simultaneous tactile stimulation of 2 sites on the body surface of a spinal turtle elicits complex blends of the scratch forms and motor patterns associated with each site. Our previous work has utilized 1-site stimulation to elicit distinct forms of the scratch reflex in the spinal turtle (Mortin et al., 1985; Robertson et al., 1985). Using this paradigm, stimulation of a site on the shell bridge anterior to the hindlimb elicits a rostral scratch reflex in which the dorsum of the foot rubs against the stimulated site; stimulation of a site near the tail elicits a caudal scratch reflex in which the heel or side of the foot rubs against the stimulated site (Mortin et al., 1985). During each scratch cycle, the monoarticular knee extensor muscle is active when the limb rubs against the stimulated site, and there is rhythmic alternation between hip protractor and hip retractor muscle activity (Robertson et al., 1985). In a rostral scratch, the monoarticular knee extensor muscle is active during the latter portion of hip protractor muscle activity; in a caudal scratch, the monoarticular knee extensor muscle is active near the end of hip retractor muscle activity. Pure-form motor patterns that are similar to those recorded from these muscles during movement can be recorded from the corresponding nerves in a spinal turtle immobilized with a neuromuscular blocking agent (Robertson et al., 1985). In this paper, we describe blend responses to simultaneous stimulation of 2 sites, one in the rostral scratch and the other in the caudal scratch receptive field. During these blends, the responding hindlimb rubs against both stimulated sites in one continuous movement sequence.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3746408

  1. Phosphorylation of Dpsyl2 (CRMP2) and Dpsyl3 (CRMP4) is required for positioning of caudal primary motor neurons in the zebrafish spinal cord.

    PubMed

    Morimura, Rii; Nozawa, Keisuke; Tanaka, Hideomi; Ohshima, Toshio

    2013-12-01

    Dpysls (CRMPs) that were initially identified as mediator proteins of Semaphorin3a (Sema3a) signaling are involved in neuronal polarity and axon elongation in cultured neurons. Previous studies have shown that knockdown of neuropilin1a, one of the sema3a receptors, exhibited ectopic primary motor neurons (PMNs) outside of the spinal cord in zebrafish. However, downstream molecules of sema3a signaling involved in the positioning of motor neurons are largely unknown. Here, we addressed the role of Dpysl2 (CRMP2) and Dpysl3 (CRMP4) in the positioning of PMNs in the zebrafish spinal cord. We found that the knockdown of dpysls by antisense morpholino oligonucleotides (AMO) causes abnormal positioning of caudal primary (CaP) motor neurons outside the spinal cord. The knockdown of cdk5 and dyrk2 by AMO also caused similar phenotype in the positioning of CaP motor neurons, and this phenotype was rescued by co-injection of phosphorylation-mimic type dpysl2 mRNA. These results suggest that the phosphorylation of Dpysl2 and Dpysl3 by Cdk5 and Dyrk2 is required for correct positioning of CaP motor neurons in the zebrafish spinal cord.

  2. Postnatal developmental profile of neurons and glia in motor nuclei of the brainstem and spinal cord, and its comparison with organotypic slice cultures.

    PubMed

    Cifra, Alessandra; Mazzone, Graciela L; Nani, Francesca; Nistri, Andrea; Mladinic, Miranda

    2012-08-01

    In vitro preparations of the neonatal rat spinal cord or brainstem are useful to investigate the organization of motor networks and their dysfunction in neurological disease models. Long-term spinal cord organotypic cultures can extend our understanding of such pathophysiological processes over longer times. It is, however, surprising that detailed descriptions of the type (and number) of neurons and glia in such preparations are currently unavailable to evaluate cell-selectivity of experimental damage. The focus of the present immunohistochemical study is the novel characterization of the cell population in the lumbar locomotor region of the rat spinal cord and in the brainstem motor nucleus hypoglossus at 0-4 postnatal days, and its comparison with spinal organotypic cultures at 2-22 days in vitro. In the nucleus hypoglossus, neurons were 40% of all cells and 80% of these were motoneurons. Astrocytes (35% of total cells) were the main glial cells, while microglia was <10%. In the spinal gray matter, the highest neuronal density was in the dorsal horn (>80%) and the lowest in the ventral horn (≤57%) with inverse astroglia numbers and few microglia. The number of neurons (including motoneurons) and astrocytes was stable after birth. Like in the spinal cord, motoneurons in organotypic spinal culture were <10% of ventral horn cells, with neurons <40%, and the rest made up by glia. The present report indicates a comparable degree of neuronal and glial maturation in brainstem and spinal motor nuclei, and that this condition is also observed in 3-week-old organotypic cultures.

  3. Descending motor pathways and cortical physiology after spinal cord injury assessed by transcranial magnetic stimulation: a systematic review.

    PubMed

    Nardone, Raffaele; Höller, Yvonne; Brigo, Francesco; Orioli, Andrea; Tezzon, Frediano; Schwenker, Kerstin; Christova, Monica; Golaszewski, Stefan; Trinka, Eugen

    2015-09-01

    We performed here a systematic review of the studies using transcranial magnetic stimulation (TMS) as a research and clinical tool in patients with spinal cord injury (SCI). Motor evoked potentials (MEPs) elicited by TMS represent a highly accurate diagnostic test that can supplement clinical examination and neuroimaging findings in the assessment of SCI functional level. MEPs allows to monitor the changes in motor function and evaluate the effects of the different therapeutic approaches. Moreover, TMS represents a useful non-invasive approach for studying cortical physiology, and may be helpful in elucidating the pathophysiological mechanisms of brain reorganization after SCI. Measures of motor cortex reactivity, e.g., the short interval intracortical inhibition and the cortical silent period, seem to point to an increased cortical excitability. However, the results of TMS studies are sometimes contradictory or divergent, and should be replicated in a larger sample of subjects. Understanding the functional changes at brain level and defining their effects on clinical outcome is of crucial importance for development of evidence-based rehabilitation therapy. TMS techniques may help in identifying neurophysiological biomarkers that can reliably assess the extent of neural damage, elucidate the mechanisms of neural repair, predict clinical outcome, and identify therapeutic targets. Some researchers have begun to therapeutically use repetitive TMS (rTMS) in patients with SCI. Initial studies revealed that rTMS can induce acute and short duration beneficial effects especially on spasticity and neuropathic pain, but the evidence is to date still very preliminary and well-designed clinical trials are warranted. This article is part of a Special Issue entitled SI: Spinal cord injury.

  4. Similarities and differences in cervical and thoracolumbar multisegmental motor responses and the combined use for testing spinal circuitries

    PubMed Central

    Sabbahi, Mohamed A.; Uzun, Selda; Ovak Bittar, Fikriye; Sengul, Yesim

    2014-01-01

    Study design Experimental study. Objective To determine similarities and differences of C7 and T11–12 multisegmental motor responses (MMR) studies for the upper limbs (UL) and lower limbs (LL). Settings Neuroscience Lab, TWU (School of Physical Therapy, TX, USA). Methods C7 and T11–12 percutaneous electrical stimulations were applied while recording muscle action potentials from ULs and LLs. Results The procedure of cervical MMR (CMMR) was easier in application than thoracolumbar MMR (TMMR), requiring less current intensities but cause more “jolts” in the trapezius/shoulder complex, due to close proximity of the stimulation electrodes. CMMR evoked large amplitude motor responses in the millivolts range in (UL) muscles, but smaller amplitude signal in (LL) muscles (in microvolts). TMMR evoked large amplitude motor responses in both UL and LL (in millivolts). The MMR amplitude was generally larger in the UL as compared to the LL, in the distal limb muscles more than in the proximal limb muscles. CMMR and TMMR for the UL were comparable in amplitude, latencies and action potential shapes. Signal latencies were longer for distal limb muscles as compared to proximal limb muscles and were slightly longer for LL as compared to UL muscles. MMR signals were either biphasic or triphasic in shape. Conclusion CMMR and TMMR have similarities and differences in the methods and recording signal that must be considered during its clinical applications. Comparing the signal of the UL muscles with CMMR and TMMR could be a useful test for the integrity of the ascending and descending spinal pathways in patients with spinal cord injuries and diseases. PMID:24621020

  5. Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases

    PubMed Central

    Butchbach, Matthew E. R.

    2016-01-01

    Proximal spinal muscular atrophy (SMA), a leading genetic cause of infant death worldwide, is an early-onset, autosomal recessive neurodegenerative disease characterized by the loss of spinal α-motor neurons. This loss of α-motor neurons is associated with muscle weakness and atrophy. SMA can be classified into five clinical grades based on age of onset and severity of the disease. Regardless of clinical grade, proximal SMA results from the loss or mutation of SMN1 (survival motor neuron 1) on chromosome 5q13. In humans a large tandem chromosomal duplication has lead to a second copy of the SMN gene locus known as SMN2. SMN2 is distinguishable from SMN1 by a single nucleotide difference that disrupts an exonic splice enhancer in exon 7. As a result, most of SMN2 mRNAs lack exon 7 (SMNΔ7) and produce a protein that is both unstable and less than fully functional. Although only 10–20% of the SMN2 gene product is fully functional, increased genomic copies of SMN2 inversely correlates with disease severity among individuals with SMA. Because SMN2 copy number influences disease severity in SMA, there is prognostic value in accurate measurement of SMN2 copy number from patients being evaluated for SMA. This prognostic value is especially important given that SMN2 copy number is now being used as an inclusion criterion for SMA clinical trials. In addition to SMA, copy number variations (CNVs) in the SMN genes can affect the clinical severity of other neurological disorders including amyotrophic lateral sclerosis (ALS) and progressive muscular atrophy (PMA). This review will discuss how SMN1 and SMN2 CNVs are detected and why accurate measurement of SMN1 and SMN2 copy numbers is relevant for SMA and other neurodegenerative diseases. PMID:27014701

  6. Dimensions of individual alpha and gamma motor fibres in the ventral funiculus of the cat spinal cord.

    PubMed Central

    Fabricius, C; Berthold, C H; Rydmark, M

    1994-01-01

    Using light and electron microscopy, axon diameter, myelin sheath thickness (measured as number of myelin lamellae) and internodal length of alpha and gamma motor axons of the L7 ventral root and spinal cord segment were investigated in serial cross-sections. The CNS internodes of the alpha motor fibres had, on average, an axon diameter of 8.6 microns, 105 myelin lamellae and a length of about 560 microns. The CNS internodes of the gamma motor fibres had, on average, an axon diameter of 3.4 microns, 66 myelin lamellae and a length of about 440 microns. Axon diameter at the nodes of Ranvier was 30-40% of the internodal axon diameter. Axon diameter, number of myelin lamellae and internodal length varied considerably between consecutive internodes. Statistical analysis showed no systematic increases or decreases. Regression analyses of the scatter plots of the number of myelin lamellae and internodal length against axon diameter showed large variations and correlation coefficients of r < 0.50. In conformity with ventral root (PNS) internodes (Nilsson & Berthold, 1988) the plotting of intrafunicular (CNS) internodal myelin volume against internodal axon mantle area showed linear correlations with correlation coefficients of r > 0.90. The mean axon diameter of the investigated CNS internodes was similar to, the mean number of myelin lamellae somewhat lower than, and the mean internodal length considerably shorter than that of internodes of axons of the L7 ventral root (Nilsson & Berthold, 1988). In contrast to the ventral root, the intrafunicular alpha motor fibres had higher g values (axon diameter/fibre diameter value) and lower il/d ratios (internodal length/axon diameter ratio) than is considered optimal for conduction. We consider that these deviations from the theoretical optimum are not large enough to impair the conduction properties of the CNS parts of the motor axons in a significant way. Images Fig. 1 Fig. 2 PMID:8014123

  7. Age-related changes in soma size of neurons in the spinal cord motor column of the cat.

    PubMed

    Liu, R H; Bertolotto, C; Engelhardt, J K; Chase, M H

    1996-06-28

    The present study was undertaken to examine the effect of the aging process on the soma size and number of motoneurons and interneurons in the motor column of the spinal cord of old cats. Neurons in the motor column were divided into small and large populations based on a bimodal distribution of their soma cross-sectional areas. A 17% decrease in the cross-sectional area of small neurons was observed, this decrease was statistically significant (P < 0.0001). The cross-sectional area of large neurons decreased by only 6%, which was statistically significant (P < 0.05). On the other hand, there was no significant difference in the number of large, small or of these combined population of ventral horn neurons in the aged cats compared with the control animals. This data suggest that neurons in the motor column are not uniformly affected by the aging process because morphological changes are proportionally greater in small neurons than in large neurons. PMID:8817566

  8. Spinal muscular atrophy phenotype is ameliorated in human motor neurons by SMN increase via different novel RNA therapeutic approaches.

    PubMed

    Nizzardo, Monica; Simone, Chiara; Dametti, Sara; Salani, Sabrina; Ulzi, Gianna; Pagliarani, Serena; Rizzo, Federica; Frattini, Emanuele; Pagani, Franco; Bresolin, Nereo; Comi, Giacomo; Corti, Stefania

    2015-01-01

    Spinal muscular atrophy (SMA) is a primary genetic cause of infant mortality due to mutations in the Survival Motor Neuron (SMN) 1 gene. No cure is available. Antisense oligonucleotides (ASOs) aimed at increasing SMN levels from the paralogous SMN2 gene represent a possible therapeutic strategy. Here, we tested in SMA human induced pluripotent stem cells (iPSCs) and iPSC-differentiated motor neurons, three different RNA approaches based on morpholino antisense targeting of the ISSN-1, exon-specific U1 small nuclear RNA (ExSpeU1), and Transcription Activator-Like Effector-Transcription Factor (TALE-TF). All strategies act modulating SMN2 RNA: ASO affects exon 7 splicing, TALE-TF increase SMN2 RNA acting on the promoter, while ExSpeU1 improves pre-mRNA processing. These approaches induced up-regulation of full-length SMN mRNA and differentially affected the Delta-7 isoform: ASO reduced this isoform, while ExSpeU1 and TALE-TF increased it. All approaches upregulate the SMN protein and significantly improve the in vitro SMA motor neurons survival. Thus, these findings demonstrate that therapeutic tools that act on SMN2 RNA are able to rescue the SMA disease phenotype. Our data confirm the feasibility of SMA iPSCs as in vitro disease models and we propose novel RNA approaches as potential therapeutic strategies for treating SMA and other genetic neurological disorders. PMID:26123042

  9. Co-aggregation of RNA binding proteins in ALS spinal motor neurons: evidence of a common pathogenic mechanism.

    PubMed

    Keller, Brian A; Volkening, Kathryn; Droppelmann, Cristian A; Ang, Lee Cyn; Rademakers, Rosa; Strong, Michael J

    2012-11-01

    While the pathogenesis of amyotrophic lateral sclerosis (ALS) remains to be clearly delineated, there is mounting evidence that altered RNA metabolism is a commonality amongst several of the known genetic variants of the disease. In this study, we evaluated the expression of 10 ALS-associated proteins in spinal motor neurons (MNs) in ALS patients with mutations in C9orf72 (C9orf72(GGGGCC)-ALS; n = 5), SOD1 (mtSOD1-ALS; n = 9), FUS/TLS (mtFUS/TLS-ALS; n = 2), or TARDBP (mtTDP-43-ALS; n = 2) and contrasted these to cases of sporadic ALS (sALS; n = 4) and familial ALS without known mutations (fALS; n = 2). We performed colorimetric immunohistochemistry (IHC) using antibodies against TDP-43, FUS/TLS, SOD1, C9orf72, ubiquitin, sequestosome 1 (p62), optineurin, phosphorylated high molecular weight neurofilament, peripherin, and Rho-guanine nucleotide exchange factor (RGNEF). We observed that RGNEF-immunoreactive neuronal cytoplasmic inclusions (NCIs) can co-localize with TDP-43, FUS/TLS and p62 within spinal MNs. We confirmed their capacity to interact by co-immunoprecipitations. We also found that mtSOD1-ALS cases possess a unique IHC signature, including the presence of C9orf72-immunoreactive diffuse NCIs, which allows them to be distinguished from other variants of ALS at the level of light microscopy. These findings support the hypothesis that alterations in RNA metabolism are a core pathogenic pathway in ALS. We also conclude that routine IHC-based analysis of spinal MNs may aid in the identification of families not previously suspected to harbor SOD1 mutations. PMID:22941224

  10. Mapping of motor and sensory activity in the human spinal cord with functional magnetic resonance imaging (fMRI)

    NASA Astrophysics Data System (ADS)

    Morales, Dinorah; Rojas, Rafael; Barrios, Fernando A.

    2001-10-01

    Spinal cord fMRI images in control human volunteers were obtained at 1.5 T. Using a T2* weighted EPI-BOLD GE pulse sequence during a motor task activation scheme. The images were centered at C7 with five axial slices, 8 mm thick with zero separation. All the images were analyzed off-line with GE's Functool software to construct a functional map. This study was compared with a previous one at 1.5 T using FLASH sequences. After a small group of volunteers we can conclude that the EPI sequences are highly sensitive to flow effects in the CSF and may not have the functional resolution to use them in functional mapping in the human spine at 1.5 T.

  11. Discovery and Optimization of Small Molecule Splicing Modifiers of Survival Motor Neuron 2 as a Treatment for Spinal Muscular Atrophy.

    PubMed

    Woll, Matthew G; Qi, Hongyan; Turpoff, Anthony; Zhang, Nanjing; Zhang, Xiaoyan; Chen, Guangming; Li, Chunshi; Huang, Song; Yang, Tianle; Moon, Young-Choon; Lee, Chang-Sun; Choi, Soongyu; Almstead, Neil G; Naryshkin, Nikolai A; Dakka, Amal; Narasimhan, Jana; Gabbeta, Vijayalakshmi; Welch, Ellen; Zhao, Xin; Risher, Nicole; Sheedy, Josephine; Weetall, Marla; Karp, Gary M

    2016-07-14

    The underlying cause of spinal muscular atrophy (SMA) is a deficiency of the survival motor neuron (SMN) protein. Starting from hits identified in a high-throughput screening campaign and through structure-activity relationship investigations, we have developed small molecules that potently shift the alternative splicing of the SMN2 exon 7, resulting in increased production of the full-length SMN mRNA and protein. Three novel chemical series, represented by compounds 9, 14, and 20, have been optimized to increase the level of SMN protein by >50% in SMA patient-derived fibroblasts at concentrations of <160 nM. Daily administration of these compounds to severe SMA Δ7 mice results in an increased production of SMN protein in disease-relevant tissues and a significant increase in median survival time in a dose-dependent manner. Our work supports the development of an orally administered small molecule for the treatment of patients with SMA.

  12. The astrocytic transporter SLC7A10 (Asc-1) mediates glycinergic inhibition of spinal cord motor neurons

    PubMed Central

    Ehmsen, Jeffrey T.; Liu, Yong; Wang, Yue; Paladugu, Nikhil; Johnson, Anna E.; Rothstein, Jeffrey D.; du Lac, Sascha; Mattson, Mark P.; Höke, Ahmet

    2016-01-01

    SLC7A10 (Asc-1) is a sodium-independent amino acid transporter known to facilitate transport of a number of amino acids including glycine, L-serine, L-alanine, and L-cysteine, as well as their D-enantiomers. It has been described as a neuronal transporter with a primary role related to modulation of excitatory glutamatergic neurotransmission. We find that SLC7A10 is substantially enriched in a subset of astrocytes of the caudal brain and spinal cord in a distribution corresponding with high densities of glycinergic inhibitory synapses. Accordingly, we find that spinal cord glycine levels are significantly reduced in Slc7a10-null mice and spontaneous glycinergic postsynaptic currents in motor neurons show substantially diminished amplitudes, demonstrating an essential role for SLC7A10 in glycinergic inhibitory function in the central nervous system. These observations establish the etiology of sustained myoclonus (sudden involuntary muscle movements) and early postnatal lethality characteristic of Slc7a10-null mice, and implicate SLC7A10 as a candidate gene and auto-antibody target in human hyperekplexia and stiff person syndrome, respectively. PMID:27759100

  13. Inosine enhances axon sprouting and motor recovery after spinal cord injury.

    PubMed

    Kim, Daniel; Zai, Laila; Liang, Peng; Schaffling, Colleen; Ahlborn, David; Benowitz, Larry I

    2013-01-01

    Although corticospinal tract axons cannot regenerate long distances after spinal cord injury, they are able to sprout collateral branches rostral to an injury site that can help form compensatory circuits in cases of incomplete lesions. We show here that inosine enhances the formation of compensatory circuits after a dorsal hemisection of the thoracic spinal cord in mature rats and improves coordinated limb use. Inosine is a naturally occurring metabolite of adenosine that crosses the cell membrane and, in neurons, activates Mst3b, a protein kinase that is part of a signal transduction pathway that regulates axon outgrowth. Compared to saline-treated controls, rats with dorsal hemisections that were treated with inosine showed three times as many synaptic contacts between corticospinal tract collaterals and long propriospinal interneurons that project from the cervical cord to the lumbar level. Inosine-treated rats also showed stronger serotonergic reinnervation of the lumbar cord than saline-treated controls, and performed well above controls in both open-field testing and a horizontal ladder rung-walking test. Inosine was equally effective whether delivered intracranially or intravenously, and has been shown to be safe for other indications in humans. Thus, inosine might be a useful therapeutic for improving outcome after spinal cord injury. PMID:24312612

  14. In vivo and in vitro studies of glycine- and glutamate-evoked acetylcholinesterase release from spinal motor neurones: implications for amyotrophic lateral sclerosis/motor neurone disease pathogenesis.

    PubMed

    Rodríguez-Ithurralde, D; Olivera, S; Vincent, O; Maruri, A

    1997-10-01

    To investigate the spinal cellular structures and molecular mechanisms involved in acetylcholinesterase (AChE) release evoked by both glycine (GLY) and glutamate (GLU)--responses that might play a role in chronic neurotoxicity--we analysed AChE histochemistry and histology upon systemic administration of aspartate (ASP), and conducted in vitro experiments in synaptosomes and slices prepared from mouse spinal ventral horns. Upon superfusion and incubation exposure of these preparations to GLY- and GLU-receptor agonists, we assayed both tissue content and release of AChE, butyrylcholinesterase and lactic dehydrogenase. Histochemical reduction of motor neurone (MN) AChE, calcium dependency, decreases in intracellular AChE and the ratio amongst molecular forms released, suggest that both synaptosomal GLY-evoked AChE release (GLY-EAR) and GLU-receptor-elicited AChE release (GEAR) have release sites located at MN presynaptic terminals. These responses exhibited remarkable postnatal regulation. GEAR seems to be mediated through alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate receptors after the fourth postnatal week and through both NMDA and non-NMDA receptors at earlier stages. Sustained rises of extracellular AChE might link acute excitotoxic injury with several long-lasting pathways leading to chronic neurotoxicity, since AChE molecular properties include: (1) the ability to block cholinergic mechanisms that protect MN against overactivity; (2) activation of ATP-dependent potassium channels; (3) promotion of neurite and axon outgrowth; and possibly (4) stimulation of brain macrophage migration and activation.

  15. Neuropathological characterization of spinal motor neuron degeneration processes induced by acute and chronic excitotoxic stimulus in vivo.

    PubMed

    Ramírez-Jarquín, Uri Nimrod; Tapia, Ricardo

    2016-09-01

    Motor neuron (MN) diseases are characterized by progressive cell degeneration, and excitotoxicity has been postulated as a causal factor. Using two experimental procedures for inducing excitotoxic spinal MN degeneration in vivo, by acute and chronic overactivation of α-amino-3-hydroxy-5-methyl-4-isoxazoleacetic acid (AMPA) receptors, we characterized the time course of the neuropathological changes. Electron transmission microscopy showed that acute AMPA perfusion by microdialysis caused MN swelling 1.5h after surgery and lysis with membrane rupture as early as 3h; no cleaved caspase 3 was detected by immunochemistry. Chronic AMPA infusion by osmotic minipumps induced a slow degeneration process along 5days, characterized by progressive changes: endoplasmic reticulum swelling, vacuolization of cytoplasm, vacuole fusion and cell membrane rupture. Quantification of these ultrastructural alterations showed that the increase of vacuolated area was at the expense of the nuclear area. Caspase 3 cleavage was observed since the first day of AMPA infusion. We conclude that acute AMPA-induced excitotoxicity induces MN loss by necrosis, while the progress of degeneration induced by chronic infusion is slow, starting with an early apoptotic process followed by necrosis. In both the acute and chronic procedures a correlation could be established between the loss of MN by necrosis, but not by caspase 3-linked apoptosis, and severe motor deficits and hindlimb paralysis. Our findings are relevant for understanding the mechanisms of neuron death in degenerative diseases and thus for the design of pharmacological therapeutic strategies. PMID:27320208

  16. Motor Neuron Diseases

    MedlinePlus

    ... called upper motor neurons ) are transmitted to nerve cells in the brain stem and spinal cord (called lower motor neurons ) and from them to particular muscles. Upper motor neurons direct the lower motor neurons ...

  17. Motor units in incomplete spinal cord injury: electrical activity, contractile properties and the effects of biofeedback.

    PubMed

    Stein, R B; Brucker, B S; Ayyar, D R

    1990-10-01

    The electrical and contractile properties of hand muscles in a selected population of quadriplegic subjects were studied intensively before and after EMG biofeedback. Spontaneously active motor units and units that could only be slowly and weakly activated were observed in these subjects, in addition to units that were voluntarily activated normally. This suggests a considerable overlap of surviving motor neurons to a single muscle that are below, near or above the level of a lesion. Despite the common occurrence of polyphasic potentials and other signs of neuromuscular reinnervation, the average twitch tension of single motor units in hand muscles of quadriplegic subjects was not significantly different from that in control subjects. Nor did it increase after biofeedback training that typically increased the peak surface EMG by a factor of 2-5 times. The percentage of spontaneously active units was also constant. The surface EMG may be increased during biofeedback by using higher firing rates in motor units that can already be activated, rather than by recruiting previously unavailable motor units. PMID:2266370

  18. The Influence of Time from Injury to Surgery on Motor Recovery and Length of Hospital Stay in Acute Traumatic Spinal Cord Injury: An Observational Canadian Cohort Study

    PubMed Central

    Noonan, Vanessa K.; Fallah, Nader; Fisher, Charles G.; Finkelstein, Joel; Kwon, Brian K.; Rivers, Carly S.; Ahn, Henry; Paquet, Jérôme; Tsai, Eve C.; Townson, Andrea; Attabib, Najmedden; Bailey, Christopher S.; Christie, Sean D.; Drew, Brian; Fourney, Daryl R.; Fox, Richard; Hurlbert, R. John; Johnson, Michael G.; Linassi, A.G.; Parent, Stefan; Fehlings, Michael G.

    2015-01-01

    Abstract To determine the influence of time from injury to surgery on neurological recovery and length of stay (LOS) in an observational cohort of individuals with traumatic spinal cord injury (tSCI), we analyzed the baseline and follow-up motor scores of participants in the Rick Hansen Spinal Cord Injury Registry to specifically assess the effect of an early (less than 24 h from injury) surgical procedure on motor recovery and on LOS. One thousand four hundred and ten patients who sustained acute tSCIs with baseline American Spinal Injury Association Impairment Scale (AIS) grades A, B, C, or D and were treated surgically were analyzed to determine the effect of the timing of surgery (24, 48, or 72 h from injury) on motor recovery and LOS. Depending on the distribution of data, we used different types of generalized linear models, including multiple linear regression, gamma regression, and negative binomial regression. Persons with incomplete AIS B, C, and D injuries from C2 to L2 demonstrated motor recovery improvement of an additional 6.3 motor points (SE=2.8 p<0.03) when they underwent surgical treatment within 24 h from the time of injury, compared with those who had surgery later than 24 h post-injury. This beneficial effect of early surgery on motor recovery was not seen in the patients with AIS A complete SCI. AIS A and B patients who received early surgery experienced shorter hospital LOS. While the issues of when to perform surgery and what specific operation to perform remain controversial, this work provides evidence that for an incomplete acute tSCI in the cervical, thoracic, or thoracolumbar spine, surgery performed within 24 h from injury improves motor neurological recovery. Early surgery also reduces LOS. PMID:25333195

  19. Role of Direct vs. Indirect Pathways from the Motor Cortex to Spinal Motoneurons in the Control of Hand Dexterity

    PubMed Central

    Isa, Tadashi; Kinoshita, Masaharu; Nishimura, Yukio

    2013-01-01

    Evolutionally, development of the direct connection from the motor cortex to spinal motoneurons [corticomotoneuronal (CM) pathway] parallels the ability of hand dexterity. Damage to the corticofugal fibers in higher primates resulted in deficit of fractionated digit movements. Based on such observations, it was generally believed that the CM pathway plays a critical role in the control of hand dexterity. On the other hand, a number of “phylogenetically older” indirect pathways from the motor cortex to motoneurons still exist in primates. The indirect pathways are mediated by intercalated neurons such as segmental interneurons (sINs), propriospinal neurons (PNs) reticulospinal neurons (RSNs), or rubrospinal neurons (RuSNs). However, their contribution to hand dexterity remains elusive. Lesion of the brainstem pyramid sparing the transmission through the RuSNs and RSNs, resulted in permanent deficit of fractionated digit movements in macaque monkeys. On the other hand, in our recent study, after lesion of the dorsolateral funiculus (DLF) at the C5 segment, which removed the lateral corticospinal tract (l-CST) including the CM pathway and the transmission through sINs and RuSNs but spared the processing through the PNs and RSNs, fractionated digit movements recovered within several weeks. These results suggest that the PNs can be involved in the recovery of fractionated digit movements, but the RSNs and RuSNs have less capacity in this regard. However, on closer inspection, it was found that the activation pattern of hand and arm muscles considerably changed after the C5 lesion, suggesting limitation of PNs for the compensation of hand dexterity. Altogether, it is suggested that PNs, RSNs RuSNs, and the CM pathway (plus sINs) make a different contribution to the hand dexterity and appearance of motor deficit of the hand dexterity caused by damage to the corticofugal fibers and potential of recovery varies depending on the rostrocaudal level of the lesion. PMID

  20. Frizzled3 controls axonal development in distinct populations of cranial and spinal motor neurons

    PubMed Central

    Hua, Zhong L; Smallwood, Philip M; Nathans, Jeremy

    2013-01-01

    Disruption of the Frizzled3 (Fz3) gene leads to defects in axonal growth in the VIIth and XIIth cranial motor nerves, the phrenic nerve, and the dorsal motor nerve in fore- and hindlimbs. In Fz3−/− limbs, dorsal axons stall at a precise location in the nerve plexus, and, in contrast to the phenotypes of several other axon path-finding mutants, Fz3−/− dorsal axons do not reroute to other trajectories. Affected motor neurons undergo cell death 2 days prior to the normal wave of developmental cell death that coincides with innervation of muscle targets, providing in vivo evidence for the idea that developing neurons with long-range axons are programmed to die unless their axons arrive at intermediate targets on schedule. These experiments implicate planar cell polarity (PCP) signaling in motor axon growth and they highlight the question of how PCP proteins, which form cell–cell complexes in epithelia, function in the dynamic context of axonal growth. DOI: http://dx.doi.org/10.7554/eLife.01482.001 PMID:24347548

  1. Reduced survival of motor neuron (SMN) protein in motor neuronal progenitors functions cell autonomously to cause spinal muscular atrophy in model mice expressing the human centromeric (SMN2) gene.

    PubMed

    Park, Gyu-Hwan; Maeno-Hikichi, Yuka; Awano, Tomoyuki; Landmesser, Lynn T; Monani, Umrao R

    2010-09-01

    Spinal muscular atrophy (SMA) is a common (approximately 1:6400) autosomal recessive neuromuscular disorder caused by a paucity of the survival of motor neuron (SMN) protein. Although widely recognized to cause selective spinal motor neuron loss when deficient, the precise cellular site of action of the SMN protein in SMA remains unclear. In this study we sought to determine the consequences of selectively depleting SMN in the motor neurons of model mice. Depleting but not abolishing the protein in motor neuronal progenitors causes an SMA-like phenotype. Neuromuscular weakness in the model mice is accompanied by peripheral as well as central synaptic defects, electrophysiological abnormalities of the neuromuscular junctions, muscle atrophy, and motor neuron degeneration. However, the disease phenotype is more modest than that observed in mice expressing ubiquitously low levels of the SMN protein, and both symptoms as well as early electrophysiological abnormalities that are readily apparent in neonates were attenuated in an age-dependent manner. We conclude that selective knock-down of SMN in motor neurons is sufficient but may not be necessary to cause a disease phenotype and that targeting these cells will be a requirement of any effective therapeutic strategy. This realization is tempered by the relatively mild SMA phenotype in our model mice, one explanation for which is the presence of normal SMN levels in non-neuronal tissue that serves to modulate disease severity.

  2. Objective measures of motor dysfunction after compression spinal cord injury in adult rats: correlations with locomotor rating scores.

    PubMed

    Semler, Joerg; Wellmann, Katharina; Wirth, Felicitas; Stein, Gregor; Angelova, Srebrina; Ashrafi, Mahak; Schempf, Greta; Ankerne, Janina; Ozsoy, Ozlem; Ozsoy, Umut; Schönau, Eckhard; Angelov, Doychin N; Irintchev, Andrey

    2011-07-01

    Precise assessment of motor deficits after traumatic spinal cord injury (SCI) in rodents is crucial for understanding the mechanisms of functional recovery and testing therapeutic approaches. Here we analyzed the applicability to a rat SCI model of an objective approach, the single-frame motion analysis, created and used for functional analysis in mice. Adult female Wistar rats were subjected to graded compression of the spinal cord. Recovery of locomotion was analyzed using video recordings of beam walking and inclined ladder climbing. Three out of four parameters used in mice appeared suitable: the foot-stepping angle (FSA) and the rump-height index (RHI), measured during beam walking, and for estimating paw placement and body weight support, respectively, and the number of correct ladder steps (CLS), assessing skilled limb movements. These parameters, similar to the Basso, Beattie, and Bresnahan (BBB) locomotor rating scores, correlated with lesion volume and showed significant differences between moderately and severely injured rats at 1-9 weeks after SCI. The beam parameters, but not CLS, correlated well with the BBB scores within ranges of poor and good locomotor abilities. FSA co-varied with RHI only in the severely impaired rats, while RHI and CLS were barely correlated. Our findings suggest that the numerical parameters estimate, as intended by design, predominantly different aspects of locomotion. The use of these objective measures combined with BBB rating provides a time- and cost-efficient opportunity for versatile and reliable functional evaluations in both severely and moderately impaired rats, combining clinical assessment with precise numerical measures. PMID:21428717

  3. A novel closed-body model of spinal cord injury caused by high-pressure air blasts produces extensive axonal injury and motor impairments.

    PubMed

    del Mar, Nobel; von Buttlar, Xinyu; Yu, Angela S; Guley, Natalie H; Reiner, Anton; Honig, Marcia G

    2015-09-01

    Diffuse axonal injury is thought to be the basis of the functional impairments stemming from mild traumatic brain injury. To examine how axons are damaged by traumatic events, such as motor vehicle accidents, falls, sports activities, or explosive blasts, we have taken advantage of the spinal cord with its extensive white matter tracts. We developed a closed-body model of spinal cord injury in mice whereby high-pressure air blasts targeted to lower thoracic vertebral levels produce tensile, compressive, and shear forces within the parenchyma of the spinal cord and thereby cause extensive axonal injury. Markers of cytoskeletal integrity showed that spinal cord axons exhibited three distinct pathologies: microtubule breakage, neurofilament compaction, and calpain-mediated spectrin breakdown. The dorsally situated axons of the corticospinal tract primarily exhibited microtubule breakage, whereas all three pathologies were common in the lateral and ventral white matter. Individual axons typically demonstrated only one of the three pathologies during the first 24h after blast injury, suggesting that the different perturbations are initiated independently of one another. For the first few days after blast, neurofilament compaction was frequently accompanied by autophagy, and subsequent to that, by the fragmentation of degenerating axons. TuJ1 immunolabeling and mice with YFP-reporter labeling each revealed more extensive microtubule breakage than did βAPP immunolabeling, raising doubts about the sensitivity of this standard approach for assessing axonal injury. Although motor deficits were mild and largely transient, some aspects of motor function gradually worsened over several weeks, suggesting that a low level of axonal degeneration continued past the initial wave. Our model can help provide further insight into how to intervene in the processes by which initial axonal damage culminates in axonal degeneration, to improve outcomes after traumatic injury. Importantly

  4. A novel closed-body model of spinal cord injury caused by high-pressure air blasts produces extensive axonal injury and motor impairments

    PubMed Central

    del Mar, Nobel; von Buttlar, Xinyu; Yu, Angela S.; Guley, Natalie H.; Reiner, Anton; Honig, Marcia G.

    2015-01-01

    Diffuse axonal injury is thought to be the basis of the functional impairments stemming from mild traumatic brain injury. To examine how axons are damaged by traumatic events, such as motor vehicle accidents, falls, sports activities, or explosive blasts, we have taken advantage of the spinal cord with its extensive white matter tracts. We developed a closed-body model of spinal cord injury in mice whereby high-pressure air blasts targeted to lower thoracic vertebral levels produce tensile, compressive, and shear forces within the parenchyma of the spinal cord and thereby cause extensive axonal injury. Markers of cytoskeletal integrity showed that spinal cord axons exhibited three distinct pathologies: microtubule breakage, neurofilament compaction, and calpain-mediated spectrin breakdown. The dorsally situated axons of the corticospinal tract primarily exhibited microtubule breakage, whereas all three pathologies were common in the lateral and ventral white matter. Individual axons typically demonstrated only one of the three pathologies during the first 24 h after blast injury, suggesting that the different perturbations are initiated independently of one another. For the first few days after blast, neurofilament compaction was frequently accompanied by autophagy, and subsequent to that, by the fragmentation of degenerating axons. TuJ1 immunolabeling and mice with YFP-reporter labeling each revealed more extensive microtubule breakage than did βAPP immunolabeling, raising doubts about the sensitivity of this standard approach for assessing axonal injury. Although motor deficits were mild and largely transient, some aspects of motor function gradually worsened over several weeks, suggesting that a low level of axonal degeneration continued past the initial wave. Our model can help provide further insight into how to intervene in the processes by which initial axonal damage culminates in axonal degeneration, to improve outcomes after traumatic injury. Importantly

  5. Ketogenic Diet Improves Forelimb Motor Function after Spinal Cord Injury in Rodents

    PubMed Central

    Streijger, Femke; Plunet, Ward T.; Lee, Jae H. T.; Liu, Jie; Lam, Clarrie K.; Park, Soeyun; Hilton, Brett J.; Fransen, Bas L.; Matheson, Keely A. J.; Assinck, Peggy; Kwon, Brian K.; Tetzlaff, Wolfram

    2013-01-01

    High fat, low carbohydrate ketogenic diets (KD) are validated non-pharmacological treatments for some forms of drug-resistant epilepsy. Ketones reduce neuronal excitation and promote neuroprotection. Here, we investigated the efficacy of KD as a treatment for acute cervical spinal cord injury (SCI) in rats. Starting 4 hours following C5 hemi-contusion injury animals were fed either a standard carbohydrate based diet or a KD formulation with lipid to carbohydrate plus protein ratio of 3:1. The forelimb functional recovery was evaluated for 14 weeks, followed by quantitative histopathology. Post-injury 3:1 KD treatment resulted in increased usage and range of motion of the affected forepaw. Furthermore, KD improved pellet retrieval with recovery of wrist and digit movements. Importantly, after returning to a standard diet after 12 weeks of KD treatment, the improved forelimb function remained stable. Histologically, the spinal cords of KD treated animals displayed smaller lesion areas and more grey matter sparing. In addition, KD treatment increased the number of glucose transporter-1 positive blood vessels in the lesion penumbra and monocarboxylate transporter-1 (MCT1) expression. Pharmacological inhibition of MCTs with 4-CIN (α-cyano-4-hydroxycinnamate) prevented the KD-induced neuroprotection after SCI, In conclusion, post-injury KD effectively promotes functional recovery and is neuroprotective after cervical SCI. These beneficial effects require the function of monocarboxylate transporters responsible for ketone uptake and link the observed neuroprotection directly to the function of ketones, which are known to exert neuroprotection by multiple mechanisms. Our data suggest that current clinical nutritional guidelines, which include relatively high carbohydrate contents, should be revisited. PMID:24223849

  6. Feasibility of visual instrumented movement feedback therapy in individuals with motor incomplete spinal cord injury walking on a treadmill

    PubMed Central

    Schließmann, Daniel; Schuld, Christian; Schneiders, Matthias; Derlien, Steffen; Glöckner, Maria; Gladow, Till; Weidner, Norbert; Rupp, Rüdiger

    2014-01-01

    Background: Incomplete spinal cord injury (iSCI) leads to motor and sensory deficits. Even in ambulatory persons with good motor function an impaired proprioception may result in an insecure gait. Limited internal afferent feedback (FB) can be compensated by provision of external FB by therapists or technical systems. Progress in computational power of motion analysis systems allows for implementation of instrumented real-time FB. The aim of this study was to test if individuals with iSCI can normalize their gait kinematics during FB and more importantly maintain an improvement after therapy. Methods: Individuals with chronic iSCI had to complete 6 days (1 day per week) of treadmill-based FB training with a 2 weeks pause after 3 days of training. Each day consists of an initial gait analysis followed by 2 blocks with FB/no-FB. During FB the deviation of the mean knee angle during swing from a speed matched reference (norm distance, ND) is visualized as a number. The task consists of lowering the ND, which was updated after every stride. Prior to the tests in patients the in-house developed FB implementation was tested in healthy subjects with an artificial movement task. Results: Four of five study participants benefited from FB in the short and medium term. Decrease of mean ND was highest during the first 3 sessions (from 3.93 ± 1.54 to 2.18 ± 1.04). After the pause mean ND stayed in the same range than before. In the last 3 sessions the mean ND decreased slower (2.40 ± 1.18 to 2.20 ± 0.90). Direct influences of FB ranged from 60 to 15% of reduction in mean ND compared to initial gait analysis and from 20 to 1% compared to no-FB sessions. Conclusions: Instrumented kinematic real-time FB may serve as an effective adjunct to established gait therapies in normalizing the gait pattern after incomplete spinal cord injury. Further studies with larger patient groups need to prove long term learning and the successful transfer of newly acquired skills to activities of

  7. Repeated Baclofen treatment ameliorates motor dysfunction, suppresses reflex activity and decreases the expression of signaling proteins in reticular nuclei and lumbar motoneurons after spinal trauma in rats.

    PubMed

    Kucharíková, Andrea; Schreiberová, Andrea; Závodská, Monika; Gedrová, Štefánia; Hricová, Ľudmila; Pavel, Jaroslav; Gálik, Ján; Maršala, Martin; Lukáčová, Nadežda

    2014-03-01

    The interruption of supraspinal input to the spinal cord leads to motor dysfunction and the development of spasticity. Clinical studies have shown that Baclofen (a GABAB agonist), while effective in modulating spasticity is associated with side-effects and the development of tolerance. The aim of the present study was to assess if discontinued Baclofen treatment and its repeated application leads antispasticity effects, and whether such changes affect neuronal nitric oxide synthase (nNOS) in the brainstem, nNOS and parvalbumin (PV) in lumbar α-motoneurons and glial fibrillary acidic protein in the ventral horn of the spinal cord. Adult male Wistar rats were exposed to Th9 spinal cord transection. Baclofen (30mg/b.w.) diluted in drinking water, was administered for 6 days, starting at week 1 after injury and then repeated till week 4 after injury. The behavior of the animals was tested (tail-flick test, BBB locomotor score) from 1 to 8 weeks. Our results clearly indicate the role of nitric oxide, produced by nNOS in the initiation and the maintenance of spasticity states 1, 6 and 8 weeks after spinal trauma. A considerable decrease of nNOS staining after Baclofen treatment correlates with improvement of motor dysfunction. The findings also show that parvalbumin and astrocytes participate in the regulation of ion concentrations in the sub-acute phase after the injury.

  8. Compound Muscle Action Potential and Motor Function in Children with Spinal Muscular Atrophy

    PubMed Central

    Lewelt, Aga J.; Krosschell, Kristin J.; Scott, Charles; Sakonju, Ai; Kissel, John T.; Crawford, Thomas O.; Acsadi, Gyula; D'Anjou, Guy; Elsheikh, Bakri; Reyna, Sandra P.; Schroth, Mary K.; Maczulski, Jo Anne; Stoddard, Gregory J.; Elovic, Elie; Swoboda, Kathryn J.

    2010-01-01

    Introduction Reliable outcome measures that reflect the underlying disease process and correlate with motor function in children with SMA are needed for clinical trials. Methods Maximum ulnar compound muscle action potential (CMAP) data were collected at 2 visits over a 4–6 week period in children with SMA types II and III, ages 2–17 years old, at 4 academic centers. Primary functional outcome measures included the Modified Hammersmith Functional Motor Scale (MHFMS) and MHFMS-Extend. Results CMAP negative peak amplitude and area showed excellent discrimination between the ambulatory and non-ambulatory SMA cohorts (ROC=0.88). CMAP had excellent test-retest reliability (ICC=0.96–0.97, n=64) and moderate to strong correlation with the MHFMS and MHFMS-Extend (r=0.61–0.73, n=68, p<0.001). Discussion Maximum ulnar CMAP amplitude and area is a feasible, valid and reliable outcome measure for use in pediatric multicenter clinical trials in SMA. CMAP correlates well with motor function and has potential value as a relevant surrogate for disease status. PMID:20737553

  9. A Prediction Model for Determining Over Ground Walking Speed After Locomotor Training in Persons With Motor Incomplete Spinal Cord Injury

    PubMed Central

    Winchester, Patricia; Smith, Patricia; Foreman, Nathan; Mosby, James M; Pacheco, Fides; Querry, Ross; Tansey, Keith

    2009-01-01

    Background/Objective: To develop and test a clinically relevant model for predicting the recovery of over ground walking speed after 36 sessions of progressive body weight–supported treadmill training (BWSTT) in individuals with motor incomplete spinal cord injury (SCI). Design: A retrospective review and stepwise regression analysis of a SCI clinical outcomes data set. Setting: Outpatient SCI laboratory. Subjects: Thirty individuals with a motor incomplete SCI who had participated in locomotor training with BWSTT. Eight individuals with similar diagnoses were used to prospectively test the prediction model. Main Outcome Measures: Over ground walking speed was assessed using the 10-m walking test. Methods: The locomotor training program consisted of 36 sessions of sequential comprehensive training comprised of robotic assisted BWSTT, followed by manual assisted BWSTT, and over ground walking. The dose of locomotor training was standardized throughout the protocol. Results: Clinical characteristics with predictive value for walking speed were time from injury onset, the presence or absence of voluntary bowel and bladder voiding, a functional spasticity assessment, and over ground walking speed before locomotor training. The model identified that these characteristics accounted for 78.3% of the variability in the actual final over ground walking speed after 36 sessions of locomotor training. The model was successful in prospectively predicting over ground walking speed in the 8 test participants within 4.15 ± 2.22 cm/s in their recovered walking speed. Conclusions: This prediction model can identify individuals who are most likely to experience success using locomotor training by determining an expected magnitude of training effect, thereby allowing individualized decisions regarding the use of this intensive approach to rehabilitation. PMID:19264051

  10. Comparison of neurological and functional outcomes after administration of granulocyte-colony-stimulating factor in motor-complete versus motor-incomplete postrehabilitated, chronic spinal cord injuries: a phase I/II study.

    PubMed

    Saberi, Hooshang; Derakhshanrad, Nazi; Yekaninejad, Mir Saeed

    2014-01-01

    Granulocyte-colony-stimulating factor (G-CSF) is a major growth factor in the activation and differentiation of granulocytes. This cytokine has been widely and safely employed in different disease conditions over many years. The administration of the growth factors in spinal cord injury (SCI) has been reported elsewhere; here we have tried to see the effect of SCI severity on the neurological outcomes after neuroprotective treatment for SCI with G-CSF. Seventy-four consecutive patients with SCI of at least 6 months' duration, with stable neurological status in the last 3 months, having informed consent for the treatment were included in the study. All the patients had undergone at least 3 months of standard rehabilitation. Patients were assessed by the American Spinal Injury Association (ASIA) scale, Spinal Cord Independence Measure (SCIM) III, and International Association of Neurorestoratology-Spinal Cord Injury Functional Rating Scale (IANR-SCIFRS) just before intervention and periodically until 6 months after subcutaneous administration of 5 µg/kg per day of G-CSF for 7 consecutive days. Multiple linear regression models were performed for statistical evaluation of lesion completeness and level of injury on changes in ASIA motor, light touch, pinprick, IANR-SCIFRS, and SCIM III scores, as a phase I/II comparative study. The study consisted of 52 motor-complete and 22 motor-incomplete SCI patients. There was no significant difference regarding age and sex, chronicity, and level of SCI between the two groups. Motor-incomplete patients had significantly more improvement in ASIA motor score compared to the motor-complete patients (7.68 scores, p < 0.001); also they had significant improvement in light touch (6.42 scores, p = 0.003) and pinprick sensory scores (4.89 scores, p = 0.011). Therefore, G-CSF administration in motor-incomplete SCIs is associated with significantly higher motor improvement, and also the higher the initial ASIA Impairment Scale

  11. Novel Transabdominal Motor Action Potential (TaMAP) Neuromonitoring System for Spinal Surgery

    PubMed Central

    Feldman, Erica; Gabel, Brandon C; Taylor, Natalie; Gharib, James; Lee, Yu-Po; Taylor, William

    2016-01-01

    Introduction Minimally invasive lateral lumbar interbody fusion (LLIF) approaches to the lumbar spine reduce patient morbidity compared to anterior or posterior alternatives. This approach, however, decreases direct anatomical visualization, creating the need for highly sensitive and specific neurophysiological monitoring. We seek to determine feasibility in 'transabdominal motor action potential (TaMAP)' monitoring as an assessment for the integrity of the neural elements during lateral-approach surgeries to the lumbar spine.  Methods Cathode and anode leads were placed on the posterior and anterior surfaces of two porcine subjects. Currents of varying degrees were transmitted across, from front to back. Motor responses were monitored and recorded by needle electrodes in specific distal muscle groups of the lower extremity. Lastly, the cathode and anode were placed anterior and posterior to the chest wall and stimulated to the maximum of 1500 mA to determine any effect on cardiac rhythm. Results Responses were seen by measuring vertical height differences between peaks of corresponding evoked potentials. Recruitment began at 200 mA in the lower extremities. Stimulation at 450 mA recruited a reliable and distinguishable electrographic response from most muscle groups. Responses were recorded and reliably measured and increased in proportion to the graduation of transabdominal stimulation current; no responses were seen in the arms or face. 1500 mA across the chest wall failed to stimulate or induce cardiac arrhythmia on repeated stimulation, indicating safety of stimulation. Conclusion TaMAPs seen in the animal model provide a potential alternative to standard transcranial motor evoked potentials done in the lateral approach of LLIFs. TaMAP recordings in most muscle groups were recordable and reliable, though some muscle groups failed to stimulate. Safety of transabdominal motor evoked potentials was confirmed in this porcine study. Future studies

  12. Bone Marrow Stromal Cell Intraspinal Transplants Fail to Improve Motor Outcomes in a Severe Model of Spinal Cord Injury.

    PubMed

    Brock, John H; Graham, Lori; Staufenberg, Eileen; Collyer, Eileen; Koffler, Jacob; Tuszynski, Mark H

    2016-06-15

    Bone marrow stromal cells (BMSCs) have been reported to exert potential neuroprotective properties in models of neurotrauma, although precise mechanisms underlying their benefits are poorly understood. Despite this lack of knowledge, several clinical trials have been initiated using these cells. To determine whether local mechanisms mediate BMSC neuroprotective actions, we grafted allogeneic BMSCs to sites of severe, compressive spinal cord injury (SCI) in Sprague-Dawley rats. Cells were administered 48 h after the original injury. Additional animals received allogeneic MSCs that were genetically modified to secrete brain-derived neurotrophic factor (BDNF) to further determine whether a locally administered neurotrophic factor provides or extends neuroprotection. When assessed 2 months post-injury in a clinically relevant model of severe SCI, BMSC grafts with or without BDNF secretion failed to improve motor outcomes. Thus, allogeneic grafts of BMSCs do not appear to act through local mechanisms, and future clinical trials that acutely deliver BMSCs to actual sites of injury within days are unlikely to be beneficial. Additional studies should address whether systemic administration of BMSCs alter outcomes from neurotrauma.

  13. Arm and leg coordination during treadmill walking in individuals with motor incomplete spinal cord injury: a preliminary study.

    PubMed

    Tester, Nicole J; Barbeau, Hugues; Howland, Dena R; Cantrell, Amy; Behrman, Andrea L

    2012-05-01

    Arm and leg coordination naturally emerges during walking, but can be affected by stroke or Parkinson's disease. The purpose of this preliminary study was to characterize arm and leg coordination during treadmill walking at self-selected comfortable walking speeds (CWSs) in individuals using arm swing with motor incomplete spinal cord injury (iSCI). Hip and shoulder angle cycle durations and amplitudes, strength of peak correlations between contralateral hip and shoulder joint angle time series, the time shifts at which these peak correlations occur, and associated variability were quantified. Outcomes in individuals with iSCI selecting fast CWSs (range, 1.0-1.3m/s) and speed-matched individuals without neurological injuries are similar. Differences, however, are detected in individuals with iSCI selecting slow CWSs (range, 0.25-0.65 m/s) and may represent compensatory strategies to improve walking balance or forward propulsion. These individuals elicit a 1:1, arm:leg frequency ratio versus the 2:1 ratio observed in non-injured individuals. Shoulder and hip movement patterns, however, are highly reproducible (coordinated) in participants with iSCI, regardless of CWS. This high degree of inter-extremity coordination could reflect an inability to modify a single movement pattern post-iSCI. Combined, these data suggest inter-extremity walking coordination may be altered, but is present after iSCI, and therefore may be regulated, in part, by neural control.

  14. Motor-related cortical activity after cervical spinal cord injury: multifaceted EEG analysis of isometric elbow flexion contractions.

    PubMed

    Cremoux, Sylvain; Tallet, Jessica; Berton, Eric; Dal Maso, Fabien; Amarantini, David

    2013-10-01

    Electroencephalographic (EEG) studies have well established that motor cortex (M1) activity ~20 Hz decreases during muscular contraction and increases as soon as contraction stops, which are known as event-related desynchronization (ERD) and event-related synchronization (ERS), respectively. ERD is supposed to reflect M1 activation, sending information to recruited muscles, while the process underlying ERS is interpreted either as active cortical inhibition or as processing of sensory inputs. Investigation of the process behind ERD/ERS in people with spinal cord injury (SCI) would be particularly relevant since their M1 remains effective despite decreased sensorimotor abilities. In this study, we recorded net joint torque and EEG in 6 participants with cervical SCI and 8 healthy participants who performed isometric elbow flexion at 3 force levels. Multifaceted EEG analysis was introduced to assess ERD/ERS according to their amplitude, frequency range and duration. The results revealed that net joint torque increased with the required force level for all participants and time to contraction inhibition was longer in the SCI group. At the cortical level, ERD/ERS frequency ranges increased with the required force level in all participants, indicating that the modulation of cortical activity with force level is preserved after SCI. However, ERS amplitude decreased only in SCI participants, which may be linked to delayed contraction inhibition. All in all, cortical modulation of frequency range and amplitude could reflect two different kinds of neural communication. PMID:23939224

  15. Spinal and supraspinal motor control predictors of rate of torque development.

    PubMed

    Johnson, S T; Kipp, K; Norcross, M F; Hoffman, M A

    2015-10-01

    During explosive movements and potentially injurious situations, the ability to rapidly generate torque is critical. Previous research has suggested that different phases of rate of torque development (RTD) are differentiately controlled. However, the extent to which supraspinal and spinal mechanisms predict RTD at different time intervals is unknown. RTD of the plantarflexors across various phases of contraction (i.e., 0-25, 0-50, 0-100, 0-150, 0-200, and 0-250 ms) was measured in 37 participants. The following predictor variables were also measured: (a) gain of the resting soleus H-reflex recruitment curve; (b) gain of the resting homonymous post-activation depression recruitment curve; (c) gain of the GABAergic presynaptic inhibition recruitment curve; (d) the level of postsynaptic recurrent inhibition at rest; (e) level of supraspinal drive assessed by measuring V waves; and (f) the gain of the resting soleus M wave. Stepwise regression analyses were used to determine which variables significantly predicted allometrically scaled RTD. The analyses indicated that supraspinal drive was the dominant predictor of RTD across all phases. Additionally, recurrent inhibition predicted RTD in all of the time intervals except 0-150 ms. These results demonstrate the importance of supraspinal drive and recurrent inhibition to RTD. PMID:25039746

  16. Contractile dysfunction in muscle may underlie androgen-dependent motor dysfunction in spinal bulbar muscular atrophy

    PubMed Central

    Oki, Kentaro; Halievski, Katherine; Vicente, Laura; Xu, Youfen; Zeolla, Donald; Poort, Jessica; Katsuno, Masahisa; Adachi, Hiroaki; Sobue, Gen; Wiseman, Robert W.; Breedlove, S. Marc

    2015-01-01

    Spinal and bulbar muscular atrophy (SBMA) is characterized by progressive muscle weakness linked to a polyglutamine expansion in the androgen receptor (AR). Current evidence indicates that mutant AR causes SBMA by acting in muscle to perturb its function. However, information about how muscle function is impaired is scant. One fundamental question is whether the intrinsic strength of muscles, an attribute of muscle independent of its mass, is affected. In the current study, we assess the contractile properties of hindlimb muscles in vitro from chronically diseased males of three different SBMA mouse models: a transgenic (Tg) model that broadly expresses a full-length human AR with 97 CAGs (97Q), a knock-in (KI) model that expresses a humanized AR containing a CAG expansion in the first exon, and a Tg myogenic model that overexpresses wild-type AR only in skeletal muscle fibers. We found that hindlimb muscles in the two Tg models (97Q and myogenic) showed marked losses in their intrinsic strength and resistance to fatigue, but were minimally affected in KI males. However, diseased muscles of all three models showed symptoms consistent with myotonic dystrophy type 1, namely, reduced resting membrane potential and deficits in chloride channel mRNA. These data indicate that muscle dysfunction is a core feature of SBMA caused by at least some of the same pathogenic mechanisms as myotonic dystrophy. Thus mechanisms controlling muscle function per se independent of mass are prime targets for SBMA therapeutics. PMID:25663674

  17. Contractile dysfunction in muscle may underlie androgen-dependent motor dysfunction in spinal bulbar muscular atrophy.

    PubMed

    Oki, Kentaro; Halievski, Katherine; Vicente, Laura; Xu, Youfen; Zeolla, Donald; Poort, Jessica; Katsuno, Masahisa; Adachi, Hiroaki; Sobue, Gen; Wiseman, Robert W; Breedlove, S Marc; Jordan, Cynthia L

    2015-04-01

    Spinal and bulbar muscular atrophy (SBMA) is characterized by progressive muscle weakness linked to a polyglutamine expansion in the androgen receptor (AR). Current evidence indicates that mutant AR causes SBMA by acting in muscle to perturb its function. However, information about how muscle function is impaired is scant. One fundamental question is whether the intrinsic strength of muscles, an attribute of muscle independent of its mass, is affected. In the current study, we assess the contractile properties of hindlimb muscles in vitro from chronically diseased males of three different SBMA mouse models: a transgenic (Tg) model that broadly expresses a full-length human AR with 97 CAGs (97Q), a knock-in (KI) model that expresses a humanized AR containing a CAG expansion in the first exon, and a Tg myogenic model that overexpresses wild-type AR only in skeletal muscle fibers. We found that hindlimb muscles in the two Tg models (97Q and myogenic) showed marked losses in their intrinsic strength and resistance to fatigue, but were minimally affected in KI males. However, diseased muscles of all three models showed symptoms consistent with myotonic dystrophy type 1, namely, reduced resting membrane potential and deficits in chloride channel mRNA. These data indicate that muscle dysfunction is a core feature of SBMA caused by at least some of the same pathogenic mechanisms as myotonic dystrophy. Thus mechanisms controlling muscle function per se independent of mass are prime targets for SBMA therapeutics.

  18. Genetics Home Reference: spinal muscular atrophy

    MedlinePlus

    ... a loss of specialized nerve cells, called motor neurons , in the spinal cord and the part of ... spinal cord ( the brainstem ). The loss of motor neurons leads to weakness and wasting ( atrophy ) of muscles ...

  19. Effect of low-energy extracorporeal shock wave on vascular regeneration after spinal cord injury and the recovery of motor function

    PubMed Central

    Wang, Lei; Jiang, Yuquan; Jiang, Zheng; Han, Lizhang

    2016-01-01

    Background Latest studies show that low-energy extracorporeal shock wave therapy (ESWT) can upregulate levels of vascular endothelial growth factor (VEGF). VEGF can ease nervous tissue harm after spinal cord injury (SCI). This study aims to explore whether low-energy ESWT can promote expression of VEGF, protect nervous tissue after SCI, and improve motor function. Methods Ninety adult female rats were divided into the following groups: Group A (simple laminectomy), Group B (laminectomy and low-energy ESWT), Group C (spinal cord injury), and Group D (spinal cord injury and low-energy ESWT). Impinger was used to cause thoracic spinal cord injury. Low-energy ESWT was applied as treatment after injury three times a week, for 3 weeks. After SCI, the Basso, Beattie, and Bresnahan (BBB) scale was used to evaluate motor function over a period of 42 days at different time points. Hematoxylin and eosin (HE) staining was used to evaluate nerve tissue injury. Neuronal nuclear antigen (NeuN) staining was also used to evaluate loss of neurons. Polymerase chain reaction was used to detect messenger RNA (mRNA) expression of VEGF and its receptor fms-like tyrosine kinase 1 (Flt-1). Immunostaining was used to evaluate VEGF protein expression level in myeloid tissue. Results BBB scores of Groups A and B showed no significant result related to dyskinesia. HE and NeuN staining indicated that only using low-energy ESWT could not cause damage of nervous tissue in Group B. Recovery of motor function at 7, 35, and 42 days after SCI in Group D was better than that in Group C (P<0.05). Compared with Group C, number of NeuN-positive cells at 42 days after SCI increased significantly (P<0.05). The mRNA levels of VEGF and Flt-1 and VEGF expression at 7 days after SCI in Group D were significantly higher than those in Group C (P<0.05). Conclusion Low-energy ESWT promotes expression of VEGF, decreases secondary damage of nerve tissue, and improves recovery of motor function. It can be regarded as

  20. Effect of low-energy extracorporeal shock wave on vascular regeneration after spinal cord injury and the recovery of motor function

    PubMed Central

    Wang, Lei; Jiang, Yuquan; Jiang, Zheng; Han, Lizhang

    2016-01-01

    Background Latest studies show that low-energy extracorporeal shock wave therapy (ESWT) can upregulate levels of vascular endothelial growth factor (VEGF). VEGF can ease nervous tissue harm after spinal cord injury (SCI). This study aims to explore whether low-energy ESWT can promote expression of VEGF, protect nervous tissue after SCI, and improve motor function. Methods Ninety adult female rats were divided into the following groups: Group A (simple laminectomy), Group B (laminectomy and low-energy ESWT), Group C (spinal cord injury), and Group D (spinal cord injury and low-energy ESWT). Impinger was used to cause thoracic spinal cord injury. Low-energy ESWT was applied as treatment after injury three times a week, for 3 weeks. After SCI, the Basso, Beattie, and Bresnahan (BBB) scale was used to evaluate motor function over a period of 42 days at different time points. Hematoxylin and eosin (HE) staining was used to evaluate nerve tissue injury. Neuronal nuclear antigen (NeuN) staining was also used to evaluate loss of neurons. Polymerase chain reaction was used to detect messenger RNA (mRNA) expression of VEGF and its receptor fms-like tyrosine kinase 1 (Flt-1). Immunostaining was used to evaluate VEGF protein expression level in myeloid tissue. Results BBB scores of Groups A and B showed no significant result related to dyskinesia. HE and NeuN staining indicated that only using low-energy ESWT could not cause damage of nervous tissue in Group B. Recovery of motor function at 7, 35, and 42 days after SCI in Group D was better than that in Group C (P<0.05). Compared with Group C, number of NeuN-positive cells at 42 days after SCI increased significantly (P<0.05). The mRNA levels of VEGF and Flt-1 and VEGF expression at 7 days after SCI in Group D were significantly higher than those in Group C (P<0.05). Conclusion Low-energy ESWT promotes expression of VEGF, decreases secondary damage of nerve tissue, and improves recovery of motor function. It can be regarded as

  1. The Extract of Roots of Sophora flavescens Enhances the Recovery of Motor Function by Axonal Growth in Mice with a Spinal Cord Injury

    PubMed Central

    Tanabe, Norio; Kuboyama, Tomoharu; Kazuma, Kohei; Konno, Katsuhiro; Tohda, Chihiro

    2016-01-01

    Although axonal extension to reconstruct spinal tracts should be effective for restoring function after spinal cord injury (SCI), chondroitin sulfate proteoglycan (CSPG) levels increase at spinal cord lesion sites, and inhibit axonal regrowth. In this study, we found that the water extract of roots of Sophora flavescens extended the axons of mouse cortical neurons, even on a CSPG-coated surface. Consecutive oral administrations of S. flavescens extract to SCI mice for 31 days increased the density of 5-HT-positive axons at the lesion site and improved the motor function. Further, the active constituents in the S. flavescens extract were identified. The water and alkaloid fractions of the S. flavescens extract each exhibited axonal extension activity in vitro. LC/MS analysis revealed that these fractions mainly contain matrine and/or oxymatrine, which are well-known major compounds in S. flavescens. Matrine and oxymatrine promoted axonal extension on the CSPG-coated surface. This study is the first to demonstrate that S. flavescens extract, matrine, and oxymatrine enhance axonal growth in vitro, even on a CSPG-coated surface, and that S. flavescens extract improves motor function and increases axonal density in SCI mice. PMID:26834638

  2. Muscle Synergies in Cycling after Incomplete Spinal Cord Injury: Correlation with Clinical Measures of Motor Function and Spasticity

    PubMed Central

    Barroso, Filipe O.; Torricelli, Diego; Bravo-Esteban, Elisabeth; Taylor, Julian; Gómez-Soriano, Julio; Santos, Cristina; Moreno, Juan C.; Pons, José L.

    2016-01-01

    Background: After incomplete spinal cord injury (iSCI), patients suffer important sensorimotor impairments, such as abnormal locomotion patterns and spasticity. Complementary to current clinical diagnostic procedures, the analysis of muscle synergies has emerged as a promising tool to study muscle coordination, which plays a major role in the control of multi-limb functional movements. Objective: Based on recent findings suggesting that walking and cycling share similar synergistic control, the analysis of muscle synergies during cycling might be explored as an early descriptor of gait-related impaired control. This idea was split into the following two hypotheses: (a) iSCI patients present a synergistic control of muscles during cycling; (b) muscle synergies outcomes extracted during cycling correlate with clinical measurements of gait performance and/or spasticity. Methods: Electromyographic (EMG) activity of 13 unilateral lower limb muscles was recorded in a group of 10 healthy individuals and 10 iSCI subjects during cycling at four different cadences. A non-negative matrix factorization (NNMF) algorithm was applied to identify synergistic components (i.e., activation coefficients and muscle synergy vectors). Reconstruction goodness scores (VAF and r2) were used to evaluate the ability of a given number of synergies to reconstruct the EMG signals. A set of metrics based on the similarity between pathologic and healthy synergies were correlated with clinical scales of gait performance and spasticity. Results: iSCI patients preserved a synergistic control of muscles during cycling. The similarity with the healthy reference was consistent with the degree of the impairment, i.e., less impaired patients showed higher similarities with the healthy reference. There was a strong correlation between reconstruction goodness scores at 42 rpm and motor performance scales (TUG, 10-m test and WISCI II). On the other hand, the similarity between the healthy and affected

  3. Differential screening of mutated SOD1 transgenic mice reveals early up-regulation of a fast axonal transport component in spinal cord motor neurons.

    PubMed

    Dupuis, L; de Tapia, M; René, F; Lutz-Bucher, B; Gordon, J W; Mercken, L; Pradier, L; Loeffler, J P

    2000-08-01

    In the present study we analyze the molecular mechanisms underlying motor neuron degeneration in familial amyotrophic lateral sclerosis (FALS). For this, we used a transgenic mouse model expressing the Cu/Zn superoxide dismutase (SOD1) gene with a Gly(86) to Arg (G86R) mutation equivalent to that found in a subset of human FALS. Using an optimized suppression subtractive hybridization method, a cDNA specifically up-regulated during the asymptomatic phase in the lumbar spinal cord of G86R mice was identified by sequence analysis as the KIF3-associated protein (KAP3), a regulator of fast axonal transport. RT-PCR analysis revealed that KAP3 induction was an early event arising long before axonal degeneration. Immunohistochemical studies further revealed that KAP3 protein predominantly accumulates in large motor neurons of the ventral spinal cord. We further demonstrated that KAP3 up-regulation occurs independent of any change in the other components of the kinesin II complex. However, since the ubiquitous KIF1A motor is up-regulated, our results show an early and complex rearrangement of the fast axonal transport machinery in the course of FALS pathology.

  4. Selective vulnerability of motor neurons and dissociation of pre- and post-synaptic pathology at the neuromuscular junction in mouse models of spinal muscular atrophy.

    PubMed

    Murray, Lyndsay M; Comley, Laura H; Thomson, Derek; Parkinson, Nick; Talbot, Kevin; Gillingwater, Thomas H

    2008-04-01

    Proximal spinal muscular atrophy (SMA) is a common autosomal recessive childhood form of motor neuron disease. Previous studies have highlighted nerve- and muscle-specific events in SMA, including atrophy of muscle fibres and post-synaptic motor endplates, loss of lower motor neuron cell bodies and denervation of neuromuscular junctions caused by loss of pre-synaptic inputs. Here we have undertaken a detailed morphological investigation of neuromuscular synaptic pathology in the Smn-/-;SMN2 and Smn-/-;SMN2;Delta7 mouse models of SMA. We show that neuromuscular junctions in the transversus abdominis (TVA), levator auris longus (LAL) and lumbrical muscles were disrupted in both mouse models. Pre-synaptic inputs were lost and abnormal accumulations of neurofilament were present, even in early/mid-symptomatic animals in the most severely affected muscle groups. Neuromuscular pathology was more extensive in the postural TVA muscle compared with the fast-twitch LAL and lumbrical muscles. Pre-synaptic pathology in Smn-/-;SMN2;Delta7 mice was reduced compared with Smn-/-;SMN2 mice at late-symptomatic time-points, although post-synaptic pathology was equally severe. We demonstrate that shrinkage of motor endplates does not correlate with loss of motor nerve terminals, signifying that one can occur in the absence of the other. We also demonstrate selective vulnerability of a subpopulation of motor neurons in the caudal muscle band of the LAL. Paralysis with botulinum toxin resulted in less terminal sprouting and ectopic synapse formation in the caudal band compared with the rostral band, suggesting that motor units conforming to a Fast Synapsing (FaSyn) phenotype are likely to be more vulnerable than those with a Delayed Synapsing (DeSyn) phenotype. PMID:18065780

  5. Clonidine, an alpha-2 adrenoceptor agonist relieves mechanical allodynia in oxaliplatin-induced neuropathic mice; potentiation by spinal p38 MAPK inhibition without motor dysfunction and hypotension.

    PubMed

    Yeo, Ji-Hee; Yoon, Seo-Yeon; Kim, Sol-Ji; Oh, Seog-Bae; Lee, Jang-Hern; Beitz, Alvin J; Roh, Dae-Hyun

    2016-05-15

    Cancer chemotherapy with platinum-based antineoplastic agents including oxaliplatin frequently results in a debilitating and painful peripheral neuropathy. We evaluated the antinociceptive effects of the alpha-2 adrenoceptor agonist, clonidine on oxaliplatin-induced neuropathic pain. Specifically, we determined if (i) the intraperitoneal (i.p.) injection of clonidine reduces mechanical allodynia in mice with an oxaliplatin-induced neuropathy and (ii) concurrent inhibition of p38 mitogen-activated protein kinase (MAPK) activity by the p38 MAPK inhibitor SB203580 enhances clonidine's antiallodynic effect. Clonidine (0.01-0.1 mg kg(-1), i.p.), with or without SB203580(1-10 nmol, intrathecal) was administered two weeks after oxaliplatin injection(10 mg kg(-1), i.p.) to mice. Mechanical withdrawal threshold, motor coordination and blood pressure were measured. Postmortem expression of p38 MAPK and ERK as well as their phosphorylated forms(p-p38 and p-ERK) were quantified 30 min or 4 hr after drug injection in the spinal cord dorsal horn of treated and control mice. Clonidine dose-dependently reduced oxaliplatin-induced mechanical allodynia and spinal p-p38 MAPK expression, but not p-ERK. At 0.1 mg kg(-1), clonidine also impaired motor coordination and decreased blood pressure. A 10 nmol dose of SB203580 alone significantly reduced mechanical allodynia and p-p38 MAPK expression, while a subeffective dose(3 nmol) potentiated the antiallodynic effect of 0.03 mg kg(-1) clonidine and reduced the increased p-p38 MAPK. Coadministration of SB203580 and 0.03 mg kg(-1) clonidine decreased allodynia similar to that of 0.10 mg kg(-1) clonidine, but without significant motor or vascular effects. These findings demonstrate that clonidine treatment reduces oxaliplatin-induced mechanical allodynia. The concurrent administration of SB203580 reduces the dosage requirements for clonidine, thereby alleviating allodynia without producing undesirable motor or cardiovascular effects.

  6. Intermittent hypoxia promotes recovery of respiratory motor function in spinal cord-injured mice depleted of serotonin in the central nervous system.

    PubMed

    Komnenov, Dragana; Solarewicz, Julia Z; Afzal, Fareeza; Nantwi, Kwaku D; Kuhn, Donald M; Mateika, Jason H

    2016-08-01

    We examined the effect of repeated daily exposure to intermittent hypoxia (IH) on the recovery of respiratory and limb motor function in mice genetically depleted of central nervous system serotonin. Electroencephalography, diaphragm activity, ventilation, core body temperature, and limb mobility were measured in spontaneously breathing wild-type (Tph2(+/+)) and tryptophan hydroxylase 2 knockout (Tph2(-/-)) mice. Following a C2 hemisection, the mice were exposed daily to IH (i.e., twelve 4-min episodes of 10% oxygen interspersed with 4-min normoxic periods followed by a 90-min end-recovery period) or normoxia (i.e., sham protocol, 21% oxygen) for 10 consecutive days. Diaphragm activity recovered to prehemisection levels in the Tph2(+/+) and Tph2(-/-) mice following exposure to IH but not normoxia [Tph2(+/+) 1.3 ± 0.2 (SE) vs. 0.3 ± 0.2; Tph2(-/-) 1.06 ± 0.1 vs. 0.3 ± 0.1, standardized to prehemisection values, P < 0.01]. Likewise, recovery of tidal volume and breathing frequency was evident, although breathing frequency values did not return to prehemisection levels within the time frame of the protocol. Partial recovery of limb motor function was also evident 2 wk after spinal cord hemisection. However, recovery was not dependent on IH or the presence of serotonin in the central nervous system. We conclude that IH promotes recovery of respiratory function but not basic motor tasks. Moreover, we conclude that spontaneous or treatment-induced recovery of respiratory and motor limb function is not dependent on serotonin in the central nervous system in a mouse model of spinal cord injury. PMID:27402561

  7. Ethanol directly depresses AMPA and NMDA glutamate currents in spinal cord motor neurons independent of actions on GABAA or glycine receptors.

    PubMed

    Wang, M Y; Rampil, I J; Kendig, J J

    1999-07-01

    Ethanol is a general anesthetic agent as defined by abolition of movement in response to noxious stimulation. This anesthetic endpoint is due to spinal anesthetic actions. This study was designed to test the hypothesis that ethanol acts directly on motor neurons to inhibit excitatory synaptic transmission at glutamate receptors. Whole cell recordings were made in visually identified motor neurons in spinal cord slices from 14- to 23-day-old rats. Currents were evoked by stimulating a dorsal root fragment or by brief pulses of glutamate. Ethanol at general anesthetic concentrations (50-200 mM) depressed both responses. Ethanol also depressed glutamate-evoked responses in the presence of tetrodotoxin (300 nM), showing that its actions are postsynaptic. Block of inhibitory gamma-aminobutyric acidA and glycine receptors by bicuculline (50 microM) and strychnine (5 microM), respectively, did not significantly reduce the effects of ethanol on glutamate currents. Ethanol also depressed glutamate-evoked currents when the inhibitory receptors were blocked and either D, L-2-amino-5-phosphonopentanoic acid (40 microM) or 6-cyano-7-nitroquinoxaline-2,3-dione disodium (10 microM) were applied to block N-methyl-D-aspartate or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptors, respectively. The results show that ethanol exerts direct depressant effects on both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate glutamate currents in motor neurons. Enhancement of gamma-aminobutyric acidA and glycine inhibition is not required for this effect. Direct depression of glutamatergic excitatory transmission by a postsynaptic action on motor neurons thus may contribute to general anesthesia as defined by immobility in response to a noxious stimulus. PMID:10381800

  8. Intermittent hypoxia promotes recovery of respiratory motor function in spinal cord-injured mice depleted of serotonin in the central nervous system.

    PubMed

    Komnenov, Dragana; Solarewicz, Julia Z; Afzal, Fareeza; Nantwi, Kwaku D; Kuhn, Donald M; Mateika, Jason H

    2016-08-01

    We examined the effect of repeated daily exposure to intermittent hypoxia (IH) on the recovery of respiratory and limb motor function in mice genetically depleted of central nervous system serotonin. Electroencephalography, diaphragm activity, ventilation, core body temperature, and limb mobility were measured in spontaneously breathing wild-type (Tph2(+/+)) and tryptophan hydroxylase 2 knockout (Tph2(-/-)) mice. Following a C2 hemisection, the mice were exposed daily to IH (i.e., twelve 4-min episodes of 10% oxygen interspersed with 4-min normoxic periods followed by a 90-min end-recovery period) or normoxia (i.e., sham protocol, 21% oxygen) for 10 consecutive days. Diaphragm activity recovered to prehemisection levels in the Tph2(+/+) and Tph2(-/-) mice following exposure to IH but not normoxia [Tph2(+/+) 1.3 ± 0.2 (SE) vs. 0.3 ± 0.2; Tph2(-/-) 1.06 ± 0.1 vs. 0.3 ± 0.1, standardized to prehemisection values, P < 0.01]. Likewise, recovery of tidal volume and breathing frequency was evident, although breathing frequency values did not return to prehemisection levels within the time frame of the protocol. Partial recovery of limb motor function was also evident 2 wk after spinal cord hemisection. However, recovery was not dependent on IH or the presence of serotonin in the central nervous system. We conclude that IH promotes recovery of respiratory function but not basic motor tasks. Moreover, we conclude that spontaneous or treatment-induced recovery of respiratory and motor limb function is not dependent on serotonin in the central nervous system in a mouse model of spinal cord injury.

  9. Spinal tumor

    MedlinePlus

    Tumor - spinal cord ... spinal tumors occur in the nerves of the spinal cord itself. Most often these are ependymomas and other ... gene mutations. Spinal tumors can occur: Inside the spinal cord (intramedullary) In the membranes (meninges) covering the spinal ...

  10. Observations on the giraffe central nervous system related to the corticospinal tract, motor cortex and spinal cord: what difference does a long neck make?

    PubMed

    Badlangana, N L; Bhagwandin, A; Fuxe, K; Manger, P R

    2007-08-24

    The mammalian corticospinal tract is known to contain axons that travel from the cerebral cortex to various levels of the spinal cord and its main function is thought to be the mediation of voluntary movement. The current study describes neuroanatomy related to the corticospinal tract of the giraffe. This animal presents a specific morphology that may present challenges to this neural pathway in terms of the metabolism required for correct functioning and maintenance of potentially very long axons. The spinal cord of the giraffe can be up to 2.6 m long and forms the conus medullaris at the level of the sacral vertebrae. Primary motor cortex was found in a location typical of that of other ungulates, and the cytoarchitectonic appearance of this cortical area was similar to that previously reported for sheep, despite the potential distance that the axons emanating from the layer 5 gigantopyramidal neurons must travel. A typically mammalian dorsal striatopallidal complex was transected by a strongly coalesced internal capsule passing through to the pons and forming clearly identifiable but somewhat flattened (in a dorsoventral plane) pyramidal tracts. These tracts terminated in a spinal cord that exhibited no unique anatomical features related to its length. Our results, at least at the level of organization investigated herein, show that the corticospinal tract of the giraffe resembled that of a typical ungulate.

  11. What Is Spinal Cord Injury?

    MedlinePlus

    ... lowest point on the spinal cord below which sensory feeling and motor movement diminish or disappear. The ... injury is so severe that almost all feeling (sensory function) and all ability to control movement (motor ...

  12. Zinc transporter 3 (ZnT3) gene deletion reduces spinal cord white matter damage and motor deficits in a murine MOG-induced multiple sclerosis model.

    PubMed

    Choi, Bo Young; Kim, In Yeol; Kim, Jin Hee; Kho, A Ra; Lee, Song Hee; Lee, Bo Eun; Sohn, Min; Koh, Jae-Young; Suh, Sang Won

    2016-10-01

    The present study aimed to evaluate the role of zinc transporter 3 (ZnT3) on multiple sclerosis (MS) pathogenesis. Experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis, was induced by immunization with myelin oligodendrocyte glycoprotein (MOG35-55) in female mice. Three weeks after the initial immunization, demyelination, immune cell infiltration and blood brain barrier (BBB) disruption in the spinal cord were analyzed. Clinical signs of EAE first appeared on day 11 and reached a peak level on day 19 after the initial immunization. ZnT3 gene deletion profoundly reduced the daily clinical score of EAE. The ZnT3 gene deletion-mediated inhibition of the clinical course of EAE was accompanied by suppression of inflammation and demyelination in the spinal cord. The motor deficit accompanying neuropathological changes associated with EAE were mild in ZnT3 gene deletion mice. This reduction in motor deficit was accompanied by coincident reductions in demyelination and infiltration of encephalitogenic immune cells including CD4+ T cells, CD8+ T cells, CD20+ B cells and F4/80+ microglia in the spinal cord. These results demonstrate that ZnT3 gene deletion inhibits the clinical features and neuropathological changes associated with EAE. ZnT3 gene deletion also remarkably inhibited formation of EAE-associated aberrant synaptic zinc patches, matrix metalloproteinases-9 (MMP-9) activation and BBB disruption. Therefore, amelioration of EAE-induced clinical and neuropathological changes by ZnT3 gene deletion suggests that vesicular zinc may be involved in several steps of MS pathogenesis.

  13. Motor-related brain activity during action observation: a neural substrate for electrocorticographic brain-computer interfaces after spinal cord injury.

    PubMed

    Collinger, Jennifer L; Vinjamuri, Ramana; Degenhart, Alan D; Weber, Douglas J; Sudre, Gustavo P; Boninger, Michael L; Tyler-Kabara, Elizabeth C; Wang, Wei

    2014-01-01

    After spinal cord injury (SCI), motor commands from the brain are unable to reach peripheral nerves and muscles below the level of the lesion. Action observation (AO), in which a person observes someone else performing an action, has been used to augment traditional rehabilitation paradigms. Similarly, AO can be used to derive the relationship between brain activity and movement kinematics for a motor-based brain-computer interface (BCI) even when the user cannot generate overt movements. BCIs use brain signals to control external devices to replace functions that have been lost due to SCI or other motor impairment. Previous studies have reported congruent motor cortical activity during observed and overt movements using magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI). Recent single-unit studies using intracortical microelectrodes also demonstrated that a large number of motor cortical neurons had similar firing rate patterns between overt and observed movements. Given the increasing interest in electrocorticography (ECoG)-based BCIs, our goal was to identify whether action observation-related cortical activity could be recorded using ECoG during grasping tasks. Specifically, we aimed to identify congruent neural activity during observed and executed movements in both the sensorimotor rhythm (10-40 Hz) and the high-gamma band (65-115 Hz) which contains significant movement-related information. We observed significant motor-related high-gamma band activity during AO in both able-bodied individuals and one participant with a complete C4 SCI. Furthermore, in able-bodied participants, both the low and high frequency bands demonstrated congruent activity between action execution and observation. Our results suggest that AO could be an effective and critical procedure for deriving the mapping from ECoG signals to intended movement for an ECoG-based BCI system for individuals with paralysis.

  14. Motor-related brain activity during action observation: a neural substrate for electrocorticographic brain-computer interfaces after spinal cord injury

    PubMed Central

    Collinger, Jennifer L.; Vinjamuri, Ramana; Degenhart, Alan D.; Weber, Douglas J.; Sudre, Gustavo P.; Boninger, Michael L.; Tyler-Kabara, Elizabeth C.; Wang, Wei

    2014-01-01

    After spinal cord injury (SCI), motor commands from the brain are unable to reach peripheral nerves and muscles below the level of the lesion. Action observation (AO), in which a person observes someone else performing an action, has been used to augment traditional rehabilitation paradigms. Similarly, AO can be used to derive the relationship between brain activity and movement kinematics for a motor-based brain-computer interface (BCI) even when the user cannot generate overt movements. BCIs use brain signals to control external devices to replace functions that have been lost due to SCI or other motor impairment. Previous studies have reported congruent motor cortical activity during observed and overt movements using magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI). Recent single-unit studies using intracortical microelectrodes also demonstrated that a large number of motor cortical neurons had similar firing rate patterns between overt and observed movements. Given the increasing interest in electrocorticography (ECoG)-based BCIs, our goal was to identify whether action observation-related cortical activity could be recorded using ECoG during grasping tasks. Specifically, we aimed to identify congruent neural activity during observed and executed movements in both the sensorimotor rhythm (10–40 Hz) and the high-gamma band (65–115 Hz) which contains significant movement-related information. We observed significant motor-related high-gamma band activity during AO in both able-bodied individuals and one participant with a complete C4 SCI. Furthermore, in able-bodied participants, both the low and high frequency bands demonstrated congruent activity between action execution and observation. Our results suggest that AO could be an effective and critical procedure for deriving the mapping from ECoG signals to intended movement for an ECoG-based BCI system for individuals with paralysis. PMID:24600359

  15. Production of high quality brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) RNA from isolated populations of rat spinal cord motor neurons obtained by Laser Capture Microdissection (LCM).

    PubMed

    Mehta, Prachi; Premkumar, Brian; Morris, Renée

    2016-08-01

    The mammalian central nervous system (CNS) is composed of multiple cellular elements, making it challenging to segregate one particular cell type to study their gene expression profile. For instance, as motor neurons represent only 5-10% of the total cell population of the spinal cord, meaningful transcriptional analysis on these neurons is almost impossible to achieve from homogenized spinal cord tissue. A major challenge faced by scientists is to obtain good quality RNA from small amounts of starting material. In this paper, we used Laser Capture Microdissection (LCM) techniques to identify and isolate spinal cord motor neurons. The present analysis revealed that perfusion with paraformaldehyde (PFA) does not alter RNA quality. RNA integrity numbers (RINs) of tissue samples from rubrospinal tract (RST)-transected, intact spinal cord or from whole spinal cord homogenate were all above 8, which indicates intact, high-quality RNA. Levels of mRNA for brain-derived neurotrophic factor (BDNF) or for its tropomyosin receptor kinase B (TrkB) were not affected by rubrospinal tract (RST) transection, a surgical procedure that deprive motor neurons from one of their main supraspinal input. The isolation of pure populations of neurons with LCM techniques allows for robust transcriptional characterization that cannot be achieved with spinal cord homogenates. Such preparations of pure population of motor neurons will provide valuable tools to advance our understanding of the molecular mechanisms underlying spinal cord injury and neuromuscular diseases. In the near future, LCM techniques might be instrumental to the success of gene therapy for these debilitating conditions.

  16. Spinal Muscular Atrophy

    MedlinePlus

    ... diseases that progressively destroy lower motor neurons—nerve cells in the brain stem and spinal cord that control essential voluntary muscle activity such as speaking, walking, breathing, and swallowing. ...

  17. Restoration of motor function following spinal cord injury via optimal control of intraspinal microstimulation: toward a next generation closed-loop neural prosthesis

    PubMed Central

    Grahn, Peter J.; Mallory, Grant W.; Berry, B. Michael; Hachmann, Jan T.; Lobel, Darlene A.; Lujan, J. Luis

    2014-01-01

    Movement is planned and coordinated by the brain and carried out by contracting muscles acting on specific joints. Motor commands initiated in the brain travel through descending pathways in the spinal cord to effector motor neurons before reaching target muscles. Damage to these pathways by spinal cord injury (SCI) can result in paralysis below the injury level. However, the planning and coordination centers of the brain, as well as peripheral nerves and the muscles that they act upon, remain functional. Neuroprosthetic devices can restore motor function following SCI by direct electrical stimulation of the neuromuscular system. Unfortunately, conventional neuroprosthetic techniques are limited by a myriad of factors that include, but are not limited to, a lack of characterization of non-linear input/output system dynamics, mechanical coupling, limited number of degrees of freedom, high power consumption, large device size, and rapid onset of muscle fatigue. Wireless multi-channel closed-loop neuroprostheses that integrate command signals from the brain with sensor-based feedback from the environment and the system's state offer the possibility of increasing device performance, ultimately improving quality of life for people with SCI. In this manuscript, we review neuroprosthetic technology for improving functional restoration following SCI and describe brain-machine interfaces suitable for control of neuroprosthetic systems with multiple degrees of freedom. Additionally, we discuss novel stimulation paradigms that can improve synergy with higher planning centers and improve fatigue-resistant activation of paralyzed muscles. In the near future, integration of these technologies will provide SCI survivors with versatile closed-loop neuroprosthetic systems for restoring function to paralyzed muscles. PMID:25278830

  18. Early predictive factors for lower-extremity motor or sensory deficits and surgical results of patients with spinal tuberculosis: A retrospective study of 329 patients.

    PubMed

    Wang, Hongwei; Yang, Xiao; Shi, Ying; Zhou, Yue; Li, Changqing; Chen, Yu; Yu, Hailong; Wang, Qi; Liu, Jun; Cheng, Jiwei; Zhao, Yiwen; Han, Jianda; Xiang, Liangbi

    2016-08-01

    Many studies about the characteristics of spinal tuberculosis (STB) have been published, but none has investigated the predictive factors for lower-extremity motor or sensory deficits (LMSD) in patients with STB.The objective of this study was to find early predictive factors for LMSD and evaluate surgical results of patients with STB.From 2001 through 2010, 329 patients with STB were treated in our department and surgical treatment was performed in 274 patients. The factors assessed included age, sex, duration of symptoms, worsening of illness, clinical symptoms, clinical signs, imaging characteristics, kyphotic angle, Oswestry disability index (ODI), and visual analogue scale (VAS) scores.Of the 329 patients studied, 164 presented with LMSD (the LMSD group), of which 93 patients (28.3%) had motor deficits and 177 patients (53.8%) had sensory disturbance. The other 165 patients were included in the control group (the No LMSD group). Using univariate logistic regression analysis, we found that the sex (P = 0.042), age (P = 0.001), worsening of sickness (P = 0.013), location (P = 0.009), and spinal compression (P = 0.035) were the risk factors of LMSD. Furthermore, the multivariate logistic regression analysis indicated that age (OR = 1.761, 95% CI: 1.227-2.526, P = 0.002), worsening of sickness (yes vs no: OR = 1.910, 95% CI: 1.161-3.141, P = 0.011), location (T vs C: OR = 0.204, 95% CI: 0.063-0.662, P = 0.008), and spinal compression (yes vs no: OR = 1.672, 95% CI: 1.020-2.741, P = 0.042) were independent risk factors of LMSD. Surgical treatment was performed in 274 patients. The kyphotic angle improved from 25.8 ± 9.1° preoperatively to 14.0 ± 7.6°, with a mean correction of 11.8 ± 4.0°, and a mean correction loss of 1.5 ± 1.8° at final visit. There were significant differences between the preoperative and the final ODI and VAS scores in both groups (P < 0.001 and P < 0

  19. Self-Sustained Motor Activity Triggered by Interlimb Reflexes in Chronic Spinal Cord Injury, Evidence of Functional Ascending Propriospinal Pathways

    PubMed Central

    McNulty, Penelope A.; Burke, David

    2013-01-01

    The loss or reduction of supraspinal inputs after spinal cord injury provides a unique opportunity to examine the plasticity of neural pathways within the spinal cord. In a series of nine experiments on a patient, quadriplegic due to spinal cord injury, we investigated interlimb reflexes and self-sustained activity in completely paralyzed and paretic muscles due to a disinhibited propriospinal pathway. Electrical stimuli were delivered over the left common peroneal nerve at the fibular head as single stimuli or in trains at 2–100 Hz lasting 1 s. Single stimuli produced a robust interlimb reflex twitch in the contralateral thumb at a mean latency 69 ms, but no activity in other muscles. With stimulus trains the thumb twitch occurred at variable subharmonics of the stimulus rate, and strong self-sustained activity developed in the contralateral wrist extensors, outlasting both the stimuli and the thumb reflex by up to 20 s. Similar behavior was recorded in the ipsilateral wrist extensors and quadriceps femoris of both legs, but not in the contralateral thenar or peroneal muscles. The patient could not terminate the self-sustained activity voluntarily, but it was abolished on the left by attempted contractions of the paralyzed thumb muscles of the right hand. These responses depend on the functional integrity of an ascending propriospinal pathway, and highlight the plasticity of spinal circuitry following spinal cord injury. They emphasize the potential for pathways below the level of injury to generate movement, and the role of self-sustained reflex activity in the sequelae of spinal cord injury. PMID:23936543

  20. Self-sustained motor activity triggered by interlimb reflexes in chronic spinal cord injury, evidence of functional ascending propriospinal pathways.

    PubMed

    McNulty, Penelope A; Burke, David

    2013-01-01

    The loss or reduction of supraspinal inputs after spinal cord injury provides a unique opportunity to examine the plasticity of neural pathways within the spinal cord. In a series of nine experiments on a patient, quadriplegic due to spinal cord injury, we investigated interlimb reflexes and self-sustained activity in completely paralyzed and paretic muscles due to a disinhibited propriospinal pathway. Electrical stimuli were delivered over the left common peroneal nerve at the fibular head as single stimuli or in trains at 2-100 Hz lasting 1 s. Single stimuli produced a robust interlimb reflex twitch in the contralateral thumb at a mean latency 69 ms, but no activity in other muscles. With stimulus trains the thumb twitch occurred at variable subharmonics of the stimulus rate, and strong self-sustained activity developed in the contralateral wrist extensors, outlasting both the stimuli and the thumb reflex by up to 20 s. Similar behavior was recorded in the ipsilateral wrist extensors and quadriceps femoris of both legs, but not in the contralateral thenar or peroneal muscles. The patient could not terminate the self-sustained activity voluntarily, but it was abolished on the left by attempted contractions of the paralyzed thumb muscles of the right hand. These responses depend on the functional integrity of an ascending propriospinal pathway, and highlight the plasticity of spinal circuitry following spinal cord injury. They emphasize the potential for pathways below the level of injury to generate movement, and the role of self-sustained reflex activity in the sequelae of spinal cord injury.

  1. Monocyte Locomotion Inhibitory Factor Produced by E. histolytica Improves Motor Recovery and Develops Neuroprotection after Traumatic Injury to the Spinal Cord

    PubMed Central

    Bermeo, Gabriela; García, Elisa; Flores-Romero, Adrian; Rico-Rosillo, Guadalupe; Marroquín, Rubén; Flores, Carmina; Blanco-Favela, Francisco; Silva-García, Raúl

    2013-01-01

    Monocyte locomotion inhibitory factor (MLIF) is a pentapeptide produced by Entamoeba histolytica that has a potent anti-inflammatory effect. Either MLIF or phosphate buffered saline (PBS) was administered directly onto the spinal cord (SC) immediately after injury. Motor recovery was evaluated. We also analyzed neuroprotection by quantifying the number of surviving ventral horn motor neurons and the persistence of rubrospinal tract neurons. To evaluate the mechanism through which MLIF improved the outcome of SC injury, we quantified the expression of inducible nitric oxide synthase (iNOS), interleukin-10 (IL-10), and transforming growth factor-β (TGF-β) genes at the site of injury. Finally, the levels of nitric oxide and of lipid peroxidation were also determined in peripheral blood. Results showed that MLIF improved the rate of motor recovery and this correlated with an increased survival of ventral horn and rubrospinal neurons. These beneficial effects were in turn associated with a reduction in iNOS gene products and a significant upregulation of IL-10 and TGF-β expression. In the same way, MLIF reduced the concentration of nitric oxide and the levels of lipid peroxidation in systemic circulation. The present results demonstrate for the first time the neuroprotective effects endowed by MLIF after SC injury. PMID:24294606

  2. Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury.

    PubMed

    McKillop, William M; Dragan, Magdalena; Schedl, Andreas; Brown, Arthur

    2013-02-01

    Chondroitin sulfate proteoglycans (CSPGs) found in perineuronal nets and in the glial scar after spinal cord injury have been shown to inhibit axonal growth and plasticity. Since we have previously identified SOX9 as a transcription factor that upregulates the expression of a battery of genes associated with glial scar formation in primary astrocyte cultures, we predicted that conditional Sox9 ablation would result in reduced CSPG expression after spinal cord injury and that this would lead to increased neuroplasticity and improved locomotor recovery. Control and Sox9 conditional knock-out mice were subject to a 70 kdyne contusion spinal cord injury at thoracic level 9. One week after injury, Sox9 conditional knock-out mice expressed reduced levels of CSPG biosynthetic enzymes (Xt-1 and C4st), CSPG core proteins (brevican, neurocan, and aggrecan), collagens 2a1 and 4a1, and Gfap, a marker of astrocyte activation, in the injured spinal cord compared with controls. These changes in gene expression were accompanied by improved hind limb function and locomotor recovery as evaluated by the Basso Mouse Scale (BMS) and rodent activity boxes. Histological assessments confirmed reduced CSPG deposition and collagenous scarring at the lesion of Sox9 conditional knock-out mice, and demonstrated increased neurofilament-positive fibers in the lesion penumbra and increased serotonin immunoreactivity caudal to the site of injury. These results suggest that SOX9 inhibition is a potential strategy for the treatment of SCI. PMID:23027386

  3. Exendin-4 Enhances Motor Function Recovery via Promotion of Autophagy and Inhibition of Neuronal Apoptosis After Spinal Cord Injury in Rats.

    PubMed

    Li, Hao-Tian; Zhao, Xing-Zhang; Zhang, Xin-Ran; Li, Gang; Jia, Zhi-Qiang; Sun, Ping; Wang, Ji-Quan; Fan, Zhong-Kai; Lv, Gang

    2016-08-01

    Autophagy occurs prior to apoptosis and plays an important role in cell death regulation during spinal cord injury (SCI). This study aimed to determine the effects and potential mechanism of the glucagon-like peptide-1 (GLP-1) agonist extendin-4 (Ex-4) in SCI. Seventy-two male Sprague Dawley rats were randomly assigned to sham, SCI, 2.5 μg Ex-4, and 10 μg Ex-4 groups. To induce SCI, a 10-g iron rod was dropped from a 20-mm height to the spinal cord surface. Ex-4 was administered via intraperitoneal injection immediately after surgery. Motor function evaluation with the Basso Beattie Bresnahan (BBB) locomotor rating scale indicated significantly increased scores (p < 0.01) in the Ex-4-treated groups, especially 10 μg, which demonstrated the neuroprotective effect of Ex-4 after SCI. The light chain 3-II (LC3-II) and Beclin 1 protein expression determined via western blot and the number of autophagy-positive neurons via immunofluorescence double labeling were increased by Ex-4, which supports promotion of autophagy (p < 0.01). The caspase-3 protein level and neuronal apoptosis via transferase UTP nick end labeling (TUNEL)/NeuN/DAPI double labeling were significantly reduced in the Ex-4-treated groups, which indicates anti-apoptotic effects (p < 0.01). Finally, histological assessment via Nissl staining demonstrated the Ex-4 groups exhibited a significantly greater number of surviving neurons and less cavity (p < 0.01). To our knowledge, this is the first study to indicate that Ex-4 significantly enhances motor function in rats after SCI, and these effects are associated with the promotion of autophagy and inhibition of apoptosis. PMID:26198566

  4. Motor imagery-induced EEG patterns in individuals with spinal cord injury and their impact on brain-computer interface accuracy

    NASA Astrophysics Data System (ADS)

    Müller-Putz, G. R.; Daly, I.; Kaiser, V.

    2014-06-01

    Objective. Assimilating the diagnosis complete spinal cord injury (SCI) takes time and is not easy, as patients know that there is no ‘cure' at the present time. Brain-computer interfaces (BCIs) can facilitate daily living. However, inter-subject variability demands measurements with potential user groups and an understanding of how they differ to healthy users BCIs are more commonly tested with. Thus, a three-class motor imagery (MI) screening (left hand, right hand, feet) was performed with a group of 10 able-bodied and 16 complete spinal-cord-injured people (paraplegics, tetraplegics) with the objective of determining what differences were present between the user groups and how they would impact upon the ability of these user groups to interact with a BCI. Approach. Electrophysiological differences between patient groups and healthy users are measured in terms of sensorimotor rhythm deflections from baseline during MI, electroencephalogram microstate scalp maps and strengths of inter-channel phase synchronization. Additionally, using a common spatial pattern algorithm and a linear discriminant analysis classifier, the classification accuracy was calculated and compared between groups. Main results. It is seen that both patient groups (tetraplegic and paraplegic) have some significant differences in event-related desynchronization strengths, exhibit significant increases in synchronization and reach significantly lower accuracies (mean (M) = 66.1%) than the group of healthy subjects (M = 85.1%). Significance. The results demonstrate significant differences in electrophysiological correlates of motor control between healthy individuals and those individuals who stand to benefit most from BCI technology (individuals with SCI). They highlight the difficulty in directly translating results from healthy subjects to participants with SCI and the challenges that, therefore, arise in providing BCIs to such individuals.

  5. Sclerostin antibody preserves the morphology and structure of osteocytes and blocks the severe skeletal deterioration after motor-complete spinal cord injury in rats.

    PubMed

    Qin, Weiping; Li, Xiaodong; Peng, Yuanzhen; Harlow, Lauren M; Ren, Yinshi; Wu, Yingjie; Li, Jiliang; Qin, Yiwen; Sun, Jie; Zheng, Shijia; Brown, Tom; Feng, Jian Q; Ke, Hua Zhu; Bauman, William A; Cardozo, Christopher C

    2015-11-01

    Unloading, neural lesions, and hormonal disorders after acute motor-complete spinal cord injury (SCI) cause one of the most severe forms of bone loss, a condition that has been refractory to available interventions tested to date. Thus, these features related to acute SCI provide a unique opportunity to study complex bone problems, potential efficacious interventions, and mechanisms of action that are associated with these dramatic pathological changes. This study was designed to explore the therapeutic potential of sclerostin antibody (Scl-Ab) in a rat model of bone loss after motor-complete SCI, and to investigate mechanisms underlying bone loss and Scl-Ab action. SCI rats were administered Scl-Ab (25 mg/kg/week) or vehicle beginning 7 days after injury then weekly for 7 weeks. SCI resulted in significant decreases in bone mineral density (-25%) and trabecular bone volume (-67%) at the distal femur; Scl-Ab completely prevented these deteriorations of bone in SCI rats, concurrent with markedly increased bone formation. Scanning electron microscopy revealed that SCI reduced numbers of osteocytes and dendrites concomitant with a morphology change from a spindle to round shape; Scl-Ab corrected these abnormalities in osteocytes. In ex vivo cultures of bone marrow cells, Scl-Ab inhibited osteoclastogenesis, and promoted osteoblastogenesis accompanied by increases in mRNA levels of LRP5, osteoprotegerin (OPG), and the OPG/RANKL ratio, and a decrease in DKK1 mRNA. Our findings provide the first evidence that robust bone loss after acute motor-complete SCI can be blocked by Scl-Ab, at least in part, through the preservation of osteocyte morphology and structure and related bone remodeling. Our findings support the inhibition of sclerostin as a promising approach to mitigate the striking bone loss that ensues after acute motor-complete SCI, and perhaps other conditions associated with disuse osteoporosis as a consequence of neurological disorders.

  6. Involvement of Peripheral Adenosine A2 Receptors in Adenosine A1 Receptor–Mediated Recovery of Respiratory Motor Function After Upper Cervical Spinal Cord Hemisection

    PubMed Central

    James, Elysia; Nantwi, Kwaku D

    2006-01-01

    Background/Objective: In an animal model of spinal cord injury, a latent respiratory motor pathway can be pharmacologically activated through central adenosine A1 receptor antagonism to restore respiratory function after cervical (C2) spinal cord hemisection that paralyzes the hemidiaphragm ipsilateral to injury. Although respiration is modulated by central and peripheral mechanisms, putative involvement of peripheral adenosine A2 receptors in functional recovery in our model is untested. The objective of this study was to assess the effects of peripherally located adenosine A2 receptors on recovery of respiratory function after cervical (C2) spinal cord hemisection. Methods: Respiratory activity was electrophysiologically assessed (under standardized recording conditions) in C2-hemisected adult rats with the carotid bodies intact (H-CBI; n =12) or excised (H-CBE; n =12). Animals were administered the adenosine A2 receptor agonist, CGS-21680, followed by the A1 receptor antagonist, 1, 3-dipropyl-8-cyclopentylxanthine (DPCPX), or administered DPCPX alone. Recovered respiratory activity, characterized as drug-induced activity in the previously quiescent left phrenic nerve of C2-hemisected animals in H-CBI and H-CBE rats, was compared. Recovered respiratory activity was calculated by dividing drug-induced activity in the left phrenic nerve by activity in the right phrenic nerve. Results: Administration of CGS-21680 before DPCPX (n = 6) in H-CBI rats induced a significantly greater recovery (58.5 ± 3.6%) than when DPCPX (42.6 ± 4.6%) was administered (n = 6) alone. In H-CBE rats, prior administration of CGS-21680 (n = 6) did not enhance recovery over that induced by DPCPX (n = 6) alone. Recovery in H-CBE rats amounted to 39.7 ± 3.7% and 38.4 + 4.2%, respectively. Conclusions: Our results suggest that adenosine A2 receptors located in the carotid bodies can enhance the magnitude of adenosine A1 receptor–mediated recovery of respiratory function after C2 hemisection

  7. Polyethylene glycol-coupled IGF1 delays motor function defects in a mouse model of spinal muscular atrophy with respiratory distress type 1.

    PubMed

    Krieger, Frank; Elflein, Nicole; Saenger, Stefanie; Wirthgen, Elisa; Rak, Kristen; Frantz, Stefan; Hoeflich, Andreas; Toyka, Klaus V; Metzger, Friedrich; Jablonka, Sibylle

    2014-05-01

    Spinal muscular atrophy with respiratory distress type 1 is a neuromuscular disorder characterized by progressive weakness and atrophy of the diaphragm and skeletal muscles, leading to death in childhood. No effective treatment is available. The neuromuscular degeneration (Nmd(2J)) mouse shares a crucial mutation in the immunoglobulin mu-binding protein 2 gene (Ighmbp2) with spinal muscular atrophy with respiratory distress type 1 patients and also displays some basic features of the human disease. This model serves as a promising tool in understanding the complex mechanisms of the disease and in exploring novel treatment modalities such as insulin-like growth factor 1 (IGF1) which supports myogenic and neurogenic survival and stimulates differentiation during development. Here we investigated the treatment effects with polyethylene glycol-coupled IGF1 and its mechanisms of action in neurons and muscles. Polyethylene glycol-coupled IGF1 was applied subcutaneously every second day from post-natal Day 14 to post-natal Day 42 and the outcome was assessed by morphology, electromyography, and molecular studies. We found reduced IGF1 serum levels in Nmd(2J) mice 2 weeks after birth, which was normalized by polyethylene glycol-coupled IGF1 treatment. Nmd(2J) mice showed marked neurogenic muscle fibre atrophy in the gastrocnemius muscle and polyethylene glycol-coupled IGF1 treatment resulted in muscle fibre hypertrophy and slowed fibre degeneration along with significantly higher numbers of functionally active axonal sprouts. In the diaphragm with predominant myogenic changes a profound protection from muscle fibre degeneration was observed under treatment. No effects of polyethylene glycol-coupled IGF1 were monitored at the level of motor neuron survival. The beneficial effects of polyethylene glycol-coupled IGF1 corresponded to a marked activation of the IGF1 receptor, resulting in enhanced phosphorylation of Akt (protein kinase B) and the ribosomal protein S6 kinase in

  8. A high-fat jelly diet restores bioenergetic balance and extends lifespan in the presence of motor dysfunction and lumbar spinal cord motor neuron loss in TDP-43A315T mutant C57BL6/J mice.

    PubMed

    Coughlan, Karen S; Halang, Luise; Woods, Ina; Prehn, Jochen H M

    2016-09-01

    Transgenic transactivation response DNA-binding protein 43 (TDP-43) mice expressing the A315T mutation under control of the murine prion promoter progressively develop motor function deficits and are considered a new model for the study of amyotrophic lateral sclerosis (ALS); however, premature sudden death resulting from intestinal obstruction halts disease phenotype progression in 100% of C57BL6/J congenic TDP-43(A315T) mice. Similar to our recent results in SOD1(G93A) mice, TDP-43(A315T) mice fed a standard pellet diet showed increased 5' adenosine monophosphate-activated protein kinase (AMPK) activation at postnatal day (P)80, indicating elevated energetic stress during disease progression. We therefore investigated the effects of a high-fat jelly diet on bioenergetic status and lifespan in TDP-43(A315T) mice. In contrast to standard pellet-fed mice, mice fed high-fat jelly showed no difference in AMPK activation up to P120 and decreased phosphorylation of acetly-CoA carboxylase (ACC) at early-stage time points. Exposure to a high-fat jelly diet prevented sudden death and extended survival, allowing development of a motor neuron disease phenotype with significantly decreased body weight from P80 onward that was characterised by deficits in Rotarod abilities and stride length measurements. Development of this phenotype was associated with a significant motor neuron loss as assessed by Nissl staining in the lumbar spinal cord. Our work suggests that a high-fat jelly diet improves the pre-clinical utility of the TDP-43(A315T) model by extending lifespan and allowing the motor neuron disease phenotype to progress, and indicates the potential benefit of this diet in TDP-43-associated ALS. PMID:27491077

  9. A high-fat jelly diet restores bioenergetic balance and extends lifespan in the presence of motor dysfunction and lumbar spinal cord motor neuron loss in TDP-43A315T mutant C57BL6/J mice

    PubMed Central

    Coughlan, Karen S.; Halang, Luise; Woods, Ina

    2016-01-01

    ABSTRACT Transgenic transactivation response DNA-binding protein 43 (TDP-43) mice expressing the A315T mutation under control of the murine prion promoter progressively develop motor function deficits and are considered a new model for the study of amyotrophic lateral sclerosis (ALS); however, premature sudden death resulting from intestinal obstruction halts disease phenotype progression in 100% of C57BL6/J congenic TDP-43A315T mice. Similar to our recent results in SOD1G93A mice, TDP-43A315T mice fed a standard pellet diet showed increased 5′ adenosine monophosphate-activated protein kinase (AMPK) activation at postnatal day (P)80, indicating elevated energetic stress during disease progression. We therefore investigated the effects of a high-fat jelly diet on bioenergetic status and lifespan in TDP-43A315T mice. In contrast to standard pellet-fed mice, mice fed high-fat jelly showed no difference in AMPK activation up to P120 and decreased phosphorylation of acetly-CoA carboxylase (ACC) at early-stage time points. Exposure to a high-fat jelly diet prevented sudden death and extended survival, allowing development of a motor neuron disease phenotype with significantly decreased body weight from P80 onward that was characterised by deficits in Rotarod abilities and stride length measurements. Development of this phenotype was associated with a significant motor neuron loss as assessed by Nissl staining in the lumbar spinal cord. Our work suggests that a high-fat jelly diet improves the pre-clinical utility of the TDP-43A315T model by extending lifespan and allowing the motor neuron disease phenotype to progress, and indicates the potential benefit of this diet in TDP-43-associated ALS. PMID:27491077

  10. Brain motor system function in a patient with complete spinal cord injury following extensive brain-computer interface training.

    PubMed

    Enzinger, Christian; Ropele, Stefan; Fazekas, Franz; Loitfelder, Marisa; Gorani, Faton; Seifert, Thomas; Reiter, Gudrun; Neuper, Christa; Pfurtscheller, Gert; Müller-Putz, Gernot

    2008-09-01

    Although several features of brain motor function appear to be preserved even in chronic complete SCI, previous functional MRI (fMRI) studies have also identified significant derangements such as a strongly reduced volume of activation, a poor modulation of function and abnormal activation patterns. It might be speculated that extensive motor imagery training may serve to prevent such abnormalities. We here report on a unique patient with a complete traumatic SCI below C5 who learned to elicit electroencephalographic signals beta-bursts in the midline region upon imagination of foot movements. This enabled him to use a neuroprosthesis and to "walk from thought" in a virtual environment via a brain-computer interface (BCI). We here used fMRI at 3T during imagined hand and foot movements to investigate the effects of motor imagery via persistent BCI training over 8 years on brain motor function and compared these findings to a group of five untrained healthy age-matched volunteers during executed and imagined movements. We observed robust primary sensorimotor cortex (SMC) activity in expected somatotopy in the tetraplegic patient upon movement imagination while such activation was absent in healthy untrained controls. Sensorimotor network activation with motor imagery in the patient (including SMC contralateral to and the cerebellum ipsilateral to the imagined side of movement as well as supplementary motor areas) was very similar to the pattern observed with actual movement in the controls. We interpret our findings as evidence that BCI training as a conduit of motor imagery training may assist in maintaining access to SMC in largely preserved somatopy despite complete deafferentation. PMID:18592230

  11. Tetraplegia or paraplegia with brachial diparesis? What is the most appropriate designation for the motor deficit in patients with lower cervical spinal cord injury?

    PubMed

    Figueiredo, Nicandro; Figueiredo, Iara Eberhard; Resnick, Daniel

    2013-02-01

    The authors seek to clarify the nomenclature used to describe cervical spinal cord injuries, particularly the use of the terms "tetraplegia", "quadriplegia", "quadriparesis", "tetraparesis", "incomplete quadriplegia" or "incomplete tetraplegia" when applied to patients with lower cervical cord injuries. A review of the origin of the terms and nomenclature used currently to describe the neurological status of patients with SCI in the literature was performed. The terms "tetraplegia", "quadriplegia", "quadriparesis", "tetraparesis", "incomplete quadriplegia" or "incomplete tetraplegia" have been used very often to describe patients with complete lower cervical SCI despite the fact that the clinical scenario is all the same for most of these patients. Most of these patients have total loss of the motor voluntary movements of their lower trunk and inferior limbs, and partial impairment of movement of their superior limbs, preserving many motor functions of the proximal muscles of their arms (superior limbs). A potentially better descriptive term may be "paraplegia with brachial diparesis". In using the most appropriate terminology, the patients with lower cervical SCI currently referred as presenting with "tetraplegia", "quadriplegia", "quadriparesis", "tetraparesis", "incomplete quadriplegia" or "incomplete tetraplegia", might be better described as having "paraplegia with brachial diparesis".

  12. Trunk and Shoulder Kinematic and Kinetic and Electromyographic Adaptations to Slope Increase during Motorized Treadmill Propulsion among Manual Wheelchair Users with a Spinal Cord Injury

    PubMed Central

    Champagne, Audrey

    2015-01-01

    The main objective was to quantify the effects of five different slopes on trunk and shoulder kinematics as well as shoulder kinetic and muscular demands during manual wheelchair (MWC) propulsion on a motorized treadmill. Eighteen participants with spinal cord injury propelled their MWC at a self-selected constant speed on a motorized treadmill set at different slopes (0°, 2.7°, 3.6°, 4.8°, and 7.1°). Trunk and upper limb movements were recorded with a motion analysis system. Net shoulder joint moments were computed with the forces applied to the handrims measured with an instrumented wheel. To quantify muscular demand, the electromyographic activity (EMG) of the pectoralis major (clavicular and sternal portions) and deltoid (anterior and posterior fibers) was recorded during the experimental tasks and normalized against maximum EMG values obtained during static contractions. Overall, forward trunk flexion and shoulder flexion increased as the slope became steeper, whereas shoulder flexion, adduction, and internal rotation moments along with the muscular demand also increased as the slope became steeper. The results confirm that forward trunk flexion and shoulder flexion movement amplitudes, along with shoulder mechanical and muscular demands, generally increase when the slope of the treadmill increases despite some similarities between the 2.7° to 3.6° and 3.6° to 4.8° slope increments. PMID:25793200

  13. Trunk and shoulder kinematic and kinetic and electromyographic adaptations to slope increase during motorized treadmill propulsion among manual wheelchair users with a spinal cord injury.

    PubMed

    Gagnon, Dany; Babineau, Annie-Claude; Champagne, Audrey; Desroches, Guillaume; Aissaoui, Rachid

    2015-01-01

    The main objective was to quantify the effects of five different slopes on trunk and shoulder kinematics as well as shoulder kinetic and muscular demands during manual wheelchair (MWC) propulsion on a motorized treadmill. Eighteen participants with spinal cord injury propelled their MWC at a self-selected constant speed on a motorized treadmill set at different slopes (0°, 2.7°, 3.6°, 4.8°, and 7.1°). Trunk and upper limb movements were recorded with a motion analysis system. Net shoulder joint moments were computed with the forces applied to the handrims measured with an instrumented wheel. To quantify muscular demand, the electromyographic activity (EMG) of the pectoralis major (clavicular and sternal portions) and deltoid (anterior and posterior fibers) was recorded during the experimental tasks and normalized against maximum EMG values obtained during static contractions. Overall, forward trunk flexion and shoulder flexion increased as the slope became steeper, whereas shoulder flexion, adduction, and internal rotation moments along with the muscular demand also increased as the slope became steeper. The results confirm that forward trunk flexion and shoulder flexion movement amplitudes, along with shoulder mechanical and muscular demands, generally increase when the slope of the treadmill increases despite some similarities between the 2.7° to 3.6° and 3.6° to 4.8° slope increments. PMID:25793200

  14. Mitigation of sensory and motor deficits by acrolein scavenger phenelzine in a rat model of spinal cord contusive injury.

    PubMed

    Chen, Zhe; Park, Jonghyuck; Butler, Breanne; Acosta, Glen; Vega-Alvarez, Sasha; Zheng, Lingxing; Tang, Jonathan; McCain, Robyn; Zhang, Wenpeng; Ouyang, Zheng; Cao, Peng; Shi, Riyi

    2016-07-01

    Currently there are no effective therapies available for the excruciating neuropathic pain that develops after spinal cord injuries (SCI). As such, a great deal of effort is being put into the investigation of novel therapeutic targets that can alleviate this pain. One such target is acrolein, a highly reactive aldehyde produced as a byproduct of oxidative stress and inflammation that is capable of activating the transient receptor potential ankyrin 1 (TRPA1) cation channel, known to be involved in the transmission and propagation of chronic neuropathic pain. One anti-acrolein agent, hydralazine, has already been shown to reduce neuropathic pain behaviors and offer neuroprotection after SCI. This study investigates another acrolein scavenger, phenelzine, for its possible role of alleviating sensory hypersensitivity through acrolein suppression. The results show that phenelzine is indeed capable of attenuating neuropathic pain behaviors in acute, delayed, and chronic administration schedules after injury in a rat model of SCI. In addition, upon the comparison of hydralazine to phenelzine, both acrolein scavengers displayed a dose-dependent response in the reduction of acrolein in vivo. Finally, phenelzine proved capable of providing locomotor function recovery and neuroprotection of spinal cord tissue when administered immediately after injury for 2 weeks. These results indicate that phenelzine may be an effective treatment for neuropathic pain after SCI and likely a viable alternative to hydralazine. We have shown that phenelzine can attenuate neuropathic pain behavior in acute, delayed, and chronic administration in post-SCI rats. This was accompanied by a dose-dependent reduction in an acrolein metabolite in urine and an acrolein adduct in spinal cord tissue, and the suppression of TRPA1 over-expression in central and peripheral locations post-trauma. Acrolein scavenging might be a novel therapeutic strategy to reduce post-SCI neuropathic pain.

  15. Mitigation of sensory and motor deficits by acrolein scavenger phenelzine in a rat model of spinal cord contusive injury.

    PubMed

    Chen, Zhe; Park, Jonghyuck; Butler, Breanne; Acosta, Glen; Vega-Alvarez, Sasha; Zheng, Lingxing; Tang, Jonathan; McCain, Robyn; Zhang, Wenpeng; Ouyang, Zheng; Cao, Peng; Shi, Riyi

    2016-07-01

    Currently there are no effective therapies available for the excruciating neuropathic pain that develops after spinal cord injuries (SCI). As such, a great deal of effort is being put into the investigation of novel therapeutic targets that can alleviate this pain. One such target is acrolein, a highly reactive aldehyde produced as a byproduct of oxidative stress and inflammation that is capable of activating the transient receptor potential ankyrin 1 (TRPA1) cation channel, known to be involved in the transmission and propagation of chronic neuropathic pain. One anti-acrolein agent, hydralazine, has already been shown to reduce neuropathic pain behaviors and offer neuroprotection after SCI. This study investigates another acrolein scavenger, phenelzine, for its possible role of alleviating sensory hypersensitivity through acrolein suppression. The results show that phenelzine is indeed capable of attenuating neuropathic pain behaviors in acute, delayed, and chronic administration schedules after injury in a rat model of SCI. In addition, upon the comparison of hydralazine to phenelzine, both acrolein scavengers displayed a dose-dependent response in the reduction of acrolein in vivo. Finally, phenelzine proved capable of providing locomotor function recovery and neuroprotection of spinal cord tissue when administered immediately after injury for 2 weeks. These results indicate that phenelzine may be an effective treatment for neuropathic pain after SCI and likely a viable alternative to hydralazine. We have shown that phenelzine can attenuate neuropathic pain behavior in acute, delayed, and chronic administration in post-SCI rats. This was accompanied by a dose-dependent reduction in an acrolein metabolite in urine and an acrolein adduct in spinal cord tissue, and the suppression of TRPA1 over-expression in central and peripheral locations post-trauma. Acrolein scavenging might be a novel therapeutic strategy to reduce post-SCI neuropathic pain. PMID:27060873

  16. Effects of 4-aminopyridine on motor evoked potentials in patients with spinal cord injury: a double-blinded, placebo-controlled crossover trial.

    PubMed

    Wolfe, D L; Hayes, K C; Hsieh, J T; Potter, P J

    2001-08-01

    4-Aminopyridine (4-AP) is a potassium (K+) channel blocking agent that has been shown to reduce the latency and increase the amplitude of motor evoked potentials (MEPs) elicited with transcranial magnetic stimulation (TMS) in patients with chronic spinal cord injury (SCI). These effects on MEPs are thought to reflect enhanced conduction in long tract axons brought about by overcoming conduction deficits due to focal demyelination and/or by enhancing neuroneuronal transmission at one or more sites of the neuraxis. The present study was designed to obtain further evidence of reduced central motor conduction time (CMCT) and to determine whether MEPs could be recorded from paretic muscles in which they were not normally elicited. MEPs were elicited with TMS being delivered to subjects (n = 25) pre- and post-administration of 4-AP (10 mg capsule) or placebo. The principal finding was that 4-AP lowered the stimulation threshold, increased the amplitude and reduced the latency of MEPs in all muscles tested, including those that were unimpaired, but did not alter measures of the peripheral nervous system (i.e., M-wave, H-reflex, F-wave). These 4-AP-induced changes in MEPs were significantly greater than those seen with placebo (p < 0.05). The primary implication of these results is that a low dose of 4-AP (immediate-release formulation) appears to improve the impaired central motor conduction of some patients with incomplete SCI. This is most likely attributable to overcoming conduction deficits at the site of injury but may also involve an increase in cortical excitability.

  17. Spinal Plasticity following Intermittent Hypoxia: Implications for Spinal Injury

    PubMed Central

    Dale-Nagle, Erica A.; Hoffman, Michael S.; MacFarlane, Peter M.; Satriotomo, Irawan; Lovett-Barr, Mary Rachael; Vinit, Stéphane; Mitchell, Gordon S.

    2011-01-01

    Plasticity is a fundamental property of the neural system controlling breathing. One frequently studied model of respiratory plasticity is long-term facilitation of phrenic motor output (pLTF) following acute intermittent hypoxia (AIH). pLTF arises from spinal plasticity, increasing respiratory motor output through a mechanism that requires new synthesis of brain derived neurotrophic factor (BDNF), activation of its high affinity receptor, tropomyosin-related kinase B (TrkB) and extracellular-related kinase (ERK) mitogen-activated protein (MAP) kinase signaling in or near phrenic motor neurons. Since intermittent hypoxia induces spinal plasticity, we are exploring the potential to harness repetitive AIH as a means of inducing functional recovery in conditions causing respiratory insufficiency, such as cervical spinal injury. Since repetitive AIH induces phenotypic plasticity in respiratory and motor neurons, it may restore respiratory motor function in patients with incomplete spinal injury. PMID:20536940

  18. Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43

    PubMed Central

    Koyama, Akihide; Sugai, Akihiro; Kato, Taisuke; Ishihara, Tomohiko; Shiga, Atsushi; Toyoshima, Yasuko; Koyama, Misaki; Konno, Takuya; Hirokawa, Sachiko; Yokoseki, Akio; Nishizawa, Masatoyo; Kakita, Akiyoshi; Takahashi, Hitoshi; Onodera, Osamu

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder. In motor neurons of ALS, TAR DNA binding protein-43 (TDP-43), a nuclear protein encoded by TARDBP, is absent from the nucleus and forms cytoplasmic inclusions. TDP-43 auto-regulates the amount by regulating the TARDBP mRNA, which has three polyadenylation signals (PASs) and three additional alternative introns within the last exon. However, it is still unclear how the autoregulatory mechanism works and how the status of autoregulation in ALS motor neurons without nuclear TDP-43 is. Here we show that TDP-43 inhibits the selection of the most proximal PAS and induces splicing of multiple alternative introns in TARDBP mRNA to decrease the amount of cytoplasmic TARDBP mRNA by nonsense-mediated mRNA decay. When TDP-43 is depleted, the TARDBP mRNA uses the most proximal PAS and is increased in the cytoplasm. Finally, we have demonstrated that in ALS motor neurons—especially neurons with mislocalized TDP-43—the amount of TARDBP mRNA is increased in the cytoplasm. Our observations indicate that nuclear TDP-43 contributes to the autoregulation and suggests that the absence of nuclear TDP-43 induces an abnormal autoregulation and increases the amount of TARDBP mRNA. The vicious cycle might accelerate the disease progression of ALS. PMID:27257061

  19. Evaluation of muscle strength and motor abilities in children with type II and III spinal muscle atrophy treated with valproic acid

    PubMed Central

    2011-01-01

    Background Spinal muscular atrophy (SMA) is an autosomal recessive disorder that affects the motoneurons of the spinal anterior horn, resulting in hypotonia and muscle weakness. The disease is caused by deletion or mutation in the telomeric copy of SMN gene (SMN1) and clinical severity is in part determined by the copy number of the centromeric copy of the SMN gene (SMN2). The SMN2 mRNA lacks exon 7, resulting in a production of lower amounts of the full-length SMN protein. Knowledge of the molecular mechanism of diseases has led to the discovery of drugs capable of increasing SMN protein level through activation of SMN2 gene. One of these drugs is the valproic acid (VPA), a histone deacetylase inhibitor. Methods Twenty-two patients with type II and III SMA, aged between 2 and 18 years, were treated with VPA and were evaluated five times during a one-year period using the Manual Muscle Test (Medical Research Council scale-MRC), the Hammersmith Functional Motor Scale (HFMS), and the Barthel Index. Results After 12 months of therapy, the patients did not gain muscle strength. The group of children with SMA type II presented a significant gain in HFMS scores during the treatment. This improvement was not observed in the group of type III patients. The analysis of the HFMS scores during the treatment period in the groups of patients younger and older than 6 years of age did not show any significant result. There was an improvement of the daily activities at the end of the VPA treatment period. Conclusion Treatment of SMA patients with VPA may be a potential alternative to alleviate the progression of the disease. Trial Registration ClinicalTrials.gov: NCT01033331 PMID:21435220

  20. Shift from extracellular signal-regulated kinase to AKT/cAMP response element-binding protein pathway increases survival-motor-neuron expression in spinal-muscular-atrophy-like mice and patient cells.

    PubMed

    Branchu, Julien; Biondi, Olivier; Chali, Farah; Collin, Thibault; Leroy, Felix; Mamchaoui, Kamel; Makoukji, Joelle; Pariset, Claude; Lopes, Philippe; Massaad, Charbel; Chanoine, Christophe; Charbonnier, Frédéric

    2013-03-01

    Spinal muscular atrophy (SMA), a recessive neurodegenerative disease, is characterized by the selective loss of spinal motor neurons. No available therapy exists for SMA, which represents one of the leading genetic causes of death in childhood. SMA is caused by a mutation of the survival-of-motor-neuron 1 (SMN1) gene, leading to a quantitative defect in the survival-motor-neuron (SMN) protein expression. All patients retain one or more copies of the SMN2 gene, which modulates the disease severity by producing a small amount of stable SMN protein. We reported recently that NMDA receptor activation, directly in the spinal cord, significantly enhanced the transcription rate of the SMN2 genes in a mouse model of very severe SMA (referred as type 1) by a mechanism that involved AKT/CREB pathway activation. Here, we provide the first compelling evidence for a competition between the MEK/ERK/Elk-1 and the phosphatidylinositol 3-kinase/AKT/CREB signaling pathways for SMN2 gene regulation in the spinal cord of type 1 SMA-like mice. The inhibition of the MEK/ERK/Elk-1 pathway promotes the AKT/CREB pathway activation, leading to (1) an enhanced SMN expression in the spinal cord of SMA-like mice and in human SMA myotubes and (2) a 2.8-fold lifespan extension in SMA-like mice. Furthermore, we identified a crosstalk between ERK and AKT signaling pathways that involves the calcium-dependent modulation of CaMKII activity. Together, all these data open new perspectives to the therapeutic strategy for SMA patients. PMID:23467345

  1. Activation of mGlu3 metabotropic glutamate receptors enhances GDNF and GLT-1 formation in the spinal cord and rescues motor neurons in the SOD-1 mouse model of amyotrophic lateral sclerosis.

    PubMed

    Battaglia, Giuseppe; Riozzi, Barbara; Bucci, Domenico; Di Menna, Luisa; Molinaro, Gemma; Pallottino, Simone; Nicoletti, Ferdinando; Bruno, Valeria

    2015-02-01

    Enhancement of glial-derived neurotrophic factor (GDNF) is an established therapeutic target for amyotrophic lateral sclerosis (ALS). Activation of group II metabotropic glutamate (mGlu) receptors with the orthosteric agonist, LY379268, enhanced GDNF levels in cultured spinal cord astrocytes from wild-type mice and mGlu2(-/-) mice, but not in astrocytes from mGlu3(-/-) mice. LY379268 protected Sternberger monoclonal incorporated antibody-32 (SMI-32)(+) motor neurons against excitotoxic death in mixed cultures of spinal cord cells, and its action was abrogated by anti-GDNF antibodies. Acute systemic injection of LY379268 (0.5, 1 or 5mg/kg, i.p.) enhanced spinal cord GDNF levels in wild-type and mGlu2(-/-) mice, but not in mGlu3(-/-) mice. No tolerance developed to the GDNF-enhancing effect of LY379268 when the drug was continuously delivered for 28days by means of s.c. osmotic minipumps (0.5-5mg/day). Double fluorescent immunostaining showed a co-localization of GDNF with the astrocyte marker, GFAP, but not with the neuronal marker, Neuronal Nuclear Antigen (NeuN), or with SMI-32. Continuous infusion of LY379268 also enhanced the expression of the glutamate transporter GLT-1, in the spinal cord. These data laid the groundwork for the study of LY379268 in ALS mice. Continuous treatment with 1 or 5mg/kg/day with LY379268 had a beneficial effect on neurological disability in SOD1G93A mice. At day 40 of treatment, LY379268 enhanced spinal cord levels of GDNF and GLT-1, and rescued spinal cord motor neurons, as assessed by stereologic counting of SMI-32(+) cells. LY379268 had no significant effect on the mortality rate of SODG93A. These findings encourage the development of selective mGlu3 receptor agonists/enhancers as neuroprotective agents in ALS. PMID:25434487

  2. A functional model and simulation of spinal motor pools and intrafascicular recordings of motoneuron activity in peripheral nerve

    PubMed Central

    Abdelghani, Mohamed N.; Abbas, James J.; Horch, Kenneth W.; Jung, Ranu

    2014-01-01

    Decoding motor intent from recorded neural signals is essential for the development of effective neural-controlled prostheses. To facilitate the development of online decoding algorithms we have developed a software platform to simulate neural motor signals recorded with peripheral nerve electrodes, such as longitudinal intrafascicular electrodes (LIFEs). The simulator uses stored motor intent signals to drive a pool of simulated motoneurons with various spike shapes, recruitment characteristics, and firing frequencies. Each electrode records a weighted sum of a subset of simulated motoneuron activity patterns. As designed, the simulator facilitates development of a suite of test scenarios that would not be possible with actual data sets because, unlike with actual recordings, in the simulator the individual contributions to the simulated composite recordings are known and can be methodically varied across a set of simulation runs. In this manner, the simulation tool is suitable for iterative development of real-time decoding algorithms prior to definitive evaluation in amputee subjects with implanted electrodes. The simulation tool was used to produce data sets that demonstrate its ability to capture some features of neural recordings that pose challenges for decoding algorithms. PMID:25452711

  3. Conditional genetic deletion of PTEN after a spinal cord injury enhances regenerative growth of CST axons and motor function recovery in mice

    PubMed Central

    Danilov, Camelia A.; Steward, Oswald

    2015-01-01

    Previous studies indicate that conditional genetic deletion of phosphatase and tensin homolog (PTEN) in neonatal mice enhances the ability of axons to regenerate following spinal cord injury (SCI) in adults. Here, we assessed whether deleting PTEN in adult neurons post-SCI is also effective, and whether enhanced regenerative growth is accompanied by enhanced recovery of voluntary motor function. PTENloxP/loxP mice received moderate contusion injuries at cervical level 5 (C5). One group received unilateral injections of adeno-associated virus expressing CRE (AAV-CRE) into the sensorimotor cortex; controls received a vector expressing green fluorescent protein (AAV-GFP) or injuries only (no vector injections). Forelimb function was tested for 14 weeks post-SCI using a grip strength meter (GSM) and a hanging task. The corticospinal tract (CST) was traced by injecting mini-ruby BDA into the sensorimotor cortex. Forelimb gripping ability was severely impaired immediately post-SCI but recovered slowly over time. The extent of recovery was significantly greater in PTEN-deleted mice in comparison to either the AAV-GFP group or the injury only group. BDA tract tracing revealed significantly higher numbers of BDA-labeled axons in caudal segments in the PTEN-deleted group compared to control groups. In addition, in the PTEN-deleted group, there were exuberant collaterals extending from the main tract rostral to the lesion, into and around the scar tissue at the injury site. These results indicate that PTEN deletion in adult mice shortly post-SCI can enhance regenerative growth of CST axons and forelimb motor function recovery. PMID:25704959

  4. Emergency department visits for motor vehicle traffic injuries: United States, 2010-2011.

    PubMed

    Albert, Michael; McCaig, Linda F

    2015-01-01

    Data from the National Hospital Ambulatory Medical Care Survey, 2010-2011. In 2010-2011, the emergency department (ED) visit rate for motor vehicle traffic injuries was highest among persons aged 16-24 years. The rates declined with age after 16-24, with rates for those aged 0-15 similar to those 65 and over. The overall ED visit rate for motor vehicle traffic injuries was higher among non-Hispanic black persons compared with non-Hispanic white and Hispanic persons. Imaging services were ordered or provided at 70.2% of ED visits for motor vehicle traffic injuries, which was higher than for other injury-related ED visits (55.9%). About one-half of ED visits for motor vehicle traffic injuries had a primary diagnosis of sprains and strains of the neck and back, contusion with intact skin surface, or spinal disorders. In spite of improvements in motor vehicle safety in recent years, motor vehicle crashes remain a major source of morbidity and mortality in the United States (1-3). Motor vehicle-related deaths and injuries also result in substantial economic and societal costs related to medical care and lost productivity (4). This report describes the rates and characteristics of emergency department (ED) visits for motor vehicle traffic injuries during 2010-2011 based on nationally representative data from the National Hospital Ambulatory Medical Care Survey (NHAMCS).

  5. Survival, Differentiation, and Migration of High-Purity Mouse Embryonic Stem Cell-derived Progenitor Motor Neurons in Fibrin Scaffolds after Sub-Acute Spinal Cord Injury.

    PubMed

    McCreedy, D A; Wilems, T S; Xu, H; Butts, J C; Brown, C R; Smith, A W; Sakiyama-Elbert, S E

    2014-11-01

    Embryonic stem (ES) cells can be differentiated into many neural cell types that hold great potential as cell replacement therapies following spinal cord injury (SCI). Coupling stem cell transplantation with biomaterial scaffolds can produce a unified combination therapy with several potential advantages including enhanced cell survival, greater transplant retention, reduced scarring, and improved integration at the transplant/host interface. Undesired cell types, however, are commonly present in ES-cell derived cultures due to the limited efficiency of most ES cell induction protocols. Heterogeneous cell populations can confound the interaction between the biomaterial and specific neural populations leading to undesired outcomes. In particular, biomaterials scaffolds may enhance tumor formation by promoting survival and proliferation of undifferentiated ES cells that can persist after induction. Methods for purification of specific ES cell-derived neural populations are necessary to recognize the full potential of combination therapies involving biomaterials and ES cell-derived neural populations. We previously developed a method for enriching ES cell-derived progenitor motor neurons (pMNs) induced from mouse ES cells via antibiotic selection and showed that the enriched cell populations are depleted of pluripotent stem cells. In this study, we demonstrate the survival and differentiation of enriched pMNs within three dimensional (3D) fibrin scaffolds in vitro and when transplanted into a sub-acute dorsal hemisection model of SCI into neurons, oligodendrocytes and astrocytes. PMID:25346848

  6. Association of copy numbers of survival motor neuron gene 2 and neuronal apoptosis inhibitory protein gene with the natural history in a Chinese spinal muscular atrophy cohort.

    PubMed

    Qu, Yu-jin; Ge, Xiu-shan; Bai, Jin-li; Wang, Li-wen; Cao, Yan-yan; Lu, Yan-yu; Jin, Yu-wei; Wang, Hong; Song, Fang

    2015-03-01

    We evaluated survival motor neuron 2 (SMN2) and neuronal apoptosis inhibitory protein (NAIP) gene copy distribution and the association of copy number with survival in 232 Chinese spinal muscular atrophy (SMA) patients. The SMN2 and NAIP copy numbers correlated positively with the median onset age (r = 0.72 and 0.377). The risk of death for patients with fewer copies of SMN2 or NAIP was much higher than for those with more copies (P < .01). The survival probabilities at 5 years were 5.1%, 90.7%, and 100% for 2, 3, and 4 SMN2 copies and 27.9%, 66.7%, and 87.2% for 0, 1, and 2 NAIP copies, respectively. Our results indicated that combined SMN1-SMN2-NAIP genotypes with fewer copies were associated with earlier onset age and poorer survival probability. Better survival status for Chinese type I SMA might due to a higher proportion of 3 SMN2 and a lower rate of zero NAIP. PMID:25330799

  7. Association of copy numbers of survival motor neuron gene 2 and neuronal apoptosis inhibitory protein gene with the natural history in a Chinese spinal muscular atrophy cohort.

    PubMed

    Qu, Yu-jin; Ge, Xiu-shan; Bai, Jin-li; Wang, Li-wen; Cao, Yan-yan; Lu, Yan-yu; Jin, Yu-wei; Wang, Hong; Song, Fang

    2015-03-01

    We evaluated survival motor neuron 2 (SMN2) and neuronal apoptosis inhibitory protein (NAIP) gene copy distribution and the association of copy number with survival in 232 Chinese spinal muscular atrophy (SMA) patients. The SMN2 and NAIP copy numbers correlated positively with the median onset age (r = 0.72 and 0.377). The risk of death for patients with fewer copies of SMN2 or NAIP was much higher than for those with more copies (P < .01). The survival probabilities at 5 years were 5.1%, 90.7%, and 100% for 2, 3, and 4 SMN2 copies and 27.9%, 66.7%, and 87.2% for 0, 1, and 2 NAIP copies, respectively. Our results indicated that combined SMN1-SMN2-NAIP genotypes with fewer copies were associated with earlier onset age and poorer survival probability. Better survival status for Chinese type I SMA might due to a higher proportion of 3 SMN2 and a lower rate of zero NAIP.

  8. Spinal muscular atrophy, John Griffin, and mentorship.

    PubMed

    Sumner, Charlotte J

    2012-12-01

    Hereditary canine spinal muscular atrophy is an inherited motor neuron disease that occurs in Brittany Spaniels and has remarkable similarities with human spinal muscular atrophy. Both disorders are characterized by proximal limb and truncal muscle weakness of variable severity. Detailed pathological studies indicate that there is early dysfunction of motor neuron synapses, particularly the neuromuscular junction synapse, prior to motor neuron death. This period of synaptic dysfunction may define a critical window of opportunity for disease reversibility in motor neuron disease.

  9. Spinal fusion

    MedlinePlus

    ... Anterior spinal fusion; Spine surgery - spinal fusion; Low back pain - fusion; Herniated disk - fusion ... If you had chronic back pain before surgery, you will likely still have some pain afterward. Spinal fusion is unlikely to take away all your pain ...

  10. Spinal injury

    MedlinePlus

    ... head. Alternative Names Spinal cord injury; SCI Images Skeletal spine Vertebra, cervical (neck) Vertebra, lumbar (low back) Vertebra, thoracic (mid back) Vertebral column Central nervous system Spinal cord injury Spinal anatomy Two person roll - ...

  11. Dense transient receptor potential cation channel, vanilloid family, type 2 (TRPV2) immunoreactivity defines a subset of motoneurons in the dorsal lateral nucleus of the spinal cord, the nucleus ambiguus and the trigeminal motor nucleus in rat.

    PubMed

    Lewinter, R D; Scherrer, G; Basbaum, A I

    2008-01-01

    The transient receptor potential cation channel, vanilloid family, type 2 (TRPV2) is a member of the TRPV family of proteins and is a homologue of the capsaicin/vanilloid receptor (transient receptor potential cation channel, vanilloid family, type 1, TRPV1). Like TRPV1, TRPV2 is expressed in a subset of dorsal root ganglia (DRG) neurons that project to superficial laminae of the spinal cord dorsal horn. Because noxious heat (>52 degrees C) activates TRPV2 in transfected cells this channel has been implicated in the processing of high intensity thermal pain messages in vivo. In contrast to TRPV1, however, which is restricted to small diameter DRG neurons, there is significant TRPV2 immunoreactivity in a variety of CNS regions. The present report focuses on a subset of neurons in the brainstem and spinal cord of the rat including the dorsal lateral nucleus (DLN) of the spinal cord, the nucleus ambiguus, and the motor trigeminal nucleus. Double label immunocytochemistry with markers of motoneurons, combined with retrograde labeling, established that these cells are, in fact, motoneurons. With the exception of their smaller diameter, these cells did not differ from other motoneurons, which are only lightly TRPV2-immunoreactive. As for the majority of DLN neurons, the densely-labeled populations co-express androgen receptor and follow normal DLN ontogeny. The functional significance of the very intense TRPV2 expression in these three distinct spinal cord and brainstem motoneurons groups remains to be determined.

  12. Changes in the Expression of FUS/TLS in Spinal Cords of SOD1 G93A Transgenic Mice and Correlation with Motor-Neuron Degeneration

    PubMed Central

    Li, Jiao; Lu, Yi; Liang, Huiting; Tang, Chunyan; Zhu, Lei; Zhang, Jie; Xu, Renshi

    2016-01-01

    In order to searching the possible pathogenesis of amyotrophic lateral sclerosis (ALS), we examined the expression and distribution of FUS/TLS protein in the different anatomic regions, segments and neural cells of adult spinal cord at the different stages of the SOD1 wild-type and G93A transgenic mice using the fluorescent immunohistochemistry. Result revealed that, in the SOD1 wild-type mice, the FUS/TLS expression almost wasn't detected. However, in the SOD1 G93A mice, the FUS/TLS expression in the white matter was significantly more than that in the gray matter. In the white matter, the FUS/TLS expression in the anterior funiculus was more than that in the lateral funiculus more than that in the posterior funiculus. In the gray matter, the FUS/TLS expression in the ventral horn was more than that surrounding the central canal more than that in the dorsal horn. The FUS/TLS expression in the thoracic segment was more than that in the cervical segment more than that in the lumbar segment. Almost all FUS/TLS expressed in the nuclear of the GFAP positive cell at the onset stage, but it expressed in both the nuclear and the cytoplasm of the GFAP positive cell at the progression stage, almost didn't detected FUS/TLS expression in the NeuN and Oligo positive cells. The FUS/TLS expression was positively correlated with the neuron death. Our data suggested that the expressive increase and mislocalization of FUS/TLS in the astrocyte cell might cause the motor neuron degenerative death in the SOD1 G93A transgenic mice. PMID:27766033

  13. The Cerebellum in Maintenance of a Motor Skill: A Hierarchy of Brain and Spinal Cord Plasticity Underlies H-Reflex Conditioning

    ERIC Educational Resources Information Center

    Wolpaw, Jonathan R.; Chen, Xiang Yang

    2006-01-01

    Operant conditioning of the H-reflex, the electrical analog of the spinal stretch reflex, is a simple model of skill acquisition and involves plasticity in the spinal cord. Previous work showed that the cerebellum is essential for down-conditioning the H-reflex. This study asks whether the cerebellum is also essential for maintaining…

  14. Retraining the injured spinal cord

    NASA Technical Reports Server (NTRS)

    Edgerton, V. R.; Leon, R. D.; Harkema, S. J.; Hodgson, J. A.; London, N.; Reinkensmeyer, D. J.; Roy, R. R.; Talmadge, R. J.; Tillakaratne, N. J.; Timoszyk, W.; Tobin, A.

    2001-01-01

    The present review presents a series of concepts that may be useful in developing rehabilitative strategies to enhance recovery of posture and locomotion following spinal cord injury. First, the loss of supraspinal input results in a marked change in the functional efficacy of the remaining synapses and neurons of intraspinal and peripheral afferent (dorsal root ganglion) origin. Second, following a complete transection the lumbrosacral spinal cord can recover greater levels of motor performance if it has been exposed to the afferent and intraspinal activation patterns that are associated with standing and stepping. Third, the spinal cord can more readily reacquire the ability to stand and step following spinal cord transection with repetitive exposure to standing and stepping. Fourth, robotic assistive devices can be used to guide the kinematics of the limbs and thus expose the spinal cord to the new normal activity patterns associated with a particular motor task following spinal cord injury. In addition, such robotic assistive devices can provide immediate quantification of the limb kinematics. Fifth, the behavioural and physiological effects of spinal cord transection are reflected in adaptations in most, if not all, neurotransmitter systems in the lumbosacral spinal cord. Evidence is presented that both the GABAergic and glycinergic inhibitory systems are up-regulated following complete spinal cord transection and that step training results in some aspects of these transmitter systems being down-regulated towards control levels. These concepts and observations demonstrate that (a) the spinal cord can interpret complex afferent information and generate the appropriate motor task; and (b) motor ability can be defined to a large degree by training.

  15. Neurocontrol of Movement in Humans With Spinal Cord Injury.

    PubMed

    Dimitrijevic, Milan R; Danner, Simon M; Mayr, Winfried

    2015-10-01

    In this review of neurocontrol of movement after spinal cord injury, we discuss neurophysiological evidences of conducting and processing mechanisms of the spinal cord. We illustrate that external afferent inputs to the spinal cord below the level of the lesion can modify, initiate, and maintain execution of movement in absence or partial presence of brain motor control after chronic spinal cord injury. We review significant differences between spinal reflex activity elicited by single and repetitive stimulation. The spinal cord can respond with sensitization, habituation, and dis-habituation to regular repetitive stimulation. Therefore, repetitive spinal cord reflex activity can contribute to the functional configuration of the spinal network. Moreover, testing spinal reflex activity in individuals with motor complete spinal cord injury provided evidences for subclinical residual brain influence, suggesting the existence of axons traversing the injury site and influencing the activities below the level of lesion. Thus, there are two motor control models of chronic spinal cord injury in humans: "discomplete" and "reduced and altered volitional motor control." We outline accomplishments in modification and initiation of altered neurocontrol in chronic spinal cord injury people with epidural and functional electrical stimulation. By nonpatterned electrical stimulation of lumbar posterior roots, it is possible to evoke bilateral extension as well as rhythmic motor outputs. Epidural stimulation during treadmill stepping shows increased and/or modified motor activity. Finally, volitional efforts can alter epidurally induced rhythmic activities in incomplete spinal cord injury. Overall, we highlight that upper motor neuron paralysis does not entail complete absence of connectivity between cortex, brain stem, and spinal motor cells, but there can be altered anatomy and corresponding neurophysiological characteristics. With specific input to the spinal cord below the level

  16. Quantitative Evaluation of 3D Mouse Behaviors and Motor Function in the Open-Field after Spinal Cord Injury Using Markerless Motion Tracking

    PubMed Central

    Sheets, Alison L.; Lai, Po-Lun; Fisher, Lesley C.; Basso, D. Michele

    2013-01-01

    Thousands of scientists strive to identify cellular mechanisms that could lead to breakthroughs in developing ameliorative treatments for debilitating neural and muscular conditions such as spinal cord injury (SCI). Most studies use rodent models to test hypotheses, and these are all limited by the methods available to evaluate animal motor function. This study’s goal was to develop a behavioral and locomotor assessment system in a murine model of SCI that enables quantitative kinematic measurements to be made automatically in the open-field by applying markerless motion tracking approaches. Three-dimensional movements of eight naïve, five mild, five moderate, and four severe SCI mice were recorded using 10 cameras (100 Hz). Background subtraction was used in each video frame to identify the animal’s silhouette, and the 3D shape at each time was reconstructed using shape-from-silhouette. The reconstructed volume was divided into front and back halves using k-means clustering. The animal’s front Center of Volume (CoV) height and whole-body CoV speed were calculated and used to automatically classify animal behaviors including directed locomotion, exploratory locomotion, meandering, standing, and rearing. More detailed analyses of CoV height, speed, and lateral deviation during directed locomotion revealed behavioral differences and functional impairments in animals with mild, moderate, and severe SCI when compared with naïve animals. Naïve animals displayed the widest variety of behaviors including rearing and crossing the center of the open-field, the fastest speeds, and tallest rear CoV heights. SCI reduced the range of behaviors, and decreased speed (r = .70 p<.005) and rear CoV height (r = .65 p<.01) were significantly correlated with greater lesion size. This markerless tracking approach is a first step toward fundamentally changing how rodent movement studies are conducted. By providing scientists with sensitive, quantitative measurement

  17. Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: New insights into molecular mechanisms responsible for the disease

    SciTech Connect

    Hahnen, E.; Schoenling, J.; Zerres, K.

    1996-11-01

    Spinal muscular atrophy (SMA) is a frequent autosomal recessive neurodegenerative disorder leading to weakness and atrophy of voluntary muscles. The survival motor-neuron gene (SMN), a strong candidate for SMA, is present in two highly homologous copies (telSMN and cenSMN) within the SMA region. Only five nucleotide differences within the region between intron 6 and exon 8 distinguish these homologues. Independent of the severity of the disease, 90%-98% of all SMA patients carry homozygous deletions in telSMN, affecting either exon 7 or both exons 7 and 8. We present the molecular analysis of 42 SMA patients who carry homozygous deletions of telSMN exon 7 but not of exon 8. The question arises whether in these cases the telSMN is truncated upstream of exon 8 or whether hybrid SMN genes exist that are composed of centromeric and telomeric sequences. By a simple PCR-based assay we demonstrate that in each case the remaining telSMN exon 8 is part of a hybrid SMN gene. Sequencing of cloned hybrid SMN genes from seven patients revealed the same composition in all but two patients: the base-pair differences in introns 6 and 7 and exon 7 are of centromeric origin whereas exon 8 is of telomeric origin. Nonetheless, haplotype analysis with polymorphic multicopy markers, Ag1-CA and C212, localized at the 5{prime} end of the SMN genes, suggests different mechanisms of occurrence, unequal rearrangements, and gene conversion involving both copies of the SMN genes. In approximately half of all patients, we identified a consensus haplotype, suggesting a common origin. Interestingly, we identified a putative recombination hot spot represented by recombination-simulating elements (TGGGG and TGAGGT) in exon 8 that is homologous to the human deletion-hot spot consensus sequence in the immunoglobulin switch region, the {alpha}-globin cluster, and the polymerase {alpha} arrest sites. This may explain why independent hybrid SMN genes show identical sequences. 35 refs., 4 figs., 1 tab.

  18. Muscles in a mouse model of spinal muscular atrophy show profound defects in neuromuscular development even in the absence of failure in neuromuscular transmission or loss of motor neurons

    PubMed Central

    Lee, Young il; Mikesh, Michelle; Smith, Ian; Rimer, Mendell; Thompson, Wesley

    2011-01-01

    A mouse model of the devastating human disease "spinal muscular atrophy" (SMA) was used to investigate the severe muscle weakness and spasticity that precedes the death of these animals near the end of the 2nd postnatal week. Counts of motor units to the soleus muscle as well as of axons in the soleus muscle nerve showed no loss of motor neurons. Similarly, neither immunostaining of neuromuscular junctions nor the measurement of the tension generated by nerve stimulation gave evidence of any significant impairment in neuromuscular transmission, even when animals were maintained up to 5 days longer via a supplementary diet. However, the muscles were clearly weaker, generating less than half their normal tension. Weakness in 3 muscles examined in the study appears due to a severe but uniform reduction in muscle fiber size. The size reduction results from a failure of muscle fibers to grow during early postnatal development and, in soleus, to a reduction in number of fibers generated. Neuromuscular development is severely delayed in these mutant animals: expression of myosin heavy chain isoforms, the elimination of polyneuronal innervation, the maturation in the shape of the AChR plaque, the arrival of SCs at the junctions and their coverage of the nerve terminal, the development of junctional folds. Thus, if SMA in this particular mouse is a disease of motor neurons, it can act in a manner that does not result in their death or disconnection from their targets but nonetheless alters many aspects of neuromuscular development. PMID:21658376

  19. Muscles in a mouse model of spinal muscular atrophy show profound defects in neuromuscular development even in the absence of failure in neuromuscular transmission or loss of motor neurons.

    PubMed

    Lee, Young Il; Mikesh, Michelle; Smith, Ian; Rimer, Mendell; Thompson, Wesley

    2011-08-15

    A mouse model of the devastating human disease "spinal muscular atrophy" (SMA) was used to investigate the severe muscle weakness and spasticity that precede the death of these animals near the end of the 2nd postnatal week. Counts of motor units to the soleus muscle as well as of axons in the soleus muscle nerve showed no loss of motor neurons. Similarly, neither immunostaining of neuromuscular junctions nor the measurement of the tension generated by nerve stimulation gave evidence of any significant impairment in neuromuscular transmission, even when animals were maintained up to 5days longer via a supplementary diet. However, the muscles were clearly weaker, generating less than half their normal tension. Weakness in 3 muscles examined in the study appears due to a severe but uniform reduction in muscle fiber size. The size reduction results from a failure of muscle fibers to grow during early postnatal development and, in soleus, to a reduction in number of fibers generated. Neuromuscular development is severely delayed in these mutant animals: expression of myosin heavy chain isoforms, the elimination of polyneuronal innervation, the maturation in the shape of the AChR plaque, the arrival of SCs at the junctions and their coverage of the nerve terminal, the development of junctional folds. Thus, if SMA in this particular mouse is a disease of motor neurons, it can act in a manner that does not result in their death or disconnection from their targets but nonetheless alters many aspects of neuromuscular development.

  20. Effect of high-frequency repetitive transcranial magnetic stimulation on motor cortical excitability and sensory nerve conduction velocity in subacute-stage incomplete spinal cord injury patients.

    PubMed

    Cha, Hyun Gyu; Ji, Sang-Goo; Kim, Myoung-Kwon

    2016-07-01

    [Purpose] The aim of the present study was to determine whether repetitive transcranial magnetic stimulation can improve sensory recovery of the lower extremities in subacute-stage spinal cord injury patients. [Subjects and Methods] This study was conducted on 20 subjects with diagnosed paraplegia due to spinal cord injury. These 20 subjects were allocated to an experimental group of 10 subjects that underwent active repetitive transcranial magnetic stimulation or to a control group of 10 subjects that underwent sham repetitive transcranial magnetic stimulation. The SCI patients in the experimental group underwent active repetitive transcranial magnetic stimulation and conventional rehabilitation therapy, whereas the spinal cord injury patients in the control group underwent sham repetitive transcranial magnetic stimulation and conventional rehabilitation therapy. Participants in both groups received therapy five days per week for six-weeks. Latency, amplitude, and sensory nerve conduction velocity were assessed before and after the six week therapy period. [Results] A significant intergroup difference was observed for posttreatment velocity gains, but no significant intergroup difference was observed for amplitude or latency. [Conclusion] repetitive transcranial magnetic stimulation may be improve sensory recovery of the lower extremities in subacute-stage spinal cord injury patients. PMID:27512251

  1. Effect of high-frequency repetitive transcranial magnetic stimulation on motor cortical excitability and sensory nerve conduction velocity in subacute-stage incomplete spinal cord injury patients

    PubMed Central

    Cha, Hyun Gyu; Ji, Sang-Goo; Kim, Myoung-Kwon

    2016-01-01

    [Purpose] The aim of the present study was to determine whether repetitive transcranial magnetic stimulation can improve sensory recovery of the lower extremities in subacute-stage spinal cord injury patients. [Subjects and Methods] This study was conducted on 20 subjects with diagnosed paraplegia due to spinal cord injury. These 20 subjects were allocated to an experimental group of 10 subjects that underwent active repetitive transcranial magnetic stimulation or to a control group of 10 subjects that underwent sham repetitive transcranial magnetic stimulation. The SCI patients in the experimental group underwent active repetitive transcranial magnetic stimulation and conventional rehabilitation therapy, whereas the spinal cord injury patients in the control group underwent sham repetitive transcranial magnetic stimulation and conventional rehabilitation therapy. Participants in both groups received therapy five days per week for six-weeks. Latency, amplitude, and sensory nerve conduction velocity were assessed before and after the six week therapy period. [Results] A significant intergroup difference was observed for posttreatment velocity gains, but no significant intergroup difference was observed for amplitude or latency. [Conclusion] repetitive transcranial magnetic stimulation may be improve sensory recovery of the lower extremities in subacute-stage spinal cord injury patients. PMID:27512251

  2. Intraoperative neurophysiological monitoring in spinal surgery

    PubMed Central

    Park, Jong-Hwa; Hyun, Seung-Jae

    2015-01-01

    Recently, many surgeons have been using intraoperative neurophysiological monitoring (IOM) in spinal surgery to reduce the incidence of postoperative neurological complications, including level of the spinal cord, cauda equina and nerve root. Several established technologies are available and combined motor and somatosensory evoked potentials are considered mandatory for practical and successful IOM. Spinal cord evoked potentials are elicited compound potentials recorded over the spinal cord. Electrical stimulation is provoked on the dorsal spinal cord from an epidural electrode. Somatosensory evoked potentials assess the functional integrity of sensory pathways from the peripheral nerve through the dorsal column and to the sensory cortex. For identification of the physiological midline, the dorsal column mapping technique can be used. It is helpful for reducing the postoperative morbidity associated with dorsal column dysfunction when distortion of the normal spinal cord anatomy caused by an intramedullary cord lesion results in confusion in localizing the midline for the myelotomy. Motor evoked potentials (MEPs) consist of spinal, neurogenic and muscle MEPs. MEPs allow selective and specific assessment of the functional integrity of descending motor pathways, from the motor cortex to peripheral muscles. Spinal surgeons should understand the concept of the monitoring techniques and interpret monitoring records adequately to use IOM for the decision making during the surgery for safe surgery and a favorable surgical outcome. PMID:26380823

  3. Spinal Cord Stimulation and Augmentative Control Strategies for Leg Movement after Spinal Paralysis in Humans.

    PubMed

    Minassian, Karen; Hofstoetter, Ursula S

    2016-04-01

    Severe spinal cord injury is a devastating condition, tearing apart long white matter tracts and causing paralysis and disability of body functions below the lesion. But caudal to most injuries, the majority of neurons forming the distributed propriospinal system, the localized gray matter spinal interneuronal circuitry, and spinal motoneuron populations are spared. Epidural spinal cord stimulation can gain access to this neural circuitry. This review focuses on the capability of the human lumbar spinal cord to generate stereotyped motor output underlying standing and stepping, as well as full weight-bearing standing and rhythmic muscle activation during assisted treadmill stepping in paralyzed individuals in response to spinal cord stimulation. By enhancing the excitability state of the spinal circuitry, the stimulation can have an enabling effect upon otherwise "silent" translesional volitional motor control. Strategies for achieving functional movement in patients with severe injuries based on minimal translesional intentional control, task-specific proprioceptive feedback, and next-generation spinal cord stimulation systems will be reviewed. The role of spinal cord stimulation can go well beyond the immediate generation of motor output. With recently developed training paradigms, it can become a major rehabilitation approach in spinal cord injury for augmenting and steering trans- and sublesional plasticity for lasting therapeutic benefits.

  4. Spinal brucellosis.

    PubMed

    Tali, E Turgut; Koc, A Murat; Oner, A Yusuf

    2015-05-01

    Spinal involvement in human brucellosis is a common condition and a significant cause of morbidity and mortality, particularly in endemic areas, because it is often associated with therapeutic failure. Most chronic brucellosis cases are the result of inadequate treatment of the initial episode. Recognition of spinal brucellosis is challenging. Early diagnosis is important to ensure proper treatment and decrease morbidity and mortality. Radiologic evaluation has gained importance in diagnosis and treatment planning, including interventional procedures and monitoring of all spinal infections.

  5. The Levels and Duration of Sensory and Motor Blockades of Spinal Anesthesia in Obese Patients That Underwent Urological Operations in the Lithotomy Position

    PubMed Central

    Ciftci, Taner; Yavasca, Hatice Pınar; İnal, Volkan

    2015-01-01

    Obesity has a significant effect on the cephalic spread of a spinal block (SB) due to a reduction in cerebrospinal fluid (CSF). SB is controlled by the tissue blood flow in addition to the CSF. Some positions and techniques of surgery used can cause changes in hemodynamics. We investigated effects of hemodynamic changes that may occur during Transurethral prostate resection (TUR-P) and lithotomy position (LP) at the SB level in obese versus nonobese individuals. Sixty patients who had undergone TUR-P operation under spinal anesthesia were divided into a nonobese (BMI < 25 kg/m2, Group N) or obese (BMI ≥ 30 kg/m2, Group O) group. SB assessments were recorded afterthe LP. SB at 6 and 120 min and the peak SB level were compared between two groups. Hemodynamics were recorded after LP. Peak and 6 min SB levels were similar between the groups, while 120 min SB levels were significantly higher for Group O (P < 0.05). Blood pressure (BP) after the LP was significantly higher for Group N (P < 0.05). LP and TUR-P increased the BP in Group N when compared to Group O. The increase in hemodynamics enhances the blood flow in the spinal cord and may form similar SB levels in nonobese patients to those in obese patients. However, SB time may be longer in obese patients. PMID:26064913

  6. Total number and size distribution of motor neurons in the spinal cord of normal and EMC-virus infected mice — a stereological study

    PubMed Central

    WEBER, UNO J.; BOCK, TROELS; BUSCHARD, KARSTEN; PAKKENBERG, BENTE

    1997-01-01

    The encephalomyocarditis virus of the diabetogenic M-strain (EMC-M) is known to cause diabetes in mice. The EMC-M virus has also been shown to cause paresis in some of the infected animals. The clinical features include an acute ascending predominantly motor paralysis, developing within days. This resembles acute idiopathic polyneuritis. The alpha motor neurons would be a possible target for the virus, so two parameters, the total number and the size distribution of motor neurons, were therefore selected for further investigation in 6 mice with neurological involvement and compared with 6 control mice. The optical fractionator method was applied for estimating the total number of motor neurons and the 3D size distribution was estimated using the rotator method in a vertical design. No difference was found in the total number of motor neurons and the size distributions were similar in the 2 groups. This design can be used as a model for the estimation of the total number of motor neurons and their size distribution in other experimental animal models. PMID:9418991

  7. Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases

    ClinicalTrials.gov

    2015-08-24

    Spinal Muscular Atrophy; Charcot-Marie-Tooth Disease; Muscular Dystrophy; Spinal Muscular Atrophy With Respiratory Distress 1; Amyotrophic Lateral Sclerosis; Motor Neuron Disease; Neuromuscular Disease; Peroneal Muscular Atrophy; Fragile X Syndrome

  8. Electrical stimulation and motor recovery.

    PubMed

    Young, Wise

    2015-01-01

    In recent years, several investigators have successfully regenerated axons in animal spinal cords without locomotor recovery. One explanation is that the animals were not trained to use the regenerated connections. Intensive locomotor training improves walking recovery after spinal cord injury (SCI) in people, and >90% of people with incomplete SCI recover walking with training. Although the optimal timing, duration, intensity, and type of locomotor training are still controversial, many investigators have reported beneficial effects of training on locomotor function. The mechanisms by which training improves recovery are not clear, but an attractive theory is available. In 1949, Donald Hebb proposed a famous rule that has been paraphrased as "neurons that fire together, wire together." This rule provided a theoretical basis for a widely accepted theory that homosynaptic and heterosynaptic activity facilitate synaptic formation and consolidation. In addition, the lumbar spinal cord has a locomotor center, called the central pattern generator (CPG), which can be activated nonspecifically with electrical stimulation or neurotransmitters to produce walking. The CPG is an obvious target to reconnect after SCI. Stimulating motor cortex, spinal cord, or peripheral nerves can modulate lumbar spinal cord excitability. Motor cortex stimulation causes long-term changes in spinal reflexes and synapses, increases sprouting of the corticospinal tract, and restores skilled forelimb function in rats. Long used to treat chronic pain, motor cortex stimuli modify lumbar spinal network excitability and improve lower extremity motor scores in humans. Similarly, epidural spinal cord stimulation has long been used to treat pain and spasticity. Subthreshold epidural stimulation reduces the threshold for locomotor activity. In 2011, Harkema et al. reported lumbosacral epidural stimulation restores motor control in chronic motor complete patients. Peripheral nerve or functional electrical

  9. Spinal reflexes in brain death.

    PubMed

    Beckmann, Yesim; Çiftçi, Yeliz; Incesu, Tülay Kurt; Seçil, Yaprak; Akhan, Galip

    2014-12-01

    Spontaneous and reflex movements have been described in brain death and these unusual movements might cause uncertainties in diagnosis. In this study we evaluated the presence of spinal reflexes in patients who fulfilled the criteria for brain death. Thirty-two (22 %) of 144 patients presented unexpected motor movements spontaneously or during examinations. These patients exhibited the following signs: undulating toe, increased deep tendon reflexes, plantar responses, Lazarus sign, flexion-withdrawal reflex, facial myokymia, neck-arm flexion, finger jerks and fasciculations. In comparison, there were no significant differences in age, sex, etiology of brain death and hemodynamic laboratory findings in patients with and without reflex motor movement. Spinal reflexes should be well recognized by physicians and it should be born in mind that brain death can be determined in the presence of spinal reflexes.

  10. Rehabilitation in spinal infection diseases.

    PubMed

    Nas, Kemal; Karakoç, Mehmet; Aydın, Abdulkadir; Öneş, Kadriye

    2015-01-18

    Spinal cord infections were the diseases defined by Hypocrite yet the absence of modern medicine and there was not a real protocol in rehabilitation although there were many aspects in surgical treatment options. The patients whether surgically or conservatively treated had a lot of neurological, motor, and sensory disturbances. Our clinic has quite experience from our previous researchs. Unfortunately, serious spinal cord infections are still present in our region. In these patients the basic rehabilitation approaches during early, pre-operation, post-operation period and in the home environment will provide significant contributions to improve the patients' sensory and motor skills, develop the balance and proriocaption, increase the independence of patients in daily living activities and minimize the assistance of other people. There is limited information in the literature related with the nature of the rehabilitation programmes to be applied for patients with spinal infections. The aim of this review is to share our clinic experience and summarise the publications about spinal infection rehabilitation. There are very few studies about the rehabilitation of spinal infections. There are still not enough studies about planning and performing rehabilitation programs in these patients. Therefore, a comprehensive rehabilitation programme during the hospitalisation and home periods is emphasised in order to provide optimal management and prevent further disability.

  11. Rehabilitation in spinal infection diseases

    PubMed Central

    Nas, Kemal; Karakoç, Mehmet; Aydın, Abdulkadir; Öneş, Kadriye

    2015-01-01

    Spinal cord infections were the diseases defined by Hypocrite yet the absence of modern medicine and there was not a real protocol in rehabilitation although there were many aspects in surgical treatment options. The patients whether surgically or conservatively treated had a lot of neurological, motor, and sensory disturbances. Our clinic has quite experience from our previous researchs. Unfortunately, serious spinal cord infections are still present in our region. In these patients the basic rehabilitation approaches during early, pre-operation, post-operation period and in the home environment will provide significant contributions to improve the patients’ sensory and motor skills, develop the balance and proriocaption, increase the independence of patients in daily living activities and minimize the assistance of other people. There is limited information in the literature related with the nature of the rehabilitation programmes to be applied for patients with spinal infections. The aim of this review is to share our clinic experience and summarise the publications about spinal infection rehabilitation. There are very few studies about the rehabilitation of spinal infections. There are still not enough studies about planning and performing rehabilitation programs in these patients. Therefore, a comprehensive rehabilitation programme during the hospitalisation and home periods is emphasised in order to provide optimal management and prevent further disability. PMID:25621205

  12. Spinal deformity.

    PubMed

    Bunnell, W P

    1986-12-01

    Spinal deformity is a relatively common disorder, particularly in teenage girls. Early detection is possible by a simple, quick visual inspection that should be a standard part of the routine examination of all preteen and teenage patients. Follow-up observation will reveal those curvatures that are progressive and permit orthotic treatment to prevent further increase in the deformity. Spinal fusion offers correction and stabilization of more severe degrees of scoliosis. PMID:3786010

  13. [Subarachnoid hematoma and spinal anesthesia].

    PubMed

    Dupeyrat, A; Dequiré, P M; Mérouani, A; Moullier, P; Eid, G

    1990-01-01

    Two cases of spinal subarachnoid haematoma occurring after spinal anaesthesia are reported. In the first case, lumbar puncture was attempted three times in a 81-year-old man; spinal anaesthesia trial was than abandoned, and the patient given a general anaesthetic. He was given prophylactic calcium heparinate soon after surgery. On the fourth day, the patient became paraparetic. Radioculography revealed a blockage between T10 and L3. Laminectomy was performed to remove the haematoma, but the patient recovered motor activity only very partially. The second case was a 67-year-old man, in whom spinal anaesthesia was easily carried out. He was also given prophylactic calcium heparinate soon after surgery. On the fourth postoperative day, pulmonary embolism was suspected. Heparin treatment was then started. Twelve hours later, lumbar and bilateral buttock pain occurred, which later spread to the neck. On the eighth day, the patient had neck stiffness and two seizures. Emergency laminectomy was carried out, which revealed a subarachnoid haematoma spreading to a level higher than T6 and below L1, with no flow of cerebrospinal fluid, and a non pulsatile spinal cord. Surgery was stopped. The patient died on the following day. Both these cases are similar to those previously reported and point out the role played by anticoagulants. Because early diagnosis of spinal cord compression is difficult, the prognosis is poor, especially in case of paraplegia. PMID:2278424

  14. Neurotrophins and spinal circuit function

    PubMed Central

    Boyce, Vanessa S.; Mendell, Lorne M.

    2014-01-01

    Work early in the last century emphasized the stereotyped activity of spinal circuits based on studies of reflexes. However, the last several decades have focused on the plasticity of these spinal circuits. These considerations began with studies of the effects of monoamines on descending and reflex circuits. In recent years new classes of compounds called growth factors that are found in peripheral nerves and the spinal cord have been shown to affect circuit behavior in the spinal cord. In this review we will focus on the effects of neurotrophins, particularly nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), on spinal circuits. We also discuss evidence that these molecules can modify functions including nociceptive behavior, motor reflexes and stepping behavior. Since these substances and their receptors are normally present in the spinal cord, they could potentially be useful in improving function in disease states and after injury. Here we review recent findings relevant to these translational issues. PMID:24926235

  15. Prediction of isometric motor tasks and effort levels based on high-density EMG in patients with incomplete spinal cord injury

    NASA Astrophysics Data System (ADS)

    Jordanić, Mislav; Rojas-Martínez, Mónica; Mañanas, Miguel Angel; Francesc Alonso, Joan

    2016-08-01

    Objective. The development of modern assistive and rehabilitation devices requires reliable and easy-to-use methods to extract neural information for control of devices. Group-specific pattern recognition identifiers are influenced by inter-subject variability. Based on high-density EMG (HD-EMG) maps, our research group has already shown that inter-subject muscle activation patterns exist in a population of healthy subjects. The aim of this paper is to analyze muscle activation patterns associated with four tasks (flexion/extension of the elbow, and supination/pronation of the forearm) at three different effort levels in a group of patients with incomplete Spinal Cord Injury (iSCI). Approach. Muscle activation patterns were evaluated by the automatic identification of these four isometric tasks along with the identification of levels of voluntary contractions. Two types of classifiers were considered in the identification: linear discriminant analysis and support vector machine. Main results. Results show that performance of classification increases when combining features extracted from intensity and spatial information of HD-EMG maps (accuracy = 97.5%). Moreover, when compared to a population with injuries at different levels, a lower variability between activation maps was obtained within a group of patients with similar injury suggesting stronger task-specific and effort-level-specific co-activation patterns, which enable better prediction results. Significance. Despite the challenge of identifying both the four tasks and the three effort levels in patients with iSCI, promising results were obtained which support the use of HD-EMG features for providing useful information regarding motion and force intention.

  16. Electrical stimulation modulates Wnt signaling and regulates genes for the motor endplate and calcium binding in muscle of rats with spinal cord transection

    PubMed Central

    2013-01-01

    Background Spinal cord injury (SCI) results in muscle atrophy and a shift of slow oxidative to fast glycolytic fibers. Electrical stimulation (ES) at least partially restores muscle mass and fiber type distribution. The objective of this study was to was to characterize the early molecular adaptations that occur in rat soleus muscle after initiating isometric resistance exercise by ES for one hour per day for 1, 3 or 7 days when ES was begun 16 weeks after SCI. Additionally, changes in mRNA levels after ES were compared with those induced in soleus at the same time points after gastrocnemius tenotomy (GA). Results ES increased expression of Hey1 and Pitx2 suggesting increased Notch and Wnt signaling, respectively, but did not normalize RCAN1.4, a measure of calcineurin/NFAT signaling, or PGC-1ß mRNA levels. ES increased PGC-1α expression but not that of slow myofibrillar genes. Microarray analysis showed that after ES, genes coding for calcium binding proteins and nicotinic acetylcholine receptors were increased, and the expression of genes involved in blood vessel formation and morphogenesis was altered. Of the 165 genes altered by ES only 16 were also differentially expressed after GA, of which 12 were altered in the same direction by ES and GA. In contrast to ES, GA induced expression of genes related to oxidative phosphorylation. Conclusions Notch and Wnt signaling may be involved in ES-induced increases in the mass of paralyzed muscle. Molecular adaptations of paralyzed soleus to resistance exercise are delayed or defective compared to normally innervated muscle. PMID:23914941

  17. Long-Term Spinal Ventral Root Reimplantation, but not Bone Marrow Mononuclear Cell Treatment, Positively Influences Ultrastructural Synapse Recovery and Motor Axonal Regrowth

    PubMed Central

    Barbizan, Roberta; Castro, Mateus V.; Ferreira Jr., Rui Seabra; Barraviera, Benedito; Oliveira, Alexandre L. R.

    2014-01-01

    We recently proposed a new surgical approach to treat ventral root avulsion, resulting in motoneuron protection. The present work combined such a surgical approach with bone marrow mononuclear cells (MC) therapy. Therefore, MC were added to the site of reimplantation. Female Lewis rats (seven weeks old) were subjected to unilateral ventral root avulsion (VRA) at L4, L5 and L6 levels and divided into the following groups (n = 5 for each group): Avulsion, sealant reimplanted roots and sealant reimplanted roots plus MC. After four weeks and 12 weeks post-surgery, the lumbar intumescences were processed by transmission electron microscopy, to analyze synaptic inputs to the repaired α motoneurons. Also, the ipsi and contralateral sciatic nerves were processed for axon counting and morphometry. The ultrastructural results indicated a significant preservation of inhibitory pre-synaptic boutons in the groups repaired with sealant alone and associated with MC therapy. Moreover, the average number of axons was higher in treated groups when compared to avulsion only. Complementary to the fiber counting, the morphometric analysis of axonal diameter and “g” ratio demonstrated that root reimplantation improved the motor component recovery. In conclusion, the data herein demonstrate that root reimplantation at the lesion site may be considered a therapeutic approach, following proximal lesions in the interface of central nervous system (CNS) and peripheral nervous system (PNS), and that MC therapy does not further improve the regenerative recovery, up to 12 weeks post lesion. PMID:25353176

  18. Long-term spinal ventral root reimplantation, but not bone marrow mononuclear cell treatment, positively influences ultrastructural synapse recovery and motor axonal regrowth.

    PubMed

    Barbizan, Roberta; Castro, Mateus V; Ferreira, Rui Seabra; Barraviera, Benedito; Oliveira, Alexandre L R

    2014-01-01

    We recently proposed a new surgical approach to treat ventral root avulsion, resulting in motoneuron protection. The present work combined such a surgical approach with bone marrow mononuclear cells (MC) therapy. Therefore, MC were added to the site of reimplantation. Female Lewis rats (seven weeks old) were subjected to unilateral ventral root avulsion (VRA) at L4, L5 and L6 levels and divided into the following groups (n = 5 for each group): Avulsion, sealant reimplanted roots and sealant reimplanted roots plus MC. After four weeks and 12 weeks post-surgery, the lumbar intumescences were processed by transmission electron microscopy, to analyze synaptic inputs to the repaired α motoneurons. Also, the ipsi and contralateral sciatic nerves were processed for axon counting and morphometry. The ultrastructural results indicated a significant preservation of inhibitory pre-synaptic boutons in the groups repaired with sealant alone and associated with MC therapy. Moreover, the average number of axons was higher in treated groups when compared to avulsion only. Complementary to the fiber counting, the morphometric analysis of axonal diameter and "g" ratio demonstrated that root reimplantation improved the motor component recovery. In conclusion, the data herein demonstrate that root reimplantation at the lesion site may be considered a therapeutic approach, following proximal lesions in the interface of central nervous system (CNS) and peripheral nervous system (PNS), and that MC therapy does not further improve the regenerative recovery, up to 12 weeks post lesion. PMID:25353176

  19. Risk of fatal rollover in utility vehicles relative to static stability.

    PubMed Central

    Robertson, L S

    1989-01-01

    The risk of fatal rollover of utility vehicles per 100,000 registered vehicles relative to cars during 1982-87 was strongly correlated to the static stability of the vehicles. Distance between the center of the tires divided by twice the height of center of gravity explained 62 per cent of the variation in fatal rollover rates where rollover was the first harmful event. Statistical controls for 20 major risk factors indicated no correlations that would deflate the correlation between stability and rollover. Low stability utility vehicles roll over more often on the road suggesting that the lateral force of turning is often the tipping force. PMID:2916715

  20. [Gene expression profile of spinal ventral horn in ALS].

    PubMed

    Yamamoto, Masahiko; Tanaka, Fumiaki; Sobue, Gen

    2007-10-01

    The causative pathomechanism of sporadic amyotrophic lateral sclerosis (ALS) is not clearly understood. Using microarray technology combined with laser-captured microdissection, gene expression profiles of degenerating spinal motor neurons as well as spinal ventral horn from autopsied patients with sporadic ALS were examined. Spinal motor neurons showed a distinct gene expression profile from the whole spinal ventral horn. Three percent of genes examined were significantly downregulated, and 1% were upregulated in motor neurons. In contrast with motor neurons, the total spinal ventral horn homogenates demonstrated 0.7% and 0.2% significant upregulation and downregulation of gene expression, respectively. Downregulated genes in motor neurons included those associated with cytoskeleton/axonal transport, transcription and cell surface antigens/receptors, such as dynactin 1 (DCTN1) and early growth response 3 (EGR3). In particular, DCTN1 was markedly downregulated in most residual motor neurons prior to the accumulation of pNF-H and ubiquitylated protein. Promoters for cell death pathway, death receptor 5 (DR5), cyclins C (CCNC) and A1 (CCNA), and caspases were upregulated, whereas cell death inhibitors, acetyl-CoA transporter (ACATN) and NF-kappaB (NFKB) were also upregulated. In terms of spinal ventral horn, the expression of genes related to cell surface antigens/receptors, transcription and cell adhesion/ECM were increased. The gene expression resulting in neurodegenerative and neuroprotective changes were both present in spinal motor neurons and ventral horn. Moreover, Inflammation-related genes, such as belonging to the cytokine family were not, however, significantly upregulated in either motor neurons or ventral horn. The sequence of motor neuron-specific gene expression changes from early DCTN1 downregulation to late CCNC upregulation in sporadic ALS can provide direct information on the genes leading to neurodegeneration and neuronal death, and are helpful

  1. Aquatic Therapy for a Child with Type III Spinal Muscular Atrophy: A Case Report

    ERIC Educational Resources Information Center

    Salem, Yasser; Gropack, Stacy Jaffee

    2010-01-01

    Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by degeneration of alpha motor neurons. This case report describes an aquatic therapy program and the outcomes for a 3-year-old girl with type III SMA. Motor skills were examined using the 88-item Gross Motor Function Measure (GMFM), the Peabody Developmental Motor Scales…

  2. Spinal Osteosarcoma

    PubMed Central

    Katonis, P.; Datsis, G.; Karantanas, A.; Kampouroglou, A.; Lianoudakis, S.; Licoudis, S.; Papoutsopoulou, E.; Alpantaki, K.

    2013-01-01

    Although osteosarcoma represents the second most common primary bone tumor, spinal involvement is rare, accounting for 3%–5% of all osteosarcomas. The most frequent symptom of osteosarcoma is pain, which appears in almost all patients, whereas more than 70% exhibit neurologic deficit. At a molecular level, it is a tumor of great genetic complexity and several genetic disorders have been associated with its appearance. Early diagnosis and careful surgical staging are the most important factors in accomplishing sufficient management. Even though overall prognosis remains poor, en-block tumor removal combined with adjuvant radiotherapy and chemotherapy is currently the treatment of choice. This paper outlines histopathological classification, epidemiology, diagnostic procedures, and current concepts of management of spinal osteosarcoma. PMID:24179411

  3. Spinal Bracing

    NASA Technical Reports Server (NTRS)

    1991-01-01

    Dr. Arthur Copes of the Copes Foundation, Baton Rouge, LA, says that 35 percent of the 50 technical reports he received from the NASA/Southern University Industrial Applications Center in Baton Rouge and the Central Industrial Applications Center, Durant, OK, were vital to the development of his Copes Scoliosis Braces, which are custom designed and feature a novel pneumatic bladder that exerts constant corrective pressure to the torso to slowly reduce or eliminate the spinal curve.

  4. Tethered Spinal Cord Syndrome

    MedlinePlus

    ... Enhancing Diversity Find People About NINDS NINDS Tethered Spinal Cord Syndrome Information Page Table of Contents (click to ... being done? Clinical Trials Organizations What is Tethered Spinal Cord Syndrome? Tethered spinal cord syndrome is a neurological ...

  5. Spinal Cord Infarction

    MedlinePlus

    ... Awards Enhancing Diversity Find People About NINDS NINDS Spinal Cord Infarction Information Page Table of Contents (click to ... Organizations Related NINDS Publications and Information What is Spinal Cord Infarction? Spinal cord infarction is a stroke either ...

  6. Spinal injury - resources

    MedlinePlus

    Resources - spinal injury ... The following organizations are good resources for information on spinal injury : National Institute of Neurological Disorders and Stroke -- www.ninds.nih.gov The National Spinal Cord Injury ...

  7. Spinal Cord Injury Map

    MedlinePlus

    ... on the severity of the injury. Tap this spinal column to see how the level of injury affects loss of function and control. Learn more about spinal cord injuries. A spinal cord injury affects the ...

  8. Spinal dysraphism.

    PubMed

    Sgouros, Spyros

    2013-09-01

    In the last decade there have been significant improvements in all the fields of management of patients with spinal dysraphism, which have increased dramatically the quality of life of these children. Prevention of spina bifida with food fortification is becoming increasingly practiced worldwide. As result, in many parts of the world the frequency of myelomeningocele has decreased. Intrauterine closure of myelomeningocele has been attempted in many institutions with variable results. While it is still at the sphere of experimental therapy, it is reasonable to anticipate progress in this field in the next decade. Antenatal MR imaging is already providing very high level of detail even before the child is born. This creates new ethical dilemmas and requires additional care, but has improved significantly the overall management of patients and their families. Further improvements are anticipated in this field. Management of neuropathic bladder has improved significantly in the last decade and is anticipated to play an increasing role in the long term follow up. Surgery for spinal cord tethering in all its forms has improved in the last decade, with far more chances of complete untethering now in comparison to 10-15 years ago, with the use of micro-neurosurgical techniques and intraoperative monitoring. It is reasonable to expect that in the next decade, intraoperative neurophysiological monitoring during spinal cord surgery will become mandatory. In the 2013 Annual Special Issue we have assembled a team of authors distinguished in their fields, who bring us up to date with all the latest developments. PMID:24013314

  9. Spinal surgery -- cervical - series (image)

    MedlinePlus

    The cervical spinal column is made up of vertebral bodies which protect the spinal cord. ... spinal nerves, trauma, and narrowing (stenosis) of the spinal column around the spinal cord. Symptoms of cervical spine ...

  10. [Non-invasive transcutaneous spinal cord stimulation facilitates locomotor activity in decerebrated and spinal cats].

    PubMed

    Musienko, P E; Bogacheva, I N; Savochin, A A; Kilimnik, V A; Gorskiĭ, O V; Nikitin, O A; Gerasimenko, Ia P

    2013-08-01

    It is known that spinal neuronal networks activated by epidural electrical stimulation (EES) can produce the stepping EMG pattern and control the locomotor behavior. At present study we showed that non-invasive transcutaneous electrical spinal cord stimulation (tESCS) applied to the lumbar-sacral enlargement can facilitate the locomotor activity in decerebrated and spinal animals. The comparison of the motor responses evoked by EES vs tESCS showed that both methods produce the locomotor patterns with close properties and similar reflex mechanisms. The data obtained suggest that tESCS is an efficient approach for investigation of the locomotor control in acute and chronic experiments as well as facilitates of the locomotor abilities after spinal cord injury. Taking to account the non-invasivity and easement of tESCS, this approach could be further implemented in clinical practice for rehabilitation of the patient with spinal cord injury.

  11. A Clinical Perspective and Definition of Spinal Cord Injury.

    PubMed

    Kretzer, Ryan M

    2016-04-01

    Spinal cord injury (SCI) can be complete or incomplete. The level of injury in SCI is defined as the most caudal segment with motor function rated at greater than or equal to 3/5, with pain and temperature preserved. The standard neurological classification of SCI provided by the American Spinal Injury Association (ASIA) assigns grades from ASIA A (complete SCI) through ASIA E (normal sensory/motor), with B, C, and D representing varying degrees of injury between these extremes. The most common causes of SCI include trauma (motor vehicle accidents, sports, violence, falls), degenerative spinal disease, vascular injury (anterior spinal artery syndrome, epidural hematoma), tumor, infection (epidural abscess), and demyelinating processes (). (SDC Figure 1, http://links.lww.com/BRS/B91)(Figure is included in full-text article.).

  12. Spinal cord lesions - The rehabilitation perspective.

    PubMed

    Faria, Filipa

    2006-02-01

    The present study provides an overview of the spinal cord injury focusing mainly on aspects related to rehabilitation. Spinal cord injury affects young people in an active phase of life, determining severe handicaps. Most of the lesions are traumatic, caused by car accidents. Until fifty years ago, the survival of individuals with spinal cord injury was very reduced and the leading cause of death was renal failure. Due to developments in medical knowledge and technical advances, the survival rates have significantly improved. The causes of death have also changed being respiratory complications, particularly pneumonia, the leading causes. Immediately after a spinal cord lesion there is a phase of spinal shock which is characterized by flaccid paralysis and bladder and bowel retention. Progressively there is a return of the spinal cord automatism with the beginning of some reflex activities. Based on neurological evaluation it is pos-sible to predict motor and functional recovery and establish the rehabilitation program. We can consider three phases on the rehabilitation program: the first while the patient is still in bed, directed to prevent or treat complications due to immobility and begin sphincters reeducation; the second phase is intended to achieve wheelchair autonomy; the last phase is training in ortostatism. The rehabilitation program also comprises sports and recreational activities, psychological and social support in order to achieve an integral of the individual with a spinal cord injury.

  13. Spinal instrumentation.

    PubMed

    Spivak, J M; Balderston, R A

    1994-03-01

    The past decade has seen a dramatic increase in the availability of spinal instrumentation devices, enabling surgeons to treat a variety of spinal disorders with improved results and lower morbidity. In each anatomic region new fixation systems exist. Improvement in fusion rates with supplemental plate fixation following anterior cervical diskectomies and reconstructions has been demonstrated; these devices can now be applied more safely than ever before. Posterior occipitocervical plating to the C-2 pedicle and C3-6 lateral masses can provide stable fixation despite incompetent posterior arch bony structures. Newer, more rigid anterior thoracolumbar instrumentation allows for correction of thoracolumbar and lumbar scoliosis along fewer levels and with better maintenance of lordosis and is also useful following anterior decompression for tumor and trauma. Segmental hook fixation of the posterior thoracolumbar spine has allowed for improved correction of deformity without increased morbidity or the need for postoperative bracing in many cases. Finally, the use of transpedicular screw fixation of the lumbosacral spine allows for excellent segmental fixation without intact posterior elements, including facet joints, and has significantly improved the fusion rate in lumbosacral fusions. PMID:8024965

  14. Motor neurons and the sense of place.

    PubMed

    Jessell, Thomas M; Sürmeli, Gülşen; Kelly, John S

    2011-11-01

    Seventy years ago George Romanes began to document the anatomical organization of the spinal motor system, uncovering a multilayered topographic plan that links the clustering and settling position of motor neurons to the spatial arrangement and biomechanical features of limb muscles. To this day, these findings have provided a structural foundation for analysis of the neural control of movement and serve as a guide for studies to explore mechanisms that direct the wiring of spinal motor circuits. In this brief essay we outline the core of Romanes's findings and place them in the context of recent studies that begin to provide insight into molecular programs that assign motor pool position and to resolve how motor neuron position shapes circuit assembly. Romanes's findings reveal how and why neuronal positioning contributes to sensory-motor connectivity and may have relevance to circuit organization in other regions of the central nervous system.

  15. Intermittent hypoxia induces functional recovery following cervical spinal injury

    PubMed Central

    Vinit, Stéphane; Lovett-Barr, Mary Rachael; Mitchell, Gordon S.

    2009-01-01

    Respiratory-related complications are the leading cause of death in spinal cord injury (SCI) patients. Few effective SCI treatments are available after therapeutic interventions are performed in the period shortly after injury (e.g. spine stabilization and prevention of further spinal damage). In this review we explore the capacity to harness endogenous spinal plasticity induced by intermittent hypoxia to optimize function of surviving (spared) neural pathways associated with breathing. Two primary questions are addressed: 1) does intermittent hypoxia induce plasticity in spinal synaptic pathways to respiratory motor neurons following experimental SCI? and 2) can this plasticity improve respiratory function? In normal rats, intermittent hypoxia induces serotonin-dependent plasticity in spinal pathways to respiratory motor neurons. Early experiments suggest that intermittent hypoxia also enhances respiratory motor output in experimental models of cervical SCI, (cervical hemisection) and that the capacity to induce functional recovery is greater with longer durations post-injury. Available evidence suggests that intermittent hypoxia-induced spinal plasticity has considerable therapeutic potential to treat respiratory insufficiency following chronic cervical spinal injury. PMID:19651247

  16. Hyperbaric oxygen therapy improves local microenvironment after spinal cord injury.

    PubMed

    Wang, Yang; Zhang, Shuquan; Luo, Min; Li, Yajun

    2014-12-15

    Clinical studies have shown that hyperbaric oxygen therapy improves motor function in patients with spinal cord injury. In the present study, we explored the mechanisms associated with the recovery of neurological function after hyperbaric oxygen therapy in a rat model of spinal cord injury. We established an acute spinal cord injury model using a modification of the free-falling object method, and treated the animals with oxygen at 0.2 MPa for 45 minutes, 4 hours after injury. The treatment was administered four times per day, for 3 days. Compared with model rats that did not receive the treatment, rats exposed to hyperbaric oxygen had fewer apoptotic cells in spinal cord tissue, lower expression levels of aquaporin 4/9 mRNA and protein, and more NF-200 positive nerve fibers. Furthermore, they had smaller spinal cord cavities, rapid recovery of somatosensory and motor evoked potentials, and notably better recovery of hindlimb motor function than model rats. Our findings indicate that hyperbaric oxygen therapy reduces apoptosis, downregulates aquaporin 4/9 mRNA and protein expression in injured spinal cord tissue, improves the local microenvironment for nerve regeneration, and protects and repairs the spinal cord after injury.

  17. Intrathecal orphenadrine elicits spinal block in the rat.

    PubMed

    Chen, Yu-Wen; Tzeng, Jann-Inn; Chen, Yu-Chung; Hung, Ching-Hsia; Wang, Jhi-Joung

    2014-11-01

    The purpose of this study was to estimate the local anesthetic effect of orphenadrine, an anti-muscarinic agent, in spinal anesthesia and its comparison with the local anesthetic lidocaine. After the rat was injected intrathecally, the spinal block of orphenadrine and lidocaine was constructed in a dosage-dependent fashion. The potency and duration of spinal anesthesia with orphenadrine were compared with that of lidocaine. Our data demonstrated that orphenadrine and lidocaine elicited dose-dependent spinal blockades on the motor function, sensory, and proprioception. On the 50% effective dose (ED50) basis, the ranks of potency in motor function, nociception, and proprioception were orphenadrine>lidocaine (P<0.01). At equipotent doses (ED25, ED50, ED75), the block duration elicited by orphenadrine was greater than that elicited by lidocaine (P<0.01). Orphenadrine, but not lidocaine, exhibited longer duration of nociceptive/sensory blockade than that of motor blockade at equipotent doses. Ineffective-dose orphenadrine as adjuvant did not enhance spinal anesthesia with lidocaine. The preclinical data revealed that orphenadrine with a more sensory-selective action over motor block exhibited more potent and longer spinal anesthesia when compared to lidocaine. PMID:25205132

  18. Vehicle Related Factors that Influence Injury Outcome in Head-On Collisions

    PubMed Central

    Blum, Jeremy J.; Scullion, Paul; Morgan, Richard M.; Digges, Kennerly; Kan, Cing-Dao; Park, Shinhee; Bae, Hanil

    2008-01-01

    This study specifically investigated a range of vehicle-related factors that are associated with a lower risk of serious or fatal injury to a belted driver in a head-on collision. This analysis investigated a range of structural characteristics, quantities that describes the physical features of a passenger vehicle, e.g., stiffness or frontal geometry. The study used a data-mining approach (classification tree algorithm) to find the most significant relationships between injury outcome and the structural variables. The algorithm was applied to 120,000 real-world, head-on collisions, from the National Highway Traffic Safety Administration’s (NHTSA’s) State Crash data files, that were linked to structural attributes derived from frontal crash tests performed as part of the USA New Car Assessment Program. As with previous literature, the analysis found that the heavier vehicles were correlated with lower injury risk to their drivers. This analysis also found a new and significant correlation between the vehicle’s stiffness and injury risk. When an airbag deployed, the vehicle’s stiffness has the most statistically significant correlation with injury risk. These results suggest that in severe collisions, lower intrusion in the occupant cabin associated with higher stiffness is at least as important to occupant protection as vehicle weight for self-protection of the occupant. Consequently, the safety community might better improve self-protection by a renewed focus on increasing vehicle stiffness in order to improve crashworthiness in head-on collisions. PMID:19026230

  19. Neuromodulation of the lumbar spinal locomotor circuit.

    PubMed

    AuYong, Nicholas; Lu, Daniel C

    2014-01-01

    The lumbar spinal cord contains the necessary circuitry to independently drive locomotor behaviors. This function is retained following spinal cord injury (SCI) and is amenable to rehabilitation. Although the effectiveness of task-specific training and pharmacologic modulation has been repeatedly demonstrated in animal studies, results from human studies are less striking. Recently, lumbar epidural stimulation (EDS) along with locomotor training was shown to restore weight-bearing function and lower-extremity voluntary control in a chronic, motor-complete human SCI subject. Related animal studies incorporating EDS as part of the therapeutic regiment are also encouraging. EDS is emerging as a promising neuromodulatory tool for SCI. PMID:24262896

  20. Neuronal control of turtle hindlimb motor rhythms.

    PubMed

    Stein, P S G

    2005-03-01

    The turtle, Trachemys scripta elegans, uses its hindlimb during the rhythmic motor behaviors of walking, swimming, and scratching. For some tasks, one or more motor strategies or forms may be produced, e.g., forward swimming or backpaddling. This review discusses experiments that reveal characteristics of the spinal neuronal networks producing these motor behaviors. Limb-movement studies show shared properties such as rhythmic alternation between hip flexion and hip extension, as well as variable properties such as the timing of knee extension in the cycle of hip movements. Motor-pattern studies show shared properties such as rhythmic alternation between hip flexor and hip extensor motor activities, as well as variable properties such as modifiable timing of knee extensor motor activity in the cycle of hip motor activity. Motor patterns also display variations such as the hip-extensor deletion of rostral scratching. Neuronal-network studies reveal mechanisms responsible for movement and motor-pattern properties. Some interneurons in the spinal cord have shared activities, e.g., each unit is active during more than one behavior, and have distinct characteristics, e.g., each unit is most excited during a specific behavior. Interneuronal recordings during variations support the concept of modular organization of central pattern generators in the spinal cord.

  1. Spinal Cord and Spinal Nerve Root Involvement (Myeloradiculopathy) in Tuberculous Meningitis

    PubMed Central

    Gupta, Rahul; Garg, Ravindra Kumar; Jain, Amita; Malhotra, Hardeep Singh; Verma, Rajesh; Sharma, Praveen Kumar

    2015-01-01

    Abstract Most of the information about spinal cord and nerve root involvement in tuberculous meningitis is available in the form of isolated case reports or case series. In this article, we evaluated the incidence, predictors, and prognostic impact of spinal cord and spinal nerve root involvement in tuberculous meningitis. In this prospective study, 71 consecutive patients of newly diagnosed tuberculous meningitis were enrolled. In addition to clinical evaluation, patients were subjected to magnetic resonance imaging (MRI) of brain and spine. Patients were followed up for at least 6 months. Out of 71 patients, 33 (46.4%) had symptoms/signs of spinal cord and spinal nerve root involvement, 22 (30.9%) of whom had symptoms/signs at enrolment. Eleven (15.4%) patients had paradoxical involvement. Paraparesis was present in 22 (31%) patients, which was of upper motor neuron type in 6 (8.4%) patients, lower motor neuron type in 10 (14%) patients, and mixed type in 6 (8.4%) patients. Quadriparesis was present in 3 (4.2%) patients. The most common finding on spinal MRI was meningeal enhancement, seen in 40 (56.3%) patients; in 22 (30.9%), enhancement was present in the lumbosacral region. Other MRI abnormalities included myelitis in 16 (22.5%), tuberculoma in 4 (5.6%), cerebrospinal fluid (CSF) loculations in 4 (5.6%), cord atrophy in 3 (4.2%), and syrinx in 2 (2.8%) patients. The significant predictor associated with myeloradiculopathy was raised CSF protein (>250 mg/dL). Myeloradiculopathy was significantly associated with poor outcome. In conclusion, spinal cord and spinal nerve root involvement in tuberculous meningitis is common. Markedly raised CSF protein is an important predictor. Patients with myeloradiculopathy have poor outcome. PMID:25621686

  2. Electrophysiological Mapping of Rat Sensorimotor Lumbosacral Spinal Networks after Complete Paralysis

    PubMed Central

    Gad, Parag; Roy, Roland R.; Choe, Jaehoon; Zhong, Hui; Nandra, Mandheeraj Singh; Tai, Y.C.; Gerasimenko, Yury; Edgerton, V. Reggie

    2015-01-01

    Stimulation of the spinal cord has been shown to have great potential for improving function after motor deficits caused by injury or pathological conditions. Using a wide range of animal models, many studies have shown that stimulation applied to the neural networks intrinsic to the spinal cord can result in a dramatic improvement of motor ability, even allowing an animal to step and stand after a complete spinal cord transection. Clinical use of this technology, however, has been slow to develop due to the invasive nature of the implantation procedures and the difficulty of ascertaining specific sites of stimulation that would provide optimal amelioration of the motor deficits. Moreover, the development of tools available to control precise stimulation chronically via biocompatible electrodes has been limited. In this paper, we outline the use of a multisite electrode array in the spinal rat model to identify and stimulate specific sites of the spinal cord to produce discrete motor behaviors in spinal rats. The results demonstrate that spinal rats can stand and step when the spinal cord is stimulated tonically via electrodes located at specific sites on the spinal cord. The quality of stepping and standing was dependent on the location of the electrodes on the spinal cord, the specific stimulation parameters, and the orientation of the cathode and anode. The spinal motor evoked potentials (sMEP) in selected muscles during standing and stepping are shown to be critical tools to study selective activation of interneuronal circuits via responses of varying latencies. The present results provide further evidence that the assessment of functional networks in the background of behaviorally relevant functional states is likely to be a physiological tool of considerable importance in developing strategies to facilitate recovery of motor function after a number of neuromotor disorders. PMID:25890138

  3. Radiosurgery of Spinal Meningiomas and Schwannomas

    PubMed Central

    Kufeld, M.; Wowra, B.; Muacevic, A.; Zausinger, Stefan; Tonn, Jörg-Christian

    2012-01-01

    Purpose of this study is to analyze local control, clinical symptoms and toxicity after image-guided radiosurgery of spinal meningiomas and schwannomas. Standard treatment of benign spinal lesions is microsurgical resection. While a few publications have reported about radiosurgery for benign spinal lesions, this is the first study analyzing the outcome of robotic radiosurgery for benign spinal tumors, treated exclusively with a non-invasive, fiducial free, single-fraction setup. Thirty-six patients with spinal meningiomas or schwannomas were treated, utilizing a robotic radiosurgery system (CyberKnife®, Accuray Inc. Sunnyvale CA), and were followed prospectively. Medical history, histology, clinical symptoms and radiographic outcome were recorded. Thirty-nine spinal lesions were treated because of tumor recurrence, remnants after microsurgery, multiple lesions, or rejection of open surgery. Median age was 45 years (range 18–80 years). Median target volume was 3.4 cm3 (range 0.2–43.4 cm3). Histology revealed 28 schwannomas and 11 meningiomas (WHO grade I). All spinal levels were affected. Median prescription dose was 14 Gray (95% C.I. 13.4–14 Gy) to the 70% isodose. After a median follow-up of 18 months (range 6–50 months) no local tumor progression was detected. 20 lesions (51%) remained stable, 19 tumors (49%) decreased in size. One patient with schwannomatosis was treated repeatedly for three new tumor locations. Pain was the initial symptom in 16 of 25 schwannoma patients, and in 3 of 11 patients with meningiomas. Pain levels decreased in 8/19 patients. All but one patient with motor deficits remained clinically stable. No myelopathic signs where found. Single-session radiosurgery for benign spinal tumors in selected patients has proven to inhibit tumor progression within the observed period without signs of early toxicity. Radiosurgery offers an additional treatment option, if microsurgery is not feasible in cases of tumor recurrence, post

  4. Spinal cord trauma

    MedlinePlus

    ... if the bones or disks have been weakened Fragments of bone (such as from broken vertebrae, which are the ... presses on the spinal cord (decompression laminectomy ) Remove bone fragments, disk fragments, or foreign objects Fuse broken spinal ...

  5. Common mechanisms of compensatory respiratory plasticity in spinal neurological disorders.

    PubMed

    Johnson, Rebecca A; Mitchell, Gordon S

    2013-11-01

    In many neurological disorders that disrupt spinal function and compromise breathing (e.g. ALS, cervical spinal injury, MS), patients often maintain ventilatory capacity well after the onset of severe CNS pathology. In progressive neurodegenerative diseases, patients ultimately reach a point where compensation is no longer possible, leading to catastrophic ventilatory failure. In this brief review, we consider evidence that common mechanisms of compensatory respiratory plasticity preserve breathing capacity in diverse clinical disorders, despite the onset of severe pathology (e.g. respiratory motor neuron denervation and/or death). We propose that a suite of mechanisms, operating at distinct sites in the respiratory control system, underlies compensatory respiratory plasticity, including: (1) increased (descending) central respiratory drive, (2) motor neuron plasticity, (3) plasticity at the neuromuscular junction or spared respiratory motor neurons, and (4) shifts in the balance from more to less severely compromised respiratory muscles. To establish this framework, we contrast three rodent models of neural dysfunction, each posing unique problems for the generation of adequate inspiratory motor output: (1) respiratory motor neuron death, (2) de- or dysmyelination of cervical spinal pathways, and (3) cervical spinal cord injury, a neuropathology with components of demyelination and motor neuron death. Through this contrast, we hope to understand the multilayered strategies used to "fight" for adequate breathing in the face of mounting pathology.

  6. Common mechanisms of compensatory respiratory plasticity in spinal neurological disorders.

    PubMed

    Johnson, Rebecca A; Mitchell, Gordon S

    2013-11-01

    In many neurological disorders that disrupt spinal function and compromise breathing (e.g. ALS, cervical spinal injury, MS), patients often maintain ventilatory capacity well after the onset of severe CNS pathology. In progressive neurodegenerative diseases, patients ultimately reach a point where compensation is no longer possible, leading to catastrophic ventilatory failure. In this brief review, we consider evidence that common mechanisms of compensatory respiratory plasticity preserve breathing capacity in diverse clinical disorders, despite the onset of severe pathology (e.g. respiratory motor neuron denervation and/or death). We propose that a suite of mechanisms, operating at distinct sites in the respiratory control system, underlies compensatory respiratory plasticity, including: (1) increased (descending) central respiratory drive, (2) motor neuron plasticity, (3) plasticity at the neuromuscular junction or spared respiratory motor neurons, and (4) shifts in the balance from more to less severely compromised respiratory muscles. To establish this framework, we contrast three rodent models of neural dysfunction, each posing unique problems for the generation of adequate inspiratory motor output: (1) respiratory motor neuron death, (2) de- or dysmyelination of cervical spinal pathways, and (3) cervical spinal cord injury, a neuropathology with components of demyelination and motor neuron death. Through this contrast, we hope to understand the multilayered strategies used to "fight" for adequate breathing in the face of mounting pathology. PMID:23727226

  7. Central motor conduction in hereditary motor and sensory neuropathy and hereditary spastic paraplegia.

    PubMed

    Cruz Martínez, A; Tejada, J

    1999-09-01

    Conduction of the central motor pathways (CMCT) by magnetic stimulation of the motor cortex (TMS) was performed in 17 patients with hereditary motor sensory neuropathy (HMSN) and 2 siblings with hereditary spastic paraplegia (HSP). CMCT was prolonged in two patients with HMSN I with associated pyramidal features and in two subjects with HMSN II without clinical pyramidal signs. CMCT may be abnormal in HMSN due to central motor pathways involvement or altered spinal excitability with increased synaptic delay. CMCT was normal in the upper limbs in patients with HSP but increased in the legs. Diagnostic yield of TMS increased in less disabled cases with HSP when selective conduction at the spinal level (C7-S1) was calculated. Abnormal spinal conduction in HSP is consistent with degeneration of the crossed corticospinal tracts at the thoracic level found in neuropathologic observations.

  8. Brain and Spinal Tumors

    MedlinePlus

    ... Awards Enhancing Diversity Find People About NINDS NINDS Brain and Spinal Tumors Information Page Synonym(s): Spinal Cord ... en Español Additional resources from MedlinePlus What are Brain and Spinal Tumors? Tumors of the brain and ...

  9. Spinal Cord Diseases

    MedlinePlus

    ... damages the vertebrae or other parts of the spine, this can also injure the spinal cord. Other spinal cord problems include Tumors Infections such as meningitis and polio Inflammatory diseases Autoimmune diseases Degenerative diseases such as amyotrophic lateral sclerosis and spinal ...

  10. Spinal Cord Injuries

    MedlinePlus

    ... your body and your brain. A spinal cord injury disrupts the signals. Spinal cord injuries usually begin with a blow that fractures or ... bone disks that make up your spine. Most injuries don't cut through your spinal cord. Instead, ...

  11. Management of Spinal Meningiomas.

    PubMed

    Ravindra, Vijay M; Schmidt, Meic H

    2016-04-01

    Spinal meningiomas are the most common spinal tumors encountered in adults, and account for 6.5% of all craniospinal tumors. The treatment for these lesions is primarily surgical, but emerging modalities may include chemotherapy and radiosurgery. In this article, the current management of spinal meningiomas and the body of literature surrounding conventional treatment is reviewed and discussed.

  12. Development of AMPA receptor and GABA B receptor-sensitive spinal hyper-reflexia after spinal air embolism in rat: a systematic neurological, electrophysiological and qualitative histopathological study

    PubMed Central

    Kakinohana, Osamu; Scadeng, Miriam; Corleto, Jose A.; Sevc, Juraj; Lukacova, Nadezda; Marsala, Martin

    2012-01-01

    Decompression sickness results from formation of bubbles in the arterial and venous system, resulting in spinal disseminated neurodegenerative changes and may clinically be presented by motor dysfunction, spinal segmental stretch hyper-reflexia (i.e., spasticity) and muscle rigidity. In our current study, we describe a rat model of spinal air embolism characterized by the development of similar spinal disseminated neurodegenerative changes and functional deficit. In addition, the anti-spastic potency of systemic AMPA receptor antagonist (NGX424) or GABA B receptor agonist (baclofen) treatment was studied. To induce spinal air embolism, animals received an intra-aortic injection of air (50–200 μl/kg). After embolism, the development of spasticity was measured using computer-controlled ankle rotation. Animals receiving 150 or 200 μl of intra-aortic air injections displayed motor dysfunction with developed spastic (50–60% of animals) or flaccid (25–35% of animals) paraplegia at 5–7 days. MRI and spinal histopathological analysis showed disseminated spinal cord infarcts in the lower thoracic to sacral spinal segments. Treatment with NGX424 or baclofen provided a potent anti-spasticity effect (i.e., stretch hyper-reflexia inhibition). This model appears to provide a valuable experimental tool to study the pathophysiology of air embolism-induced spinal injury and permits the assessment of new treatment efficacy targeted to modulate neurological symptoms resulting from spinal air embolism. PMID:22721766

  13. Muscle proprioceptive feedback and spinal networks.

    PubMed

    Windhorst, U

    2007-07-12

    This review revolves primarily around segmental feedback systems established by muscle spindle and Golgi tendon organ afferents, as well as spinal recurrent inhibition via Renshaw cells. These networks are considered as to their potential contributions to the following functions: (i) generation of anti-gravity thrust during quiet upright stance and the stance phase of locomotion; (ii) timing of locomotor phases; (iii) linearization and correction for muscle nonlinearities; (iv) compensation for muscle lever-arm variations; (v) stabilization of inherently unstable systems; (vi) compensation for muscle fatigue; (vii) synergy formation; (viii) selection of appropriate responses to perturbations; (ix) correction for intersegmental interaction forces; (x) sensory-motor transformations; (xi) plasticity and motor learning. The scope will at times extend beyond the narrow confines of spinal circuits in order to integrate them into wider contexts and concepts. PMID:17562384

  14. Biological Basis of Exercise-based Treatments: Spinal Cord Injury

    PubMed Central

    Basso, D. Michele; Hansen, Christopher N.

    2016-01-01

    Despite intensive neurorehabilitation, extensive functional recovery after spinal cord injury is unattainable for most individuals. Optimal recovery will likely depend on activity-based, task-specific training that personalizes the timing of intervention with the severity of injury. Exercise paradigms elicit both beneficial and deleterious biophysical effects after spinal cord injury. Modulating the type, intensity, complexity, and timing of training may minimize risk and induce greater recovery. This review discusses the following: (a) the biological underpinning of training paradigms that promote motor relearning and recovery, and (b) how exercise interacts with cellular cascades after spinal cord injury. Clinical implications are discussed throughout. PMID:21703584

  15. Spinal pain.

    PubMed

    Izzo, R; Popolizio, T; D'Aprile, P; Muto, M

    2015-05-01

    The spinal pain, and expecially the low back pain (LBP), represents the second cause for a medical consultation in primary care setting and a leading cause of disability worldwide [1]. LBP is more often idiopathic. It has as most frequent cause the internal disc disruption (IDD) and is referred to as discogenic pain. IDD refers to annular fissures, disc collapse and mechanical failure, with no significant modification of external disc shape, with or without endplates changes. IDD is described as a separate clinical entity in respect to disc herniation, segmental instability and degenerative disc desease (DDD). The radicular pain has as most frequent causes a disc herniation and a canal stenosis. Both discogenic and radicular pain also have either a mechanical and an inflammatory genesis. For to be richly innervated, facet joints can be a direct source of pain, while for their degenerative changes cause compression of nerve roots in lateral recesses and in the neural foramina. Degenerative instability is a common and often misdiagnosed cause of axial and radicular pain, being also a frequent indication for surgery. Acute pain tends to extinguish along with its cause, but the setting of complex processes of peripheral and central sensitization may influence its evolution in chronic pain, much more difficult to treat. The clinical assessment of pain source can be a challenge because of the complex anatomy and function of the spine; the advanced imaging methods are often not sufficient for a definitive diagnosis because similar findings could be present in either asymptomatic and symptomatic subjects: a clinical correlation is always mandatory and the therapy cannot rely uniquely upon any imaging abnormalities. Purpose of this review is to address the current concepts on the pathophysiology of discogenic, radicular, facet and dysfunctional pain, focusing on the role of the imaging in the diagnostic setting, to potentially address a correct approach also to minimally

  16. Monitoring of Motor and Somatosensory Evoked Potentials During Spine Surgery: Intraoperative Changes and Postoperative Outcomes

    PubMed Central

    2016-01-01

    Objective To evaluate whether the combination of muscle motor evoked potentials (mMEPs) and somatosensory evoked potentials (SEPs) measured during spinal surgery can predict immediate and permanent postoperative motor deficits. Methods mMEP and SEP was monitored in patients undergoing spinal surgery between November 2012 and July 2014. mMEPs were elicited by a train of transcranial electrical stimulation over the motor cortex and recorded from the upper/lower limbs. SEPs were recorded by stimulating the tibial and median nerves. Results Combined mMEP/SEP recording was successfully achieved in 190 operations. In 117 of these, mMEPs and SEPs were stable and 73 showed significant changes. In 20 cases, motor deficits in the first 48 postoperative hours were observed and 6 patients manifested permanent neurological deficits. The two potentials were monitored in a number of spinal surgeries. For surgery on spinal deformities, the sensitivity and specificity of combined mMEP/SEP monitoring were 100% and 92.4%, respectively. In the case of spinal cord tumor surgeries, sensitivity was only 50% but SEP changes were observed preceding permanent motor deficits in some cases. Conclusion Intraoperative monitoring is a useful tool in spinal surgery. For spinal deformity surgery, combined mMEP/SEP monitoring showed high sensitivity and specificity; in spinal tumor surgery, only SEP changes predicted permanent motor deficits. Therefore, mMEP, SEP, and joint monitoring may all be appropriate and beneficial for the intraoperative monitoring of spinal surgery. PMID:27446784

  17. Spinal cord contusion models.

    PubMed

    Young, Wise

    2002-01-01

    Most human spinal cord injuries involve contusions of the spinal cord. Many investigators have long used weight-drop contusion animal models to study the pathophysiology and genetic responses of spinal cord injury. All spinal cord injury therapies tested to date in clinical trial were validated in such models. In recent years, the trend has been towards use of rats for spinal cord injury studies. The MASCIS Impactor is a well-standardized rat spinal cord contusion model that produces very consistent graded spinal cord damage that linearly predicts 24-h lesion volumes, 6-week white matter sparing, and locomotor recovery in rats. All aspects of the model, including anesthesia for male and female rats, age rather than body weight criteria, and arterial blood gases were empirically selected to enhance the consistency of injury. PMID:12440371

  18. Intrathecal rimantadine induces motor, proprioceptive, and nociceptive blockades in rats.

    PubMed

    Tzeng, Jann-Inn; Wang, Jieh-Neng; Wang, Jhi-Joung; Chen, Yu-Wen; Hung, Ching-Hsia

    2016-04-01

    The purpose of the experiment was to evaluate the local anesthetic effect of rimantadine in spinal anesthesia. Rimantadine in a dose-dependent fashion was constructed after intrathecally injecting the rats with four different doses. The potency and duration of rimantadine were compared with that of the local anesthetic lidocaine at producing spinal motor, nociceptive, and proprioceptive blockades. We demonstrated that intrathecal rimantadine dose-dependently produced spinal motor, nociceptive, and proprioceptive blockades. On the 50% effective dose (ED50) basis, the ranks of potencies at inducing spinal motor, nociceptive, and proprioceptive blockades was lidocaine>rimantadine (P<0.01). Rimantadine exhibited more nociceptive block (ED50) than motor block (P<0.05). At equi-anesthetic doses (ED25, ED50, and ED75), the spinal block duration produced by rimantadine was longer than that produced by lidocaine (P<0.01). Furthermore, rimantadine (26.52μmol/kg) prolonged the nociceptive nerve block more than the motor block (P<0.001). Our preclinical data showed that rimantadine, with a more sensory-selective action over motor block, was less potent than lidocaine. Rimantadine produced longer duration in spinal anesthesia when compared with lidocaine.

  19. Development of a multi-electrode array for spinal cord epidural stimulation to facilitate stepping and standing after a complete spinal cord injury in adult rats

    PubMed Central

    2013-01-01

    Background Stimulation of the spinal cord has been shown to have great potential for improving function after motor deficits caused by injury or pathological conditions. Using a wide range of animal models, many studies have shown that stimulation applied to the neural networks intrinsic to the spinal cord can result in a dramatic improvement of motor ability, even allowing an animal to step and stand after a complete spinal cord transection. Clinical use of this technology, however, has been slow to develop due to the invasive nature of the implantation procedures, the lack of versatility in conventional stimulation technology, and the difficulty of ascertaining specific sites of stimulation that would provide optimal amelioration of the motor deficits. Moreover, the development of tools available to control precise stimulation chronically via biocompatible electrodes has been limited. In this paper, we outline the development of this technology and its use in the spinal rat model, demonstrating the ability to identify and stimulate specific sites of the spinal cord to produce discrete motor behaviors in spinal rats using this array. Methods We have designed a chronically implantable, rapidly switchable, high-density platinum based multi-electrode array that can be used to stimulate at 1–100 Hz and 1–10 V in both monopolar and bipolar configurations to examine the electrophysiological and behavioral effects of spinal cord epidural stimulation in complete spinal cord transected rats. Results In this paper, we have demonstrated the effectiveness of using high-resolution stimulation parameters in the context of improving motor recovery after a spinal cord injury. We observed that rats whose hindlimbs were paralyzed can stand and step when specific sets of electrodes of the array are stimulated tonically (40 Hz). Distinct patterns of stepping and standing were produced by stimulation of different combinations of electrodes on the array located at specific

  20. Neuromuscular interaction is required for neurotrophins-mediated locomotor recovery following treadmill training in rat spinal cord injury.

    PubMed

    Wu, Qinfeng; Cao, Yana; Dong, Chuanming; Wang, Hongxing; Wang, Qinghua; Tong, Weifeng; Li, Xiangzhe; Shan, Chunlei; Wang, Tong

    2016-01-01

    Recent results have shown that exercise training promotes the recovery of injured rat distal spinal cords, but are still unclear about the function of skeletal muscle in this process. Herein, rats with incomplete thoracic (T10) spinal cord injuries (SCI) with a dual spinal lesion model were subjected to four weeks of treadmill training and then were treated with complete spinal transection at T8. We found that treadmill training allowed the retention of hind limb motor function after incomplete SCI, even with a heavy load after complete spinal transection. Moreover, treadmill training alleviated the secondary injury in distal lumbar spinal motor neurons, and enhanced BDNF/TrkB expression in the lumbar spinal cord. To discover the influence of skeletal muscle contractile activity on motor function and gene expression, we adopted botulinum toxin A (BTX-A) to block the neuromuscular activity of the rat gastrocnemius muscle. BTX-A treatment inhibited the effects of treadmill training on motor function and BDNF/TrKB expression. These results indicated that treadmill training through the skeletal muscle-motor nerve-spinal cord retrograde pathway regulated neuralplasticity in the mammalian central nervous system, which induced the expression of related neurotrophins and promoted motor function recovery. PMID:27190721

  1. Neuromuscular interaction is required for neurotrophins-mediated locomotor recovery following treadmill training in rat spinal cord injury.

    PubMed

    Wu, Qinfeng; Cao, Yana; Dong, Chuanming; Wang, Hongxing; Wang, Qinghua; Tong, Weifeng; Li, Xiangzhe; Shan, Chunlei; Wang, Tong

    2016-01-01

    Recent results have shown that exercise training promotes the recovery of injured rat distal spinal cords, but are still unclear about the function of skeletal muscle in this process. Herein, rats with incomplete thoracic (T10) spinal cord injuries (SCI) with a dual spinal lesion model were subjected to four weeks of treadmill training and then were treated with complete spinal transection at T8. We found that treadmill training allowed the retention of hind limb motor function after incomplete SCI, even with a heavy load after complete spinal transection. Moreover, treadmill training alleviated the secondary injury in distal lumbar spinal motor neurons, and enhanced BDNF/TrkB expression in the lumbar spinal cord. To discover the influence of skeletal muscle contractile activity on motor function and gene expression, we adopted botulinum toxin A (BTX-A) to block the neuromuscular activity of the rat gastrocnemius muscle. BTX-A treatment inhibited the effects of treadmill training on motor function and BDNF/TrKB expression. These results indicated that treadmill training through the skeletal muscle-motor nerve-spinal cord retrograde pathway regulated neuralplasticity in the mammalian central nervous system, which induced the expression of related neurotrophins and promoted motor function recovery.

  2. Neuromuscular interaction is required for neurotrophins-mediated locomotor recovery following treadmill training in rat spinal cord injury

    PubMed Central

    Wu, Qinfeng; Cao, Yana; Dong, Chuanming; Wang, Hongxing; Wang, Qinghua; Tong, Weifeng; Li, Xiangzhe

    2016-01-01

    Recent results have shown that exercise training promotes the recovery of injured rat distal spinal cords, but are still unclear about the function of skeletal muscle in this process. Herein, rats with incomplete thoracic (T10) spinal cord injuries (SCI) with a dual spinal lesion model were subjected to four weeks of treadmill training and then were treated with complete spinal transection at T8. We found that treadmill training allowed the retention of hind limb motor function after incomplete SCI, even with a heavy load after complete spinal transection. Moreover, treadmill training alleviated the secondary injury in distal lumbar spinal motor neurons, and enhanced BDNF/TrkB expression in the lumbar spinal cord. To discover the influence of skeletal muscle contractile activity on motor function and gene expression, we adopted botulinum toxin A (BTX-A) to block the neuromuscular activity of the rat gastrocnemius muscle. BTX-A treatment inhibited the effects of treadmill training on motor function and BDNF/TrKB expression. These results indicated that treadmill training through the skeletal muscle-motor nerve-spinal cord retrograde pathway regulated neuralplasticity in the mammalian central nervous system, which induced the expression of related neurotrophins and promoted motor function recovery. PMID:27190721

  3. Integration of sensory, spinal, and volitional descending inputs in regulation of human locomotion.

    PubMed

    Gerasimenko, Yury; Gad, Parag; Sayenko, Dimitry; McKinney, Zach; Gorodnichev, Ruslan; Puhov, Aleksandr; Moshonkina, Tatiana; Savochin, Aleksandr; Selionov, Victor; Shigueva, Tatiana; Tomilovskaya, Elena; Kozlovskaya, Inessa; Edgerton, V Reggie

    2016-07-01

    We reported previously that both transcutaneous electrical spinal cord stimulation and direct pressure stimulation of the plantar surfaces of the feet can elicit rhythmic involuntary step-like movements in noninjured subjects with their legs in a gravity-neutral apparatus. The present experiments investigated the convergence of spinal and plantar pressure stimulation and voluntary effort in the activation of locomotor movements in uninjured subjects under full body weight support in a vertical position. For all conditions, leg movements were analyzed using electromyographic (EMG) recordings and optical motion capture of joint kinematics. Spinal cord stimulation elicited rhythmic hip and knee flexion movements accompanied by EMG bursting activity in the hamstrings of 6/6 subjects. Similarly, plantar stimulation induced bursting EMG activity in the ankle flexor and extensor muscles in 5/6 subjects. Moreover, the combination of spinal and plantar stimulation exhibited a synergistic effect in all six subjects, eliciting greater motor responses than either modality alone. While the motor responses to spinal vs. plantar stimulation seems to activate distinct but overlapping spinal neural networks, when engaged simultaneously, the stepping responses were functionally complementary. As observed during induced (involuntary) stepping, the most significant modulation of voluntary stepping occurred in response to the combination of spinal and plantar stimulation. In light of the known automaticity and plasticity of spinal networks in absence of supraspinal input, these findings support the hypothesis that spinal and plantar stimulation may be effective tools for enhancing the recovery of motor control in individuals with neurological injuries and disorders. PMID:27075538

  4. Behavioural assessment of functional recovery after spinal cord hemisection in the bonnet monkey (Macaca radiata).

    PubMed

    Suresh Babu, R; Muthusamy, R; Namasivayam, A

    2000-09-15

    In spinal cord research, current approaches to behavioural assessment often fail in defining the exact nature of motor deficits or in evaluating the return of motor behaviour from lost functions following spinal cord injury. In addition to the assessment of gross motor behaviour, it is often appropriate to use complex tests for locomotion to evaluate the masked deficits in the evaluation of functional recovery after spinal cord injury. We designed a series of sensitive quantitative tests for reflex responses and complex locomotor behaviour in the form of a combined behavioural score (CBS) to assess the recovery of function in the Bonnet monkey (Macaca radiata). Monkeys were tested for various motor/reflex components, trained to cross different complex runways, and to walk on a treadmill bipedally. The overall performance of animal's motor behaviour and the functional status of individual limb movement during bipedal locomotion was graded and scored by the CBS. Surgical hemisection was then performed on the right side of the spinal cord at the T12-L1 level. Spinal cord hemisected animals showed a significant alteration in certain reflex responses such as grasping, extension withdrawal, and placing reflexes, which persisted through 1 year of follow-up. The spinal cord hemisected animals traversed the complex locomotor runways (Narrow beam and Grid runway) with more steps and few errors, at similar levels to control animals. These observations indicate that the various motor/reflex components and bipedal locomotor behaviour of spinal cord hemisected monkeys return to control levels gradually. These results are similar to those obtained in rat models by other investigators. These results demonstrate that the basic motor strategy and the spinal pattern generator for locomotion (SPGL) in adult monkeys for the accomplishment of complex motor tasks is similar, but not identical, to that in adult rats. This suggests that the mechanisms underlying recovery are probably

  5. Neuroprotective role of neurophysiological monitoring during endovascular procedures in the spinal cord.

    PubMed

    Sala, F; Niimi, Y; Berenstein, A; Deletis, V

    2001-06-01

    The endovascular treatment of spinal vascular malformations places the spinal cord at risk for ischemia. When these procedures are performed using general anesthesia, the neurophysiological monitoring methods currently available provide the only means by which to assess the functional integrity of sensory and motor pathways. Neurophysiological monitoring allows a warning for the neuroradiologist of impending irreversible neurological damage so that action may be taken for the prompt restoration of adequate spinal cord perfusion. Muscle motor evoked potentials (mMEPs) better reflect spinal cord perfusion in the anterior spinal artery territory than do somatosensory evoked potentials (SEPs), although their use during spinal endovascular procedures remains anecdotal in the literature. In the study reported here we assessed: (1) the feasibility of intraoperative neurophysiological monitoring, (2) the role of provocative tests with Amytal and Xylocaine, and (3) the specific but complementary role played by SEPs and mMEPs, during endovascular embolization of spinal vascular malformations and tumors. The results suggest that: (1) neurophysiological monitoring is feasible during most endovascular procedures in the spine and spinal cord under general anesthesia, (2) provocative tests enhance the safety of the procedure, (3) mMEPs are more feasible than SEPs and more sensitive than SEPs to provocative tests. We strongly suggest the use of multimodal neurophysiological monitoring and provocative tests during the endovascular treatment of spinal and spinal cord vascular lesions.

  6. Spinal Muscular Atrophy

    MedlinePlus

    ... or missing gene known as the survival motor neuron gene 1 (SMN1), which is responsible for the production of a protein essential to motor neurons. Without this protein, lower motor neurons in the ...

  7. Evaluation of optimal electrode configurations for epidural spinal cord stimulation in cervical spinal cord injured rats

    PubMed Central

    Alam, Monzurul; Garcia-Alias, Guillermo; Shah, Prithvi K.; Gerasimenko, Yury; Zhong, Hui; Roy, Roland R.; Edgerton, V. Reggie

    2015-01-01

    Background Epidural spinal cord stimulation is a promising technique for modulating the level of excitability and reactivation of dormant spinal neuronal circuits after spinal cord injury (SCI). We examined the ability of chronically implanted epidural stimulation electrodes within the cervical spinal cord to (1) directly elicit spinal motor evoked potentials (sMEPs) in forelimb muscles and (2) determine whether these sMEPs can serve as a biomarker of forelimb motor function after SCI. New method We implanted EMG electrodes in forelimb muscles and epidural stimulation electrodes at C6 and C8 in adult rats. After recovering from a dorsal funiculi crush (C4), rats were tested with different stimulation configurations and current intensities to elicit sMEPs and determined forelimb grip strength. Results: sMEPs were evoked in all muscles tested and their characteristics were dependent on electrode configurations and current intensities. C6(−) stimulation elicited more robust sMEPs than stimulation at C8(−). Stimulating C6 and C8 simultaneously produced better muscle recruitment and higher grip strengths than stimulation at one site. Comparison with existing method(s) Classical method to select the most optimal stimulation configuration is to empirically test each combination individually for every subject and relate to functional improvements. This approach is impractical, requiring extensively long experimental time to determine the more effective stimulation parameters. Our proposed method is fast and physiologically sound. Conclusions Results suggest that sMEPs from forelimb muscles can be useful biomarkers for identifying optimal parameters for epidural stimulation of the cervical spinal cord after SCI. PMID:25791014

  8. Monoaminergic modulation of spinal viscero-sympathetic function in the neonatal mouse thoracic spinal cord.

    PubMed

    Zimmerman, Amanda L; Sawchuk, Michael; Hochman, Shawn

    2012-01-01

    Descending serotonergic, noradrenergic, and dopaminergic systems project diffusely to sensory, motor and autonomic spinal cord regions. Using neonatal mice, this study examined monoaminergic modulation of visceral sensory input and sympathetic preganglionic output. Whole-cell recordings from sympathetic preganglionic neurons (SPNs) in spinal cord slice demonstrated that serotonin, noradrenaline, and dopamine modulated SPN excitability. Serotonin depolarized all, while noradrenaline and dopamine depolarized most SPNs. Serotonin and noradrenaline also increased SPN current-evoked firing frequency, while both increases and decreases were seen with dopamine. In an in vitro thoracolumbar spinal cord/sympathetic chain preparation, stimulation of splanchnic nerve visceral afferents evoked reflexes and subthreshold population synaptic potentials in thoracic ventral roots that were dose-dependently depressed by the monoamines. Visceral afferent stimulation also evoked bicuculline-sensitive dorsal root potentials thought to reflect presynaptic inhibition via primary afferent depolarization. These dorsal root potentials were likewise dose-dependently depressed by the monoamines. Concomitant monoaminergic depression of population afferent synaptic transmission recorded as dorsal horn field potentials was also seen. Collectively, serotonin, norepinephrine and dopamine were shown to exert broad and comparable modulatory regulation of viscero-sympathetic function. The general facilitation of SPN efferent excitability with simultaneous depression of visceral afferent-evoked motor output suggests that descending monoaminergic systems reconfigure spinal cord autonomic function away from visceral sensory influence. Coincident monoaminergic reductions in dorsal horn responses support a multifaceted modulatory shift in the encoding of spinal visceral afferent activity. Similar monoamine-induced changes have been observed for somatic sensorimotor function, suggesting an integrative

  9. Epidemiology of spinal cord injury.

    PubMed

    Kurtzke, J F

    1977-01-01

    Accidents are the cause of some 50 deaths per 100 000 population each year in the US; some 3% of these are from traumatic spinal cord injury alone. Traumatic spinal cord injury in socioeconomically advanced countries, has a probably annual incidence rate of 3 per 100 000 population. Males are affected five times as often as females, and in the US, Negroes have twice the rates of whites. Half the cases are due to motor vehicle accidents, 1/4 to falls, and 1/10 to sports injuries. Maximal ages at risk are 15 to 34; only for cord damage due to falls do this risk differ, and here elderly are the more prone. Associated injuries are common in traumatic cord injury, and head injury and pulmonary dysfunction are frequent causes of the acute deaths in traumatic SCI which is why complete quadriplegia has a high early case-fatality ratio. Late deaths in SCI are principally the direct or indirect result of the neurogenic bladder. With treatment in comprehensive spinal cord injury centers, more than 4 of 5 traumatic SCI patients will survive ten years with an average of almost 18 years. Median survival may be almost 14 years for complete quadriplegia, 17 for complete paraplegia, 19 for incomplete quadriplegia, 20 for incomplete paraplegia and 28 for cauda equina lesions. Prevalence is likely to be some 50 per 100 000 population with about 20 per 100 000 completely paralyzed (3 quadriplegic and 19 paraplegic). Some 4 out of 5 survivors of traumatic SCI should be able to live at home and perform gainful work after such treatment. PMID:616527

  10. Human Neural Stem Cell Replacement Therapy for Amyotrophic Lateral Sclerosis by Spinal Transplantation

    PubMed Central

    Hefferan, Michael P.; Galik, Jan; Kakinohana, Osamu; Sekerkova, Gabriela; Santucci, Camila; Marsala, Silvia; Navarro, Roman; Hruska-Plochan, Marian; Johe, Karl; Feldman, Eva; Cleveland, Don W.; Marsala, Martin

    2012-01-01

    Background Mutation in the ubiquitously expressed cytoplasmic superoxide dismutase (SOD1) causes an inherited form of Amyotrophic Lateral Sclerosis (ALS). Mutant synthesis in motor neurons drives disease onset and early disease progression. Previous experimental studies have shown that spinal grafting of human fetal spinal neural stem cells (hNSCs) into the lumbar spinal cord of SOD1G93A rats leads to a moderate therapeutical effect as evidenced by local α-motoneuron sparing and extension of lifespan. The aim of the present study was to analyze the degree of therapeutical effect of hNSCs once grafted into the lumbar spinal ventral horn in presymptomatic immunosuppressed SOD1G93A rats and to assess the presence and functional integrity of the descending motor system in symptomatic SOD1G93A animals. Methods/Principal Findings Presymptomatic SOD1G93A rats (60–65 days old) received spinal lumbar injections of hNSCs. After cell grafting, disease onset, disease progression and lifespan were analyzed. In separate symptomatic SOD1G93A rats, the presence and functional conductivity of descending motor tracts (corticospinal and rubrospinal) was analyzed by spinal surface recording electrodes after electrical stimulation of the motor cortex. Silver impregnation of lumbar spinal cord sections and descending motor axon counting in plastic spinal cord sections were used to validate morphologically the integrity of descending motor tracts. Grafting of hNSCs into the lumbar spinal cord of SOD1G93A rats protected α-motoneurons in the vicinity of grafted cells, provided transient functional improvement, but offered no protection to α-motoneuron pools distant from grafted lumbar segments. Analysis of motor-evoked potentials recorded from the thoracic spinal cord of symptomatic SOD1G93A rats showed a near complete loss of descending motor tract conduction, corresponding to a significant (50–65%) loss of large caliber descending motor axons. Conclusions/Significance These data

  11. Influence of Spinal Cord Integrity on Gait Control in Human Spinal Cord Injury.

    PubMed

    Awai, Lea; Bolliger, Marc; Ferguson, Adam R; Courtine, Grégoire; Curt, Armin

    2016-07-01

    Background Clinical trials in spinal cord injury (SCI) primarily rely on simplified outcome metrics (ie, speed, distance) to obtain a global surrogate for the complex alterations of gait control. However, these assessments lack sufficient sensitivity to identify specific patterns of underlying impairment and to target more specific treatment interventions. Objective To disentangle the differential control of gait patterns following SCI beyond measures of time and distance. Methods The gait of 22 individuals with motor-incomplete SCI and 21 healthy controls was assessed using a high-resolution 3-dimensional motion tracking system and complemented by clinical and electrophysiological evaluations applying unbiased multivariate analysis. Results Motor-incomplete SCI patients showed varying degrees of spinal cord integrity (spinal conductivity) with severe limitations in walking speed and altered gait patterns. Principal component (PC) analysis applied on all the collected data uncovered robust coherence between parameters related to walking speed, distortion of intralimb coordination, and spinal cord integrity, explaining 45% of outcome variance (PC 1). Distinct from the first PC, the modulation of gait-cycle variables (step length, gait-cycle phases, cadence; PC 2) remained normal with respect to regained walking speed, whereas hip and knee ranges of motion were distinctly altered with respect to walking speed (PC 3). Conclusions In motor-incomplete SCI, distinct clusters of discretely controlled gait parameters can be discerned that refine the evaluation of gait impairment beyond outcomes of walking speed and distance. These findings are specifically different from that in other neurological disorders (stroke, Parkinson) and are more discrete at targeting and disentangling the complex effects of interventions to improve walking outcome following motor-incomplete SCI.

  12. [Spontaneous spinal epidural hematoma during pregnancy: report of a case].

    PubMed

    Hack, I; Cademartori, M S; Mamani, R S; Beltrame, C M; Cademartori, C G

    1984-03-01

    A case of spontaneous dorso- lumbar spinal epidural hematoma during pregnancy is reported. The hematoma was removed 8 hours after the onset of paraplegia, and there was no evidence of vascular malformation. The motor deficit remained unchanged post-operatively. The etiology, clinical findings and the value of early laminectomy are discussed.

  13. Spinal blockades of class I antiarrythmic drugs with bupivacaine by isobolographic analysis in rats.

    PubMed

    Chen, Yu-Wen; Chu, Chin-Chen; Chen, Yu-Chung; Leung, Yuk-Man; Wang, Jhi-Joung

    2012-10-18

    Flecainide, quinidine, and mexiletine have been shown to be sodium channel blockers and local anesthetics. The purpose of this study was to examine the interaction of the traditional local anesthetic bupivacaine with flecainide, quinidine, or mexiletine on spinal blockades. To obtain the 50% effective dose (ED(50)) of drugs, dose-dependent responses of spinal blockades of motor and sensory functions with intrathecal flecainide, quinidine, mexiletine, and bupivacaine in rats were constructed. Using a continuum of different fixed drug dose ratios, the interactions of bupivacaine with drugs (flecainide, quinidine, or mexiletine) were evaluated by an isobolographic analysis. Our resulting data showed that flecainide, quinidine, and mexiletine, as well as local anesthetic bupivacaine produced dose-dependent spinal blockades in motor function and nociception. Flecainide had the most potent spinal antinociceptive effect (P<0.01) among these three class I antiarrhythmic drugs. Co-administration of bupivacaine with flecainide, quinidine, or mexiletine displayed an additive effect on spinal blockades of motor function and nociception. We concluded that bupivacaine combined with flecainide, quinidine, or mexiletine exhibited an additive effect on spinal blockades of motor function and nociception. Using such a combination strategy to produce antinociception may potentially provide an improved therapeutic separation from myocardial toxicity occurred after spinal bupivacaine. PMID:22985507

  14. The role of propriospinal interneurons in recovery from spinal cord injury.

    PubMed

    Flynn, Jamie R; Graham, Brett A; Galea, Mary P; Callister, Robert J

    2011-04-01

    Over one hundred years ago, Sir Charles Sherrington described a population of spinal cord interneurons (INs) that connect multiple spinal cord segments and participate in complex or 'long' motor reflexes. These neurons were subsequently termed propriospinal neurons (PNs) and are known to play a crucial role in motor control and sensory processing. Recent work has shown that PNs may also be an important substrate for recovery from spinal cord injury (SCI) as they contribute to plastic reorganisation of spinal circuits. The location, inter-segmental projection pattern and sheer number of PNs mean that after SCI, a significant number of them are capable of 'bridging' an incomplete spinal cord lesion. When these properties are combined with the capacity of PNs to activate and coordinate locomotor central pattern generators (CPGs), it is clear they are ideally placed to assist locomotor recovery. Here we summarise the anatomy, organisation and function of PNs in the uninjured spinal cord, briefly outline the pathophysiology of SCI, describe how PNs contribute to recovery of motor function, and finally, we discuss the mechanisms that underlie PN plasticity. We propose there are two major challenges for PN research. The first is to learn more about ways we can promote PN plasticity and manipulate the 'hostile' micro-environment that limits regeneration in the damaged spinal cord. The second is to study the cellular/intrinsic properties of PNs to better understand their function in both the normal and injured spinal cord. This article is part of a Special Issue entitled 'Synaptic Plasticity & Interneurons'.

  15. Hyperbaric oxygen therapy combined with Schwann cell transplantation promotes spinal cord injury recovery

    PubMed Central

    Peng, Chuan-gang; Zhang, Shu-quan; Wu, Min-fei; Lv, Yang; Wu, Dan-kai; Yang, Qi; Gu, Rui

    2015-01-01

    Schwann cell transplantation and hyperbaric oxygen therapy each promote recovery from spinal cord injury, but it remains unclear whether their combination improves therapeutic results more than monotherapy. To investigate this, we used Schwann cell transplantation via the tail vein, hyperbaric oxygen therapy, or their combination, in rat models of spinal cord contusion injury. The combined treatment was more effective in improving hindlimb motor function than either treatment alone; injured spinal tissue showed a greater number of neurite-like structures in the injured spinal tissue, somatosensory and motor evoked potential latencies were notably shorter, and their amplitudes greater, after combination therapy than after monotherapy. These findings indicate that Schwann cell transplantation combined with hyperbaric oxygen therapy is more effective than either treatment alone in promoting the recovery of spinal cord in rats after injury. PMID:26604910

  16. Senegenin inhibits neuronal apoptosis after spinal cord contusion injury

    PubMed Central

    Zhang, Shu-quan; Wu, Min-fei; Gu, Rui; Liu, Jia-bei; Li, Ye; Zhu, Qing-san; Jiang, Jin-lan

    2016-01-01

    Senegenin has been shown to inhibit neuronal apoptosis, thereby exerting a neuroprotective effect. In the present study, we established a rat model of spinal cord contusion injury using the modified Allen's method. Three hours after injury, senegenin (30 mg/g) was injected into the tail vein for 3 consecutive days. Senegenin reduced the size of syringomyelic cavities, and it substantially reduced the number of apoptotic cells in the spinal cord. At the site of injury, Bax and Caspase-3 mRNA and protein levels were decreased by senegenin, while Bcl-2 mRNA and protein levels were increased. Nerve fiber density was increased in the spinal cord proximal to the brain, and hindlimb motor function and electrophysiological properties of rat hindlimb were improved. Taken together, our results suggest that senegenin exerts a neuroprotective effect by suppressing neuronal apoptosis at the site of spinal cord injury. PMID:27212931

  17. Molecular and cellular development of spinal cord locomotor circuitry

    PubMed Central

    Lu, Daniel C.; Niu, Tianyi; Alaynick, William A.

    2015-01-01

    The spinal cord of vertebrate animals is comprised of intrinsic circuits that are capable of sensing the environment and generating complex motor behaviors. There are two major perspectives for understanding the biology of this complicated structure. The first approaches the spinal cord from the point of view of function and is based on classic and ongoing research in electrophysiology, adult behavior, and spinal cord injury. The second view considers the spinal cord from a developmental perspective and is founded mostly on gene expression and gain-of-function and loss-of-function genetic experiments. Together these studies have uncovered functional classes of neurons and their lineage relationships. In this review, we summarize our knowledge of developmental classes, with an eye toward understanding the functional roles of each group. PMID:26136656

  18. Transcutaneous electrical spinal-cord stimulation in humans

    PubMed Central

    Gerasimenko, Yury; Gorodnichev, Ruslan; Moshonkina, Tatiana; Sayenko, Dimitry; Gad, Parag; Edgerton, V. Reggie

    2016-01-01

    Locomotor behavior is controlled by specific neural circuits called central pattern generators primarily located at the lumbosacral spinal cord. These locomotor-related neuronal circuits have a high level of automaticity; that is, they can produce a “stepping” movement pattern also seen on electromyography (EMG) in the absence of supraspinal and/or peripheral afferent inputs. These circuits can be modulated by epidural spinal-cord stimulation and/or pharmacological intervention. Such interventions have been used to neuromodulate the neuronal circuits in patients with motor-complete spinal-cord injury (SCI) to facilitate postural and locomotor adjustments and to regain voluntary motor control. Here, we describe a novel non-invasive stimulation strategy of painless transcutaneous electrical enabling motor control (pcEmc) to neuromodulate the physiological state of the spinal cord. The technique can facilitate a stepping performance in non-injured subjects with legs placed in a gravity-neutral position. The stepping movements were induced more effectively with multi-site than single-site spinal-cord stimulation. From these results, a multielectrode surface array technology was developed. Our preliminary data indicate that use of the multielectrode surface array can fine-tune the control of the locomotor behavior. As well, the pcEmc strategy combined with exoskeleton technology is effective for improving motor function in paralyzed patients with SCI. The potential impact of using pcEmc to neuromodulate the spinal circuitry has significant implications for furthering our understanding of the mechanisms controlling locomotion and for rehabilitating sensorimotor function even after severe SCI. PMID:26205686

  19. Developmental regulation of N-methyl-D-aspartate- and kainate-type glutamate receptor expression in the rat spinal cord

    NASA Technical Reports Server (NTRS)

    Stegenga, S. L.; Kalb, R. G.

    2001-01-01

    Spinal motor neurons undergo experience-dependent development during a critical period in early postnatal life. It has been suggested that the repertoire of glutamate receptor subunits differs between young and mature motor neurons and contributes to this activity-dependent development. In the present study we examined the expression patterns of N-methyl-D-aspartate- and kainate-type glutamate receptor subunits during the postnatal maturation of the spinal cord. Young motor neurons express much higher levels of the N-methyl-D-aspartate receptor subunit NR1 than do adult motor neurons. Although there are eight potential splice variants of NR1, only a subgroup is expressed by motor neurons. With respect to NR2 receptor subunits, young motor neurons express NR2A and C, while adult motor neurons express only NR2A. Young motor neurons express kainate receptor subunits GluR5, 6 and KA2 but we are unable to detect these or any other kainate receptor subunits in the adult spinal cord. Other spinal cord regions display a distinct pattern of developmental regulation of N-methyl-D-aspartate and kainate receptor subunit expression in comparison to motor neurons. Our findings indicate a precise spatio-temporal regulation of individual subunit expression in the developing spinal cord. Specific combinations of subunits in developing neurons influence their excitable properties and could participate in the emergence of adult neuronal form and function.

  20. Proprioceptive pathways of the spinal cord.

    PubMed Central

    Schneider, R J; Kulics, A T; Ducker, T B

    1977-01-01

    In the Macaque, surgical lesions were made in the dorsal funiculus, in the dorsolateral funiculus, and through half of the spinal cord. The somatosensory and motor capacity of the animal were examined neurologically and electrophysiologically. The exact lesion was then confirmed pathologically in detail. The results of these experiments indicate that limb position information from the distal limb and proximal limb are relayed to the brain in two different fashions. Distal limb position information, especially the cortical representation of the limbs' volar surface as it moves in space, is drastically impaired by dorsal funiculus or posterior white column lesions. Proximal limb position may or may not be impaired by similar lesions, for this information while initially in the dorsal or posterior white columns is sorted out (as it ascends in the spinal cord) to the dorsolateral funiculus or white columns. For example, in the lower thoracic spinal cord, both distal and proximal hind limb sensation are impaired by posterior white column damage; in the cervical cord, only distal sensation is impaired by the same lesion, and proximal information is spared. We refer to this neuroanatomic rearranging as "fibre sorting", and we believe that it is clinically significant in spinal cord disease. Images PMID:408463

  1. Neurological complications in adult spinal deformity surgery.

    PubMed

    Iorio, Justin A; Reid, Patrick; Kim, Han Jo

    2016-09-01

    The number of surgeries performed for adult spinal deformity (ASD) has been increasing due to an aging population, longer life expectancy, and studies supporting an improvement in health-related quality of life scores after operative intervention. However, medical and surgical complication rates remain high, and neurological complications such as spinal cord injury and motor deficits can be especially debilitating to patients. Several independent factors potentially influence the likelihood of neurological complications including surgical approach (anterior, lateral, or posterior), use of osteotomies, thoracic hyperkyphosis, spinal region, patient characteristics, and revision surgery status. The majority of ASD surgeries are performed by a posterior approach to the thoracic and/or lumbar spine, but anterior and lateral approaches are commonly performed and are associated with unique neural complications such as femoral nerve palsy and lumbar plexus injuries. Spinal morphology, such as that of hyperkyphosis, has been reported to be a risk factor for complications in addition to three-column osteotomies, which are often utilized to correct large deformities. Additionally, revision surgeries are common in ASD and these patients are at an increased risk of procedure-related complications and nervous system injury. Patient selection, surgical technique, and use of intraoperative neuromonitoring may reduce the incidence of complications and optimize outcomes. PMID:27250041

  2. Spinal subarachnoid haematoma after spinal anaesthesia: case report.

    PubMed

    Vidal, Marion; Strzelecki, Antoine; Houadec, Mireille; Krikken, Isabelle Ranz; Danielli, Antoine; Souza Neto, Edmundo Pereira de

    2016-01-01

    Subarachnoid haematoma after spinal anaesthesia is known to be very rare. In the majority of these cases, spinal anaesthesia was difficult to perform and/or unsuccessful; other risk factors included antiplatelet or anticoagulation therapy, and direct spinal cord trauma. We report a case of subarachnoid haematoma after spinal anaesthesia in a young patient without risk factors. PMID:27591468

  3. Injury alters intrinsic functional connectivity within the primate spinal cord.

    PubMed

    Chen, Li Min; Mishra, Arabinda; Yang, Pai-Feng; Wang, Feng; Gore, John C

    2015-05-12

    Recent demonstrations of correlated low-frequency MRI signal variations between subregions of the spinal cord at rest in humans, similar to those found in the brain, suggest that such resting-state functional connectivity constitutes a common feature of the intrinsic organization of the entire central nervous system. We report our detection of functional connectivity within the spinal cords of anesthetized squirrel monkeys at rest and show that the strength of connectivity within these networks is altered by the effects of injuries. By quantifying the low-frequency MRI signal correlations between different horns within spinal cord gray matter, we found distinct functional connectivity relationships between the different sensory and motor horns, a pattern that was similar to activation patterns evoked by nociceptive heat or tactile stimulation of digits. All horns within a single spinal segment were functionally connected, with the strongest connectivity occurring between ipsilateral dorsal and ventral horns. Each horn was strongly connected to the same horn on neighboring segments, but this connectivity reduced drastically along the spinal cord. Unilateral injury to the spinal cord significantly weakened the strength of the intrasegment horn-to-horn connectivity only on the injury side and in slices below the lesion. These findings suggest resting-state functional connectivity may be a useful biomarker of functional integrity in injured and recovering spinal cords. PMID:25902510

  4. Curcumin protects against ischemic spinal cord injury: The pathway effect

    PubMed Central

    Zhang, Jinhua; Wei, Hao; Lin, Meimei; Chen, Chunmei; Wang, Chunhua; Liu, Maobai

    2013-01-01

    Inducible nitric oxide synthase and N-methyl-D-aspartate receptors have been shown to participate in nerve cell injury during spinal cord ischemia. This study observed a protective effect of curcumin on ischemic spinal cord injury. Models of spinal cord ischemia were established by ligating the lumbar artery from the left renal artery to the bifurcation of the abdominal aorta. At 24 hours after model establishment, the rats were intraperitoneally injected with curcumin. Reverse transcription-polymerase chain reaction and immunohistochemical results demonstrated that after spinal cord ischemia, inducible nitric oxide synthase and N-methyl-D-aspartate receptor mRNA and protein expression significantly increased. However, curcumin significantly decreased inducible nitric oxide synthase and N-methyl-D-aspartate receptor mRNA and protein expression in the ischemic spinal cord. Tarlov scale results showed that curcumin significantly improved motor function of the rat hind limb after spinal cord ischemia. The results demonstrate that curcumin exerts a neuroprotective fect against ischemic spinal cord injury by decreasing inducible nitric oxide synthase and N-methyl-D-aspartate receptor expression. PMID:25206661

  5. Breathing patterns after mid-cervical spinal contusion in rats

    PubMed Central

    Golder, FJ; Fuller, DD; Lovett-Barr, MR; Vinit, S; Resnick, DK; Mitchell, GS

    2011-01-01

    Respiratory failure is the leading cause of death after cervical spinal injury. We hypothesized that incomplete cervical spinal injuries would alter respiratory pattern and initiate plasticity in the neural control of breathing. Further, we hypothesized that the severity of cervical spinal contusion would correlate with changes in breathing pattern. Fourteen days after C4–C5 contusions, respiratory frequency and tidal volume were measured in unanesthetized Sprague Dawley rats in a whole body plethysmograph. Phrenic motor output was monitored in the same rats which were anesthetized, vagotomized, paralyzed and ventilated to eliminate and/or control sensory feedback that could alter breathing patterns. The extent of spinal injury was approximated histologically by measurements of the injury-induced cyst area in transverse sections; cysts ranged from 2 to 28% of spinal cross-sectional area, and had a unilateral bias. In unanesthetized rats, the severity of spinal injury correlated negatively with tidal volume (R2=0.85; p<0.001) and positively with breathing frequency (R2=0.65; p<0.05). Thus, the severity of C4–C5 spinal contusion dictates post-injury breathing pattern. In anesthetized rats, phrenic burst amplitude was decreased on the side of injury, and burst frequency correlated negatively with contusion size (R2=0.51; p<0.05). A strong correlation between unanesthetized breathing pattern and the pattern of phrenic bursts in anesthetized, vagotomized and ventilated rats suggests that changes in respiratory motor output after spinal injury reflect, at least in part, intrinsic neural mechanisms of CNS plasticity initiated by injury. PMID:21683697

  6. Transplantation of placenta-derived mesenchymal stem cell-induced neural stem cells to treat spinal cord injury.

    PubMed

    Li, Zhi; Zhao, Wei; Liu, Wei; Zhou, Ye; Jia, Jingqiao; Yang, Lifeng

    2014-12-15

    Because of their strong proliferative capacity and multi-potency, placenta-derived mesenchymal stem cells have gained interest as a cell source in the field of nerve damage repair. In the present study, human placenta-derived mesenchymal stem cells were induced to differentiate into neural stem cells, which were then transplanted into the spinal cord after local spinal cord injury in rats. The motor functional recovery and pathological changes in the injured spinal cord were observed for 3 successive weeks. The results showed that human placenta-derived mesenchymal stem cells can differentiate into neuron-like cells and that induced neural stem cells contribute to the restoration of injured spinal cord without causing transplant rejection. Thus, these cells promote the recovery of motor and sensory functions in a rat model of spinal cord injury. Therefore, human placenta-derived mesenchymal stem cells may be useful as seed cells during the repair of spinal cord injury.

  7. Pharmacological activation of locomotor patterns in larval and adult frog spinal cords.

    PubMed

    McClellan, A D; Farel, P B

    1985-04-15

    The effects of amino acids, catecholamines, and their agonists shown to elicit locomotor activity in several vertebrate species were examined in spinal animals and isolated nervous systems of developing tadpoles (Rana catesbiana) and adult frogs (R. catesbiana and pipiens). Elicited activity was correlated in spinal animals by video and electromyographic analysis, and in in vitro spinal cords by recordings of tail and hindlimb motor activity. Of the agents tested, only N-methyl-DL-aspartate (NMA), an amino acid agonist, was effective in eliciting motor activity in spinal animals. In isolated nervous systems, both NMA and D-glutamate added to the bath activated locomotor activity. NMA injected i.p. into tadpoles with high spinal cord transections elicited coordinated swimming motor activity in axial and hindlimb muscles that was roughly typical for the stage of development of the animal. In late stage tadpoles (st. XX), NMA also elicited wiping and alternating or synchronous (i.e. kicking or jumping) hindlimb movements. Addition of NMA or glutamate to a bath containing an in vitro tadpole spinal cord preparation elicited ventral root motor activity characteristic of swimming, but without a rostrocaudal phase lag. Rhythmic activity thought to underlie stepping and kicking was seen in lateral ventral rootlets innervating the hindlimbs. In adult frogs with high spinal cord transections, injection of NMA elicited a general sequence of spontaneous hindlimb motor functions: reflex wiping, stepping, and kicking or jumping. Isolated frog spinal cords were not responsive to bath applied NMA, under the present conditions. The activation by amino acids or their agonists of different motor functions in both larval and adult frogs, as well as in higher and lower vertebrates, suggests a general significance of amino acid-activated receptors in the neural networks controlling locomotor function. PMID:3888346

  8. Neuromodulation of lower limb motor control in restorative neurology

    PubMed Central

    Minassian, Karen; Hofstoetter, Ursula; Tansey, Keith; Mayr, Winfried

    2012-01-01

    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. PMID:22464657

  9. Ranking and selection of motor carrier safety performance by commodity.

    PubMed

    Horrace, William C; Keane, Thomas P

    2004-11-01

    We use recent safety performance data to rank US motor carrier commodity segments (e.g., Tank segment or Produce segment) in terms of several driver-related, vehicle-related, and crash-related safety measures. Ranking and selection inference techniques are used to determine the best and worst performing commodity segments at the 95% confidence level. The results are mixed, however the Passenger segment is generally best, while the Produce, Intermodal, and Refrigerated segments tend to be worst. PMID:15350872

  10. Propofol promotes spinal cord injury repair by bone marrow mesenchymal stem cell transplantation

    PubMed Central

    Zhou, Ya-jing; Liu, Jian-min; Wei, Shu-ming; Zhang, Yun-hao; Qu, Zhen-hua; Chen, Shu-bo

    2015-01-01

    Propofol is a neuroprotective anesthetic. Whether propofol can promote spinal cord injury repair by bone marrow mesenchymal stem cells remains poorly understood. We used rats to investigate spinal cord injury repair using bone marrow mesenchymal stem cell transplantation combined with propofol administration via the tail vein. Rat spinal cord injury was clearly alleviated; a large number of newborn non-myelinated and myelinated nerve fibers appeared in the spinal cord, the numbers of CM-Dil-labeled bone marrow mesenchymal stem cells and fluorogold-labeled nerve fibers were increased and hindlimb motor function of spinal cord-injured rats was markedly improved. These improvements were more prominent in rats subjected to bone marrow mesenchymal cell transplantation combined with propofol administration than in rats receiving monotherapy. These results indicate that propofol can enhance the therapeutic effects of bone marrow mesenchymal stem cell transplantation on spinal cord injury in rats. PMID:26487860

  11. Inhibition downunder: an update from the spinal cord

    PubMed Central

    Goulding, Martyn; Bourane, Steeve; Garcia-Campany, Lidia; Dalet, Antoine; Koch, Stephanie

    2014-01-01

    Inhibitory neurons in the spinal cord perform dedicated roles in processing somatosensory information and shaping motor behaviors that range from simple protective reflexes to more complex motor tasks such as locomotion, reaching and grasping. Recent efforts examining inhibition in the spinal cord have been directed toward determining how inhibitory cell types are specified and incorporated into the sensorimotor circuitry, identifying and characterizing molecularly-defined cohorts of inhibitory neurons and interrogating the functional contribution these cells make to sensory processing and motor behaviors. Rapid progress is being made on all these fronts, driven in large part by molecular genetic and optogenetic approaches that are being creatively combined with neuroanatomical, electrophysiological and behavioral techniques. PMID:24743058

  12. Serotonin Affects Movement Gain Control in the Spinal Cord

    PubMed Central

    Glaser, Joshua I.; Deng, Linna; Thompson, Christopher K.; Stevenson, Ian H.; Wang, Qining; Hornby, Thomas George; Heckman, Charles J.; Kording, Konrad P.

    2014-01-01

    A fundamental challenge for the nervous system is to encode signals spanning many orders of magnitude with neurons of limited bandwidth. To meet this challenge, perceptual systems use gain control. However, whether the motor system uses an analogous mechanism is essentially unknown. Neuromodulators, such as serotonin, are prime candidates for gain control signals during force production. Serotonergic neurons project diffusely to motor pools, and, therefore, force production by one muscle should change the gain of others. Here we present behavioral and pharmaceutical evidence that serotonin modulates the input–output gain of motoneurons in humans. By selectively changing the efficacy of serotonin with drugs, we systematically modulated the amplitude of spinal reflexes. More importantly, force production in different limbs interacts systematically, as predicted by a spinal gain control mechanism. Psychophysics and pharmacology suggest that the motor system adopts gain control mechanisms, and serotonin is a primary driver for their implementation in force production. PMID:25232107

  13. Spinal Muscular Atrophy: Current Therapeutic Strategies

    NASA Astrophysics Data System (ADS)

    Kiselyov, Alex S.; Gurney, Mark E.

    Proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by death of motor neurons in the spinal cord. SMA is caused by deletion and/or mutation of the survival motor neuron gene (SMN1) on chromosome 5q13. There are variable numbers of copies of a second, related gene named SMN2 located in the proximity to SMN1. Both genes encode the same protein (Smn). Loss of SMN1 and incorrect splicing of SMN2 affect cellular levels of Smn triggering death of motor neurons. The severity of SMA is directly related to the normal number of copies of SMN2 carried by the patient. A considerable effort has been dedicated to identifying modalities including both biological and small molecule agents that increase SMN2 promoter activity to upregulate gene transcription and produce increased quantities of full-length Smn protein. This review summarizes recent progress in the area and suggests potential target product profile for an SMA therapeutic.

  14. Disease Mechanisms and Therapeutic Approaches in Spinal Muscular Atrophy

    PubMed Central

    Tisdale, Sarah

    2015-01-01

    Motor neuron diseases are neurological disorders characterized primarily by the degeneration of spinal motor neurons, skeletal muscle atrophy, and debilitating and often fatal motor dysfunction. Spinal muscular atrophy (SMA) is an autosomal-recessive motor neuron disease of high incidence and severity and the most common genetic cause of infant mortality. SMA is caused by homozygous mutations in the survival motor neuron 1 (SMN1) gene and retention of at least one copy of the hypomorphic gene paralog SMN2. Early studies established a loss-of-function disease mechanism involving ubiquitous SMN deficiency and suggested SMN upregulation as a possible therapeutic approach. In recent years, greater knowledge of the central role of SMN in RNA processing combined with deep characterization of animal models of SMA has significantly advanced our understanding of the cellular and molecular basis of the disease. SMA is emerging as an RNA disease not limited to motor neurons, but one that involves dysfunction of motor circuits that comprise multiple neuronal subpopulations and possibly other cell types. Advances in SMA research have also led to the development of several potential therapeutics shown to be effective in animal models of SMA that are now in clinical trials. These agents offer unprecedented promise for the treatment of this still incurable neurodegenerative disease. PMID:26063904

  15. Effect of lycopene on the blood-spinal cord barrier after spinal cord injury in mice.

    PubMed

    Zhang, Qian; Wang, Jianbo; Gu, Zhengsong; Zhang, Qing; Zheng, Hong

    2016-09-01

    The current study aimed to investigate the effect of lycopene on the blood-spinal cord barrier (BSCB) after spinal cord injury (SCI) in a mouse model. Lycopene inhibited lipid peroxidation and oxidative DNA damage as a highly efficient antioxidant and free radical scavenger. Lycopene (4 mg/kg/d) was administrated immediately following SCI. The permeability of the BSCB and water content in the spinal cord tissue were evaluated. Additionally, levels of expression of tight junction proteins and heme oxygenase-1 (HO-1) were determined with Western blotting. An enzyme-linked immunosorbent assay analysis of spinal cord tissue homogenates was performed 48 h after SCI to evaluate the expression of inflammation-related cytokines. In addition, recovery of motor function was assessed 1 d, 2 d, 5 d, 10 d, and 15 d after SCI using the Basso Mouse Scale to score locomotion. Compared to the group with an untreated SCI, mice with an SCI treated with lycopene had significantly reduced spinal cord tissue water content and BSCB permeability. Furthermore, motor function of mice with an SCI was also greatly improved by lycopene administration. The expression of the proinflammatory factors TNF-α and NF-kB increased markedly 48 h after SCI, and their upregulation was significantly attenuated by lycopene treatment. The expression of molecules that protect tight junctions, zonula occluden-1 and claudin-5, was upregulated by lycopene treatment after SCI. Taken together, these results clearly indicate that lycopene attenuated SCI by promoting repair of the damaged BSCB, so lycopene is a novel and promising treatment for SCI in humans. PMID:27357536

  16. Lower motor neuron dysfunction in ALS.

    PubMed

    de Carvalho, Mamede; Swash, Michael

    2016-07-01

    In the motor system there is a complex interplay between cortical structures and spinal cord lower motor neurons (LMN). In this system both inhibitory and excitatory neurons have relevant roles. LMN loss is a marker of motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). Conventional needle electromyography (EMG) does not allow LMN loss to be quantified. Measurement of compound muscle action potential (CMAP) amplitude or area, and the neurophysiological index, provide a surrogate estimate of the number of functional motor units. Increased motor neuronal excitability is a neurophysiological marker of ALS in the context of a suspected clinical and electrophysiological diagnosis. In the LMN system, fasciculation potentials (FPs) are the earliest changes observed in affected muscles, a feature of LMN hyperexcitability. Reinnervation is best investigated by needle EMG although other methods can be explored. Moreover needle EMG give information about the temporal profile of the reinnervation process, important ancillary data. Quantitative motor unit potential analysis is a valuable method of evaluating reinnervation. The importance of FPs has been recognized in the Awaji criteria for the electrodiagnosis of ALS, criteria that are a sensitive adjunct to the revised El Escorial criteria. Finally, functionality of LMN's, and perhaps excitability studies in motor nerves, aids understanding of the disease process, allowing measurement of potential treatment effects in clinical trials. Other investigational techniques, such as electrical impedance myography, muscle and nerve ultrasound, and spinal cord imaging methods may prove useful in future. PMID:27117334

  17. Do Not Resonate with Actions: Sentence Polarity Modulates Cortico-Spinal Excitability during Action-Related Sentence Reading

    PubMed Central

    Liuzza, Marco Tullio; Candidi, Matteo; Aglioti, Salvatore Maria

    2011-01-01

    Background Theories of embodied language suggest that the motor system is differentially called into action when processing motor-related versus abstract content words or sentences. It has been recently shown that processing negative polarity action-related sentences modulates neural activity of premotor and motor cortices. Methods and Findings We sought to determine whether reading negative polarity sentences brought about differential modulation of cortico-spinal motor excitability depending on processing hand-action related or abstract sentences. Facilitatory paired-pulses Transcranial Magnetic Stimulation (pp-TMS) was applied to the primary motor representation of the right-hand and the recorded amplitude of induced motor-evoked potentials (MEP) was used to index M1 activity during passive reading of either hand-action related or abstract content sentences presented in both negative and affirmative polarity. Results showed that the cortico-spinal excitability was affected by sentence polarity only in the hand-action related condition. Indeed, in keeping with previous TMS studies, reading positive polarity, hand action-related sentences suppressed cortico-spinal reactivity. This effect was absent when reading hand action-related negative polarity sentences. Moreover, no modulation of cortico-spinal reactivity was associated with either negative or positive polarity abstract sentences. Conclusions Our results indicate that grammatical cues prompting motor negation reduce the cortico-spinal suppression associated with affirmative action sentences reading and thus suggest that motor simulative processes underlying the embodiment may involve even syntactic features of language. PMID:21347305

  18. Distribution of Neuron Cell Bodies in the Intraspinal Portion of the Spinal Accessory Nerve in Humans.

    PubMed

    Boehm, Karl E; Kondrashov, Peter

    2016-01-01

    The spinal accessory nerve is often identified as a purely motor nerve innervating the trapezius and sternocleidomastoid muscles. Although it may contain proprioceptive neurons found in cervical spinal levels C2-C4, limited research has focused on the histology of the spinal accessory nerve. The objective of the present study was to examine the spinal accessory nerve to determine if there are neuronal cell bodies within the spinal accessory nerve in humans. Cervical spinal cords were dissected from eight cadavers that had previously been used for dissection in other body regions. The segmental rootlets were removed to quantify the neuron cell bodies present at each spinal level. Samples were embedded in paraffin; sectioned; stained with hematoxylin and eosin; and examined using a microscope at 4×, 10×, and 40× magnification. Digital photography was used to image the samples. Neuronal cell bodies were found in 100% of the specimens examined, with non-grossly visible ganglia found at spinal levels C1-C4. The C1 spinal level of the spinal accessory nerve had the highest number of neuron cell bodies.

  19. Potential associations between chronic whiplash and incomplete spinal cord injury

    PubMed Central

    Smith, Andrew C.; Parrish, Todd B.; Hoggarth, Mark A.; McPherson, Jacob G.; Tysseling, Vicki M.; Wasielewski, Marie; Kim, Hyosub E.; Hornby, T. George; Elliott, James M.

    2016-01-01

    Study Design This research utilized a cross-sectional design with control group inclusion. Objectives Preliminary evidence suggests that a portion of the patient population with chronic whiplash may have sustained spinal cord damage. Our hypothesis is that in some cases of chronic whiplash-associated disorders (WAD), observed muscle weakness in the legs will be associated with local signs of a partial spinal cord injury of the cervical spine. Setting University based laboratory in Chicago, IL, USA. Methods Five participants with chronic WAD were compared with five gender/age/height/weight/body mass index (BMI) control participants. For a secondary investigation, the chronic WAD group was compared with five unmatched participants with motor incomplete spinal cord injury (iSCI). Spinal cord motor tract integrity was assessed using magnetization transfer imaging. Muscle fat infiltration (MFI) was quantified using fat/water separation magnetic resonance imaging. Central volitional muscle activation of the plantarflexors was assessed using a burst superimposition technique. Results We found reduced spinal cord motor tract integrity, increased MFI of the neck and lower extremity muscles and significantly impaired voluntary plantarflexor muscle activation in five participants with chronic WAD. The lower extremity structural changes and volitional weakness in chronic WAD were comparable to participants with iSCI. Conclusion The results support the position that a subset of the chronic whiplash population may have sustained partial damage to the spinal cord. Sponsorship NIH R01HD079076-01A1, NIH T32 HD057845 and the Foundation for Physical Therapy Promotion of Doctoral Studies program.

  20. Potential associations between chronic whiplash and incomplete spinal cord injury

    PubMed Central

    Smith, Andrew C.; Parrish, Todd B.; Hoggarth, Mark A.; McPherson, Jacob G.; Tysseling, Vicki M.; Wasielewski, Marie; Kim, Hyosub E.; Hornby, T. George; Elliott, James M.

    2016-01-01

    Study Design This research utilized a cross-sectional design with control group inclusion. Objectives Preliminary evidence suggests that a portion of the patient population with chronic whiplash may have sustained spinal cord damage. Our hypothesis is that in some cases of chronic whiplash-associated disorders (WAD), observed muscle weakness in the legs will be associated with local signs of a partial spinal cord injury of the cervical spine. Setting University based laboratory in Chicago, IL, USA. Methods Five participants with chronic WAD were compared with five gender/age/height/weight/body mass index (BMI) control participants. For a secondary investigation, the chronic WAD group was compared with five unmatched participants with motor incomplete spinal cord injury (iSCI). Spinal cord motor tract integrity was assessed using magnetization transfer imaging. Muscle fat infiltration (MFI) was quantified using fat/water separation magnetic resonance imaging. Central volitional muscle activation of the plantarflexors was assessed using a burst superimposition technique. Results We found reduced spinal cord motor tract integrity, increased MFI of the neck and lower extremity muscles and significantly impaired voluntary plantarflexor muscle activation in five participants with chronic WAD. The lower extremity structural changes and volitional weakness in chronic WAD were comparable to participants with iSCI. Conclusion The results support the position that a subset of the chronic whiplash population may have sustained partial damage to the spinal cord. Sponsorship NIH R01HD079076-01A1, NIH T32 HD057845 and the Foundation for Physical Therapy Promotion of Doctoral Studies program. PMID:27630770

  1. Spinal and epidural anesthesia

    MedlinePlus

    Intraspinal anesthesia; Subarachnoid anesthesia; Epidural; Peridural anesthesia ... Spinal and epidural anesthesia have fewer side effects and risks than general anesthesia (asleep and pain-free). Patients usually recover their senses ...

  2. Spinal Cord Injury 101

    MedlinePlus

    ... is "Braingate" research? What is the status of stem-cell research? How would stem-cell therapies work in the treatment of spinal cord injuries? What does stem-cell research on animals tell us? When can we expect ...

  3. Spinal Cord Injury

    MedlinePlus

    ... Dramatically Improves Function After Spinal Cord Injury in Rats May 2004 press release on an experimental treatment ... NINDS). Signaling Molecule Improves Nerve Cell Regeneration in Rats August 2002 news summary on a signaling molecule ...

  4. What Is Spinal Stenosis?

    MedlinePlus

    ... To order the Sports Injuries Handout on Health full-text version, please contact NIAMS using the contact information ... publication. To order the Spinal Stenosis Q&A full-text version, please contact NIAMS using the contact information ...

  5. Spinal cord abscess

    MedlinePlus

    ... irritation (inflammation) and the collection of infected material (pus) in or around the spinal cord. ... occurs as a complication of an epidural abscess . Pus forms as a collection of: Destroyed tissue cells ...

  6. Greatly improved neurological outcome after spinal cord compression injury in AQP4-deficient mice.

    PubMed

    Saadoun, Samira; Bell, B Anthony; Verkman, A S; Papadopoulos, Marios C

    2008-04-01

    Aquaporin-4 (AQP4) is a water channel protein expressed in astrocytes throughout the CNS. In brain, AQP4 facilitates water balance and glial scar formation, which are important determinants of outcome after injury. Here, we provide evidence for AQP4-dependent spinal cord swelling following compression injury, resulting in remarkably improved outcome in AQP4-null mice. Two days after transient T6 spinal cord compression injury, wild-type mice developed more severe hindlimb weakness than AQP4-null mice, as assayed by the Basso open-field motor score, inclined plane method and footprint analysis. Basso motor scores were 1.3 +/- 0.5 (wild-type) versus 4.9 +/- 0.6 (AQP4-null) (SE, P < 0.001). Improved motor outcome in AQP4-null mice was independent of mouse strain and persisted at least 4 weeks. AQP4-null mice also had improved sensory outcome at 2 days, as assessed by spinal somatosensory evoked responses, with signal amplitudes approximately 10 microV (uninjured), 1.7 +/- 0.7 microV (wild-type) and 6.4 +/- 1.3 microV (AQP4-null) (P < 0.01). The improved motor and sensory indices in AQP4-null mice corresponded to remarkably less neuronal death and myelin vacuolation, as well as reduced spinal cord swelling and intraparenchymal spinal cord pressure measured at T6 at 2 days after injury. AQP4 immunoreactivity at the injury site was increased in grey and white matter at 48 h. Taken together, our findings indicate that AQP4 provides a major route for excess water entry into the injured spinal cord, which in turn causes spinal cord swelling and elevated spinal cord pressure. Our data suggest AQP4 inhibition or downregulation as novel early neuroprotective manoeuvres in spinal cord injury.

  7. Spinal and Bulbar Muscular Atrophy Overview

    PubMed Central

    Fischbeck, Kenneth H.

    2016-01-01

    Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by an expanded repeat in the androgen receptor gene. The mutant protein is toxic to motor neurons and muscle. The toxicity is ligand-dependent and likely involves aberrant interaction of the mutant androgen receptor with other nuclear factors leading to transcriptional dysregulation. Various therapeutic strategies have been effective in transgenic animal models, and the challenge now is to translate these strategies into safe and effective treatment in patients. PMID:26547319

  8. Forelimb EMG-based trigger to control an electronic spinal bridge to enable hindlimb stepping after a complete spinal cord lesion in rats

    PubMed Central

    2012-01-01

    Background A complete spinal cord transection results in loss of all supraspinal motor control below the level of the injury. The neural circuitry in the lumbosacral spinal cord, however, can generate locomotor patterns in the hindlimbs of rats and cats with the aid of motor training, epidural stimulation and/or administration of monoaminergic agonists. We hypothesized that there are patterns of EMG signals from the forelimbs during quadrupedal locomotion that uniquely represent a signal for the “intent” to step with the hindlimbs. These observations led us to determine whether this type of “indirect” volitional control of stepping can be achieved after a complete spinal cord injury. The objective of this study was to develop an electronic bridge across the lesion of the spinal cord to facilitate hindlimb stepping after a complete mid-thoracic spinal cord injury in adult rats. Methods We developed an electronic spinal bridge that can detect specific patterns of EMG activity from the forelimb muscles to initiate electrical-enabling motor control (eEmc) of the lumbosacral spinal cord to enable quadrupedal stepping after a complete spinal cord transection in rats. A moving window detection algorithm was implemented in a small microprocessor to detect biceps brachii EMG activity bilaterally that then was used to initiate and terminate epidural stimulation in the lumbosacral spinal cord. We found dominant frequencies of 180–220 Hz in the EMG of the forelimb muscles during active periods, whereas these frequencies were between 0–10 Hz when the muscles were inactive. Results and conclusions Once the algorithm was validated to represent kinematically appropriate quadrupedal stepping, we observed that the algorithm could reliably detect, initiate, and facilitate stepping under different pharmacological conditions and at various treadmill speeds. PMID:22691460

  9. Spinal cord pathways involved in initiation of swimming in the stingray, Dasyatis sabina: spinal cord stimulation and lesions.

    PubMed

    Williams, B J; Livingston, C A; Leonard, R B

    1984-03-01

    In spinally transected stingrays, electrical stimulation of a site just ventral to the dorsal root entry zone or a site in the intermediate portions of the lateral funiculus produced rhythmic swimming like movements of the contralateral pectoral fin. Electromyographic (EMG) records collected during cord-stimulated rhythms had the same pattern of activity and sometimes the same intersegmental coordination as those collected during spontaneous swimming of the same animal. In paralyzed, high-spinal stingrays, the only stimulation sites that produced rhythmic activity (fictive swimming) in the pectoral fin motor nerves were in the intermediate portion of the lateral funiculus. The evoked rhythm occurred in the motor nerves that were contralateral to the stimulated side of the spinal cord. The effects of subtotal lesions of the rostral spinal cord on spontaneous swimming behavior were assessed by analysis of EMG records taken before and after the lesions were made. Severe deficits in swimming occurred after bilateral ablation of intermediate portions of the lateral funiculi. In agreement with previous results, the stimulation experiments indicate that the stingray spinal cord contains an inherent capacity to generate properly coordinated rhythmic swimming. The current experiments also suggest that the descending pathways(s) that normally functions to initiate swimming projects through the intermediate aspects of the lateral funiculi. PMID:6699678

  10. Motor Starters

    NASA Astrophysics Data System (ADS)

    1986-01-01

    The power factor controller (PFC) was invented by a NASA engineer. It matches voltage with a motor's actual need by sensing shifts in the relationship between voltage and current flow. With the device, power can be trimmed as much as 65%. Intellinet adopted this technology and designed "soft start" and "load-responsive" control modes to start engines gradually and recycle voltage without reducing motor speed. Other features are lower motor heat and faster fault identification.

  11. [Meningitis after spinal anesthesia].

    PubMed

    Mouchrif, Issam; Berdaii, Adnane; Labib, Ismail; Harrandou, Moustapha

    2016-01-01

    Meningitis is a rare but serious complication of epidural and spinal anesthesia. Bacterial meningitis is mainly caused by Gram-positive cocci, implying an exogenous contamination which suggests a lack of asepsis. The evolution is usually favorable after treatment, but at the expense of increased health care costs and, sometimes, of significant neurological sequelae. We report a case of bacterial meningitis after spinal anesthesia for caesarean section. PMID:27642477

  12. Multidisciplinary Interventions in Motor Neuron Disease

    PubMed Central

    Williams, U. E.; Philip-Ephraim, E. E.; Oparah, S. K.

    2014-01-01

    Motor neuron disease is a neurodegenerative disease characterized by loss of upper motor neuron in the motor cortex and lower motor neurons in the brain stem and spinal cord. Death occurs 2–4 years after the onset of the disease. A complex interplay of cellular processes such as mitochondrial dysfunction, oxidative stress, excitotoxicity, and impaired axonal transport are proposed pathogenetic processes underlying neuronal cell loss. Currently evidence exists for the use of riluzole as a disease modifying drug; multidisciplinary team care approach to patient management; noninvasive ventilation for respiratory management; botulinum toxin B for sialorrhoea treatment; palliative care throughout the course of the disease; and Modafinil use for fatigue treatment. Further research is needed in management of dysphagia, bronchial secretion, pseudobulbar affect, spasticity, cramps, insomnia, cognitive impairment, and communication in motor neuron disease. PMID:26317009

  13. Modeling spinal cord biomechanics

    NASA Astrophysics Data System (ADS)

    Luna, Carlos; Shah, Sameer; Cohen, Avis; Aranda-Espinoza, Helim

    2012-02-01

    Regeneration after spinal cord injury is a serious health issue and there is no treatment for ailing patients. To understand regeneration of the spinal cord we used a system where regeneration occurs naturally, such as the lamprey. In this work, we analyzed the stress response of the spinal cord to tensile loading and obtained the mechanical properties of the cord both in vitro and in vivo. Physiological measurements showed that the spinal cord is pre-stressed to a strain of 10%, and during sinusoidal swimming, there is a local strain of 5% concentrated evenly at the mid-body and caudal sections. We found that the mechanical properties are homogeneous along the body and independent of the meninges. The mechanical behavior of the spinal cord can be characterized by a non-linear viscoelastic model, described by a modulus of 20 KPa for strains up to 15% and a modulus of 0.5 MPa for strains above 15%, in agreement with experimental data. However, this model does not offer a full understanding of the behavior of the spinal cord fibers. Using polymer physics we developed a model that relates the stress response as a function of the number of fibers.

  14. GDE2 regulates subtype-specific motor neuron generation through inhibition of Notch signaling.

    PubMed

    Sabharwal, Priyanka; Lee, Changhee; Park, Sungjin; Rao, Meenakshi; Sockanathan, Shanthini

    2011-09-22

    The specification of spinal interneuron and motor neuron identities initiates within progenitor cells, while motor neuron subtype diversification is regulated by hierarchical transcriptional programs implemented postmitotically. Here we find that mice lacking GDE2, a six-transmembrane protein that triggers motor neuron generation, exhibit selective losses of distinct motor neuron subtypes, specifically in defined subsets of limb-innervating motor pools that correlate with the loss of force-generating alpha motor neurons. Mechanistically, GDE2 is expressed by postmitotic motor neurons but utilizes extracellular glycerophosphodiester phosphodiesterase activity to induce motor neuron generation by inhibiting Notch signaling in neighboring motor neuron progenitors. Thus, neuronal GDE2 controls motor neuron subtype diversity through a non-cell-autonomous feedback mechanism that directly regulates progenitor cell differentiation, implying that subtype specification initiates within motor neuron progenitor populations prior to their differentiation into postmitotic motor neurons.

  15. Ginsenoside Rd inhibits apoptosis following spinal cord ischemia/reperfusion injury

    PubMed Central

    Wang, Baogang; Zhu, Qingsan; Man, Xiaxia; Guo, Li; Hao, Liming

    2014-01-01

    Ginsenoside Rd has a clear neuroprotective effect against ischemic stroke. We aimed to verify the neuroprotective effect of ginsenoside Rd in spinal cord ischemia/reperfusion injury and explore its anti-apoptotic mechanisms. We established a spinal cord ischemia/reperfusion injury model in rats through the occlusion of the abdominal aorta below the level of the renal artery for 1 hour. Successfully established models were injected intraperitoneally with 6.25, 12.5, 25 or 50 mg/kg per day ginsenoside Rd. Spinal cord morphology was observed at 1, 3, 5 and 7 days after spinal cord ischemia/reperfusion injury. Intraperitoneal injection of ginsenoside Rd in ischemia/reperfusion injury rats not only improved hindlimb motor function and the morphology of motor neurons in the anterior horn of the spinal cord, but it also reduced neuronal apoptosis. The optimal dose of ginsenoside Rd was 25 mg/kg per day and the optimal time point was 5 days after ischemia/reperfusion. Immunohistochemistry and western blot analysis showed ginsenoside Rd dose-dependently inhibited expression of pro-apoptotic Caspase 3 and down-regulated the expression of the apoptotic proteins ASK1 and JNK in the spinal cord of rats with spinal cord ischemia/reperfusion injury. These findings indicate that ginsenoside Rd exerts neuroprotective effects against spinal cord ischemia/reperfusion injury and the underlying mechanisms are achieved through the inhibition of ASK1-JNK pathway and the down-regulation of Caspase 3 expression. PMID:25374589

  16. Enhancement of motor rehabilitation through the use of information technologies.

    PubMed

    Liebermann, Dario G; Buchman, Aron S; Franks, Ian M

    2006-01-01

    The recent development of information technologies has dramatically increased the tools available for facilitating motor rehabilitation. This review focuses on technologies which can be used to augment movement-related information both to patients as well as to their therapists. A brief outline of the motor system emphasizes the role of spinal motor neurons in the control of voluntary movement and rehabilitative efforts. Technologies which induce passive motion to stimulate spinal motor output as well as technologies that stimulate active voluntary movements are discussed. Finally, we review technologies and notational methods that can be used to quantify and assess the quality of movement for evaluating the efficacy of motor rehabilitation efforts. We conclude that stronger evidence is necessary to determine the applicability of the wide range of technologies now available to clinical rehabilitation efforts. PMID:16198463

  17. Spinal Cord Anatomy and Clinical Syndromes.

    PubMed

    Diaz, Eric; Morales, Humberto

    2016-10-01

    We review the anatomy of the spinal cord, providing correlation with key functional and clinically relevant neural pathways, as well as magnetic resonance imaging. Peripherally, the main descending (corticospinal tract) and ascending (gracilis or cuneatus fasciculi and spinothalamic tracts) pathways compose the white matter. Centrally, the gray matter can be divided into multiple laminae. Laminae 1-5 carry sensitive neuron information in the posterior horn, and lamina 9 carries most lower motor neuron information in the anterior horn. Damage to the unilateral corticospinal tract (upper motor neuron information) or gracillis-cuneatus fasciculi (touch and vibration) correlates with ipsilateral clinical findings, whereas damage to unilateral spinothalamic tract (pain-temperature) correlates with contralateral clinical findings. Damage to commissural fibers correlates with a suspended bilateral "girdle" sensory level. Autonomic dysfunction is expected when there is bilateral cord involvement. PMID:27616310

  18. Spinal Plasticity and Behavior: BDNF-Induced Neuromodulation in Uninjured and Injured Spinal Cord

    PubMed Central

    Huie, J. Russell

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophic factor family of signaling molecules. Since its discovery over three decades ago, BDNF has been identified as an important regulator of neuronal development, synaptic transmission, and cellular and synaptic plasticity and has been shown to function in the formation and maintenance of certain forms of memory. Neural plasticity that underlies learning and memory in the hippocampus shares distinct characteristics with spinal cord nociceptive plasticity. Research examining the role BDNF plays in spinal nociception and pain overwhelmingly suggests that BDNF promotes pronociceptive effects. BDNF induces synaptic facilitation and engages central sensitization-like mechanisms. Also, peripheral injury-induced neuropathic pain is often accompanied with increased spinal expression of BDNF. Research has extended to examine how spinal cord injury (SCI) influences BDNF plasticity and the effects BDNF has on sensory and motor functions after SCI. Functional recovery and adaptive plasticity after SCI are typically associated with upregulation of BDNF. Although neuropathic pain is a common consequence of SCI, the relation between BDNF and pain after SCI remains elusive. This article reviews recent literature and discusses the diverse actions of BDNF. We also highlight similarities and differences in BDNF-induced nociceptive plasticity in naïve and SCI conditions. PMID:27721996

  19. Restoring walking after spinal cord injury: operant conditioning of spinal reflexes can help.

    PubMed

    Thompson, Aiko K; Wolpaw, Jonathan R

    2015-04-01

    People with incomplete spinal cord injury (SCI) frequently suffer motor disabilities due to spasticity and poor muscle control, even after conventional therapy. Abnormal spinal reflex activity often contributes to these problems. Operant conditioning of spinal reflexes, which can target plasticity to specific reflex pathways, can enhance recovery. In rats in which a right lateral column lesion had weakened right stance and produced an asymmetrical gait, up-conditioning of the right soleus H-reflex, which increased muscle spindle afferent excitation of soleus, strengthened right stance and eliminated the asymmetry. In people with hyperreflexia due to incomplete SCI, down-conditioning of the soleus H-reflex improved walking speed and symmetry. Furthermore, modulation of electromyographic activity during walking improved bilaterally, indicating that a protocol that targets plasticity to a specific pathway can trigger widespread plasticity that improves recovery far beyond that attributable to the change in the targeted pathway. These improvements were apparent to people in their daily lives. They reported walking faster and farther, and noted less spasticity and better balance. Operant conditioning protocols could be developed to modify other spinal reflexes or corticospinal connections; and could be combined with other therapies to enhance recovery in people with SCI or other neuromuscular disorders.

  20. 41 CFR 102-34.320 - What Government-issued charge cards may I use to purchase fuel and motor vehicle related services?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...: General Services Administration, ATTN: GSA SmartPay® (QMB), 2200 Crystal Drive, Arlington, VA 22202. (b... program requirements and guidance issued by the Office of Management and Budget, GSA, Department of...

  1. 41 CFR 102-34.320 - What Government-issued charge cards may I use to purchase fuel and motor vehicle related services?

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ...: General Services Administration, ATTN: GSA SmartPay® (QMB), 2200 Crystal Drive, Arlington, VA 22202. (b... program requirements and guidance issued by the Office of Management and Budget, GSA, Department of...

  2. Exercise recommendations for individuals with spinal cord injury.

    PubMed

    Jacobs, Patrick L; Nash, Mark S

    2004-01-01

    Persons with spinal cord injury (SCI) exhibit deficits in volitional motor control and sensation that limit not only the performance of daily tasks but also the overall activity level of these persons. This population has been characterised as extremely sedentary with an increased incidence of secondary complications including diabetes mellitus, hypertension and atherogenic lipid profiles. As the daily lifestyle of the average person with SCI is without adequate stress for conditioning purposes, structured exercise activities must be added to the regular schedule if the individual is to reduce the likelihood of secondary complications and/or to enhance their physical capacity. The acute exercise responses and the capacity for exercise conditioning are directly related to the level and completeness of the spinal lesion. Appropriate exercise testing and training of persons with SCI should be based on the individual's exercise capacity as determined by accurate assessment of the spinal lesion. The standard means of classification of SCI is by application of the International Standards for Classification of Spinal Cord Injury, written by the Neurological Standards Committee of the American Spinal Injury Association. Individuals with complete spinal injuries at or above the fourth thoracic level generally exhibit dramatically diminished cardiac acceleration with maximal heart rates less than 130 beats/min. The work capacity of these persons will be limited by reductions in cardiac output and circulation to the exercising musculature. Persons with complete spinal lesions below the T(10) level will generally display injuries to the lower motor neurons within the lower extremities and, therefore, will not retain the capacity for neuromuscular activation by means of electrical stimulation. Persons with paraplegia also exhibit reduced exercise capacity and increased heart rate responses (compared with the non-disabled), which have been associated with circulatory limitations

  3. Molecular motors

    NASA Astrophysics Data System (ADS)

    Allemand, Jean François Desbiolles, Pierre

    2015-10-01

    How do we move? More precisely, what are the molecular mechanisms that can explain that our muscles, made of very small components can move at a osopic scale? To answer these questions we must introduce molecular motors. Those motors are proteins, or small protein assemblies that, in our cells, transform chemical energy into mechanical work. Then, like we could do for a oscopic motor, used in a car or in a fan, we are going to study the basic behavior of these molecular machines, present what are their energy sources, calculate their power, their yield. If molecular motors are crucial for our oscopic movements, we are going to see that they are also essential to cellular transport and that considering the activity of some enzymes as molecular motors bring some interesting new insights on their activity.

  4. New evidence of corticospinal network modulation induced by motor imagery.

    PubMed

    Grosprêtre, Sidney; Lebon, Florent; Papaxanthis, Charalambos; Martin, Alain

    2016-03-01

    Motor imagery (MI) is the mental simulation of movement, without the corresponding muscle contraction. Whereas the activation of cortical motor areas during MI is established, the involvement of spinal structures is still under debate. We used original and complementary techniques to probe the influence of MI on spinal structures. Amplitude of motor-evoked potentials (MEPs), cervico-medullary-evoked potentials (CMEPs), and Hoffmann (H)-reflexes of the flexor carpi radialis (FCR) muscle and of the triceps surae muscles was measured in young, healthy subjects at rest and during MI. Participants were asked to imagine maximal voluntary contraction of the wrist and ankle, while the targeted limb was fixed (static condition). We confirmed previous studies with an increase of FCR MEPs during MI compared with rest. Interestingly, CMEPs, but not H-reflexes, also increased during MI, revealing a possible activation of subcortical structures. Then, to investigate the effect of MI on the spinal network, we used two techniques: 1) passive lengthening of the targeted muscle via an isokinetic dynamometer and 2) conditioning of H-reflexes with stimulation of the antagonistic nerve. Both techniques activate spinal inhibitory presynaptic circuitry, reducing the H-reflex amplitude at rest. In contrast, no reduction of H-reflex amplitude was observed during MI. These findings suggest that MI has modulatory effects on the spinal neuronal network. Specifically, the activation of low-threshold spinal structures during specific conditions (lengthening and H-reflex conditioning) highlights the possible generation of subliminal cortical output during MI. PMID:26719089

  5. Rostro-Caudal Inhibition of Hindlimb Movements in the Spinal Cord of Mice

    PubMed Central

    Caggiano, Vittorio; Sur, Mirganka; Bizzi, Emilio

    2014-01-01

    Inhibitory neurons in the adult mammalian spinal cord are known to locally modulate afferent feedback - from muscle proprioceptors and from skin receptors - to pattern motor activity for locomotion and postural control. Here, using optogenetic tools, we explored how the same population of inhibitory interneurons globally affects hindlimb movements in the spinal cord of both anesthetized and freely moving mice. Activation of inhibitory interneurons up to the middle/lower spinal cord i.e. T8–T9, were able to completely and globally suppress all ipsilateral hindlimb movements. Furthermore, the same population of interneurons - which inhibited movements - did not significantly change the sensory and proprioceptive information from the affected limbs to the cortex. These results suggest a rostro-caudal organization of inhibition in the spinal cord motor output without modulation of ascending sensory pathways. PMID:24963653

  6. Human neural progenitors differentiate into astrocytes and protect motor neurons in aging rats.

    PubMed

    Das, Melanie M; Avalos, Pablo; Suezaki, Patrick; Godoy, Marlesa; Garcia, Leslie; Chang, Christine D; Vit, Jean-Philippe; Shelley, Brandon; Gowing, Genevieve; Svendsen, Clive N

    2016-06-01

    Age-associated health decline presents a significant challenge to healthcare, although there are few animal models that can be used to test potential treatments. Here, we show that there is a significant reduction in both spinal cord motor neurons and motor function over time in the aging rat. One explanation for this motor neuron loss could be reduced support from surrounding aging astrocytes. Indeed, we have previously shown using in vitro models that aging rat astrocytes are less supportive to rat motor neuron function and survival over time. Here, we test whether rejuvenating the astrocyte niche can improve the survival of motor neurons in an aging spinal cord. We transplanted fetal-derived human neural progenitor cells (hNPCs) into the aging rat spinal cord and found that the cells survive and differentiate into astrocytes with a much higher efficiency than when transplanted into younger animals, suggesting that the aging environment stimulates astrocyte maturation. Importantly, the engrafted astrocytes were able to protect against motor neuron loss associated with aging, although this did not result in an increase in motor function based on behavioral assays. We also transplanted hNPCs genetically modified to secrete glial cell line-derived neurotrophic factor (GDNF) into the aging rat spinal cord, as this combination of cell and protein delivery can protect motor neurons in animal models of ALS. During aging, GDNF-expressing hNPCs protected motor neurons, though to the same extent as hNPCs alone, and again had no effect on motor function. We conclude that hNPCs can survive well in the aging spinal cord, protect motor neurons and mature faster into astrocytes when compared to transplantation into the young spinal cord. While there was no functional improvement, there were no functional deficits either, further supporting a good safety profile of hNPC transplantation even into the older patient population. PMID:27032721

  7. The stress response and anesthetic potency of unilateral spinal anesthesia for total Hip Replacement in geriatric patients.

    PubMed

    Zhu, Li; Tian, Chun; Li, Min; Peng, Ming-Qing; Ma, Kun-Long; Wang, Zhong-Lin; Ding, Jia-Hui; Cai, Yi

    2014-11-01

    Recently, some scholars suggested that it is important to keep a stablehemodynamic state and prevent the stress responses in geriatric patients undergoing total hip replacement (THR). We conducted this randomized prospective study to observe anesthetic potency of unilateral spinal anesthesia and stress response to it in geriatric patients during THR. We compared the effect of unilateral spinal and bilateral spinal on inhibition of stress response through measuring Norepinephrine (NE), epinephrine (E) and cortisol (CORT). Plasma concentrations of NE, E and CORT were determined in blood samples using ELISA (enzyme-linked immunosorbent assays) at three time points: To (prior to anesthesia) T1 (at the time point of skin closure), T2 (twenty-four hours after the operation). Sixty patients were randomly divided into two groups: group A (unilateral spinal anesthesia) and group B (conventional bilateral spinal anesthesia). 7.5tymg of hypobaric bupivacaine were injected into subarachnoid cavity at group A and 12mg hypobaric bupivacaine were given at group B. The onset time of sensory and motor block, loss of pinprick sensation, degree of motor block, regression of sensory and motor blocks and hemodynamic changes were also recorded. These data were used to evaluate anesthetic potency of spinal anesthesia. The results of this experiment show that unilateral spinal anesthesia can provide restriction of sensory and motor block, minimize the incidence of hypotension and prevent the stress responses undergoing THR. It is optimal anesthesia procedure for geriatric patients by rapid subarachnoid injection of small doses of bupivacaine. PMID:25410068

  8. The stress response and anesthetic potency of unilateral spinal anesthesia for total Hip Replacement in geriatric patients.

    PubMed

    Zhu, Li; Tian, Chun; Li, Min; Peng, Ming-Qing; Ma, Kun-Long; Wang, Zhong-Lin; Ding, Jia-Hui; Cai, Yi

    2014-11-01

    Recently, some scholars suggested that it is important to keep a stablehemodynamic state and prevent the stress responses in geriatric patients undergoing total hip replacement (THR). We conducted this randomized prospective study to observe anesthetic potency of unilateral spinal anesthesia and stress response to it in geriatric patients during THR. We compared the effect of unilateral spinal and bilateral spinal on inhibition of stress response through measuring Norepinephrine (NE), epinephrine (E) and cortisol (CORT). Plasma concentrations of NE, E and CORT were determined in blood samples using ELISA (enzyme-linked immunosorbent assays) at three time points: To (prior to anesthesia) T1 (at the time point of skin closure), T2 (twenty-four hours after the operation). Sixty patients were randomly divided into two groups: group A (unilateral spinal anesthesia) and group B (conventional bilateral spinal anesthesia). 7.5tymg of hypobaric bupivacaine were injected into subarachnoid cavity at group A and 12mg hypobaric bupivacaine were given at group B. The onset time of sensory and motor block, loss of pinprick sensation, degree of motor block, regression of sensory and motor blocks and hemodynamic changes were also recorded. These data were used to evaluate anesthetic potency of spinal anesthesia. The results of this experiment show that unilateral spinal anesthesia can provide restriction of sensory and motor block, minimize the incidence of hypotension and prevent the stress responses undergoing THR. It is optimal anesthesia procedure for geriatric patients by rapid subarachnoid injection of small doses of bupivacaine.

  9. Pediatric spinal trauma.

    PubMed

    Huisman, Thierry A G M; Wagner, Matthias W; Bosemani, Thangamadhan; Tekes, Aylin; Poretti, Andrea

    2015-01-01

    Pediatric spinal trauma is unique. The developing pediatric spinal column and spinal cord deal with direct impact and indirect acceleration/deceleration or shear forces very different compared to adult patients. In addition children are exposed to different kind of traumas. Moreover, each age group has its unique patterns of injury. Familiarity with the normal developing spinal anatomy and kind of traumas is essential to correctly diagnose injury. Various imaging modalities can be used. Ultrasound is limited to the neonatal time period; plain radiography and computer tomography are typically used in the acute work-up and give highly detailed information about the osseous lesions. Magnetic resonance imaging is more sensitive for disco-ligamentous and spinal cord injuries. Depending on the clinical presentation and timing of trauma the various imaging modalities will be employed. In the current review article, a summary of the epidemiology and distribution of posttraumatic lesions is discussed in the context of the normal anatomical variations due to progressing development of the child. PMID:25512255

  10. Speed and spinal injuries.

    PubMed

    Healy, D G; Connolly, P; Stephens, M M; O'Byrne, J M; McManus, F; McCormack, D

    2004-09-01

    Road traffic accidents (RTA) are a significant cause of spinal trauma. On the 31st of October 2002 a new penalty system for speed related driving offences was introduced in Ireland. Our intention was to assess the effects of the introduction of this system on the activity of the National Spinal Injuries Centre (NSIC) with a retrospective review of all admissions from November 1998 until October 2003. The number of new acute admissions to the spinal injury unit during the study period was 831. In the first 6 months of the new system the number of RTA related admissions fell significantly to 17 compared to an average of 33 in the preceding 4 years. However, this effect was not maintained in the second 6 months. The fall in spinal injuries following RTA in the first 6 months of the new system parallels the pattern of road death reduction in this period. This suggests that driving behaviour can be modified with direct benefits in reducing spinal injuries. However, this effect has not persisted in the second 6 months of the new system suggesting that to maintain this change the perception and familiarity of a penalty are important factors in its impact.

  11. Learning Spinal Manipulation

    PubMed Central

    Harvey, Marie-Pierre; Wynd, Shari; Richardson, Lance; Dugas, Claude; Descarreaux, Martin

    2011-01-01

    Purpose: The goal of the present study was to quantify the high-velocity, low-amplitude spinal manipulation biomechanical parameters in two cohorts of students from different teaching institutions. The first cohort of students was taught chiropractic techniques in a patient–doctor positioning practice setting, while the second cohort of students was taught in a “complete practice” manipulation setting, thus performing spinal manipulation skills on fellow student colleagues. It was hypothesized that the students exposed to complete practice would perform the standardized spinal manipulation with better biomechanical parameters. Methods: Participants (n = 88) were students enrolled in two distinct chiropractic programs. Thoracic spine manipulation skills were assessed using an instrumented manikin, which allowed the measurement of applied force. Dependent variables included peak force, time to peak force, rate of force production, peak force variability, and global coordination. Results: The results revealed that students exposed to complete practice demonstrated lower time to peak force values, higher peak force, and a steeper rate of force production compared with students in the patient–doctor positioning scenario. A significant group by gender interaction was also noted for the time to peak force and rate of force production variables. Conclusion: The results of the present study confirm the importance of chiropractic technique curriculum and perhaps gender in spinal manipulation skill learning. It also stresses the importance of integrating spinal manipulation skills practice early in training to maximize the number and the quality of significant learner–instructor interactions. PMID:22069337

  12. Intraoperative and pathological findings of intramedullary amputation neuroma associated with spinal ependymoma.

    PubMed

    Arishima, Hidetaka; Takeuchi, Hiroaki; Tsunetoshi, Kenzo; Kodera, Toshiaki; Kitai, Ryuhei; Kikuta, Ken-ichiro

    2013-07-01

    Amputation neuromas typically arise in injured peripheral nerves; rarely, however, they arise in the spinal cord. We report a rare case of intramedullary amputation neuroma associated with ependymoma in the cervical spinal cord. A 73-year-old woman presented with a 5-year history of progressive gait disturbance. Neurological examination revealed complete motor deficit of her hands and legs. Magnetic resonance imaging of the cervical spine revealed an enhancing mass within the spinal cord at the C6/7 level. The patient underwent C5-C7 laminectomy surgery. During resection of the spinal tumor, we found a whitish string resembling an aberrant nerve root or schwannoma with adhesion to the tumor on the ventral side of the spinal cord. After resecting the tumor, the surgical specimen was cut and separated into a soft greyish tumor (spinal tumor) and the tough whitish string. Histopathological and immunohistochemical examination revealed the former was a spinal ependymoma and the latter was a neuroma. An intramedullary amputation neuroma associated with a spinal ependymoma is rare, and this is the first known case in which intraoprerative findings were clearly shown. Neurosurgeons should be aware that spinal ependymomas might coexist with neuromas.

  13. Patterns of Phrenic Nerve Discharge after Complete High Cervical Spinal Cord Injury in the Decerebrate Rat.

    PubMed

    Ghali, Michael George Zaki; Marchenko, Vitaliy

    2016-06-15

    Studies conducted since the second half of the 19th century have revealed spontaneous as well as pharmacologically induced phasic/rhythmic discharge in spinal respiratory motor outputs of cats, dogs, rabbits, and neonatal rats following high cervical transection (Tx). The extent to which these various studies validate the existence of a true spinal respiratory rhythm generator remains debated. In this set of studies, we seek to characterize patterns of spontaneous phasic/rhythmic, asphyxia-induced, and pharmacologically induced activity occurring in phrenic nerve (PhN) discharge after complete high cervical (C1-C2) spinal cord transection. Experiments were performed on 20 unanesthetized decerebrate Sprague-Dawley adult male rats. Patterns of spontaneous activity after spinalization included tonic, phasic, slow oscillatory, and long-lasting tonic discharges. Topical application of antagonists of GABAA and glycine receptors to C1- and C2- spinal segments induced left-right synchronized phasic decrementing activity in PhN discharge that was abolished by an additional C2Tx. Asphyxia elicited increases in tonic activity and left-right synchronized gasp-like bursts in PhN discharge, demonstrating the presence of spinal circuits that may underlie a spinal gasping-like mechanism. We conclude that intrinsic slow oscillators and a phasic burst/rhythm generator exist in the spinal cord of the adult rat. If present in humans, this mechanism may be exploited to recover respiratory function in patients sustaining severe spinal cord injury. PMID:26239508

  14. Stem cell-based therapies for spinal cord injury.

    PubMed

    Nandoe Tewarie, Rishi S; Hurtado, Andres; Bartels, Ronald H; Grotenhuis, Andre; Oudega, Martin

    2009-01-01

    Spinal cord injury (SCI) results in loss of nervous tissue and consequently loss of motor and sensory function. There is no treatment available that restores the injury-induced loss of function to a degree that an independent life can be guaranteed. Transplantation of stem cells or progenitors may support spinal cord repair. Stem cells are characterized by self-renewal and their ability to become any cell in an organism. Promising results have been obtained in experimental models of SCI. Stem cells can be directed to differentiate into neurons or glia in vitro, which can be used for replacement of neural cells lost after SCI. Neuroprotective and axon regeneration-promoting effects have also been credited to transplanted stem cells. There are still issues related to stem cell transplantation that need to be resolved, including ethical concerns. This paper reviews the current status of stem cell application for spinal cord repair.

  15. State of the art: Intraoperative neuromonitoring in spinal deformity surgery.

    PubMed

    Takata, Yoichiro; Sakai, Toshinori; Higashino, Kosaku; Matsuura, Tetsuya; Suzue, Naoto; Hamada, Daisuke; Goto, Tomohiro; Nishisho, Toshihiko; Tsutsui, Takahiko; Goda, Yuichiro; Morimoto, Masatoshi; Abe, Mitsunobu; Mineta, Kazuaki; Kimura, Tetsuya; Nitta, Akihiro; Hama, Shingo; Higuchi, Tadahiro; C Jha, Subash; Takahashi, Rui; Fukuta, Shoji; Sairyo, Koichi

    2015-01-01

    Application of deformity correction spinal surgery has increased substantially over the past three decades in parallel with improvements in surgical techniques. Intraoperative neuromonitoring (IOM) techniques,including somatosensory evoked potentials (SEPs), muscle evoked potentials (MEPs), and spontaneous electromyography (free-run EMG), have also improved surgical outcome by reducing the risk of iatrogenic neural injury. In this article, we review IOM techniques and their applications in spinal deformity surgery. We also summarize results of selected studies including hundreds of spinal correction surgeries. These studies indicate that multimodal IOM of both motor and sensory responses is superior to either modality alone for reducing the incidence of neural injury during surgery. J. Med. Invest. 62: 103-108, August, 2015. PMID:26399330

  16. Stepper motor

    NASA Technical Reports Server (NTRS)

    Dekramer, Cornelis

    1994-01-01

    The purpose of this document is to describe the more commonly used permanent magnet stepper motors for spaceflight. It will discuss the mechanical and electrical aspects of the devices, their torque behavior, those parameters which need to be controlled and measured, and test methods to be employed. It will also discuss torque margins, compare these to the existing margin requirements, and determine the applicability of these requirements. Finally it will attempt to generate a set of requirements which will be used in any stepper motor procurement and will fully characterize the stepper motor behavior in a consistent and repeatable fashion.

  17. [Lumbar spinal angiolipoma].

    PubMed

    Isla, Alberto; Ortega Martinez, Rodrigo; Pérez López, Carlos; Gómez de la Riva, Alvaro; Mansilla, Beatriz

    2016-01-01

    Spinal angiolipomas are fairly infrequent benign tumours that are usually located in the epidural space of the thoracic column and represent 0.14% to 1.3% of all spinal tumours. Lumbar angiolipomas are extremely rare, representing only 9.6% of all spinal extradural angiolipomas. We report the case of a woman who complained of a lumbar pain of several months duration with no neurological focality and that had intensified in the last three days without her having had any injury or made a physical effort. The MR revealed an extradural mass L1-L2, on the posterior face of the medulla, decreasing the anteroposterior diameter of the canal. The patient symptoms improved after surgery. Total extirpation of the lesion is possible in most cases, and the prognosis is excellent even if the lesion is infiltrative. For this reason, excessively aggressive surgery is not necessary to obtain complete resection. PMID:27263067

  18. Spinal injuries in children.

    PubMed

    Babcock, J L

    1975-05-01

    Spinal injuries with neurologic sequelae are a rare but catastrophic injury. Many of these injuries might be preventable through proper parent and child education, particularly in water sports and vehicles accidents. A significant number of neurologic injuries are incomplete at the time of injury and proper rescue and initial care may make the difference between life as a quadriplegic and life as a normal individual. Because of the complexity of the management of the child with spinal injuries and their relative rarity, the definitive care is best undertaken at hospitals which specialize in the care of spinal injuries. Progressive deformity of the spine, a problem unique to childhood and adolescent paralysis, is often preventable with prolonged immobilization and protection of the spine. Progressive deformities which interfere with function or result in neurologic deterioration require an aggressive surgical approach. PMID:1124228

  19. Spinal Subdural Haematoma

    PubMed Central

    Manish K, Kothari; Chandrakant, Shah Kunal; Abhay M, Nene

    2015-01-01

    Introduction: Spinal Subdural hematoma is a rare cause of radiculopathy and spinal cord compression syndromes. It’s early diagnosis is essential. Chronological appearance of these bleeds vary on MRI. Case Report: A 56 year old man presented with progressive left lower limb radiculopathy and paraesthesias with claudication of three days duration. MRI revealed a subdural space occupying lesion compressing the cauda equina at L5-S1 level producing a ‘Y’ shaped dural sac (Y sign), which was hyperintense on T1W imaging and hypointense to cord on T2W image. The STIR sequence showed hyperintensity to cord. There was no history of bleeding diathesis. The patient underwent decompressive durotomy and biopsy which confirmed the diagnosis. Conclusion: Spinal subdural hematoma may present with rapidly progressive neurological symptoms. MRI is the investigation of choice. The knowledge of MRI appearance with respect to the chronological stage of the bleed is essential to avoid diagnostic and hence surgical dilemma PMID:27299051

  20. [Spinal cord infarction].

    PubMed

    Naumann, N; Shariat, K; Ulmer, S; Stippich, C; Ahlhelm, F J

    2012-05-01

    Infarction of the spinal cord can cause a variety of symptoms and neurological deficits because of the complex vascular supply of the myelon. The most common leading symptom is distal paresis ranging from paraparesis to tetraplegia caused by arterial ischemia or infarction of the myelon. Venous infarction, however, cannot always be distinguished from arterial infarction based on the symptoms alone.Modern imaging techniques, such as computed tomography angiography (CTA) and magnetic resonance angiography (MRA) assist in preoperative planning of aortic operations to reliably identify not only the most important vascular structure supplying the spinal cord, the artery of Adamkiewicz, but also other pathologies such as tumors or infectious disorders. In contrast to CT, MRI can reliably depict infarction of the spinal cord.

  1. [Lumbar spinal angiolipoma].

    PubMed

    Isla, Alberto; Ortega Martinez, Rodrigo; Pérez López, Carlos; Gómez de la Riva, Alvaro; Mansilla, Beatriz

    2016-01-01

    Spinal angiolipomas are fairly infrequent benign tumours that are usually located in the epidural space of the thoracic column and represent 0.14% to 1.3% of all spinal tumours. Lumbar angiolipomas are extremely rare, representing only 9.6% of all spinal extradural angiolipomas. We report the case of a woman who complained of a lumbar pain of several months duration with no neurological focality and that had intensified in the last three days without her having had any injury or made a physical effort. The MR revealed an extradural mass L1-L2, on the posterior face of the medulla, decreasing the anteroposterior diameter of the canal. The patient symptoms improved after surgery. Total extirpation of the lesion is possible in most cases, and the prognosis is excellent even if the lesion is infiltrative. For this reason, excessively aggressive surgery is not necessary to obtain complete resection.

  2. Skiing and spinal trauma.

    PubMed

    Frymoyer, J W; Pope, M H; Kristiansen, T

    1982-07-01

    Spinal injury in skiers can either be acute or chronic. Acute spinal injury accounts for 3 to 3.6 per cent of all injuries occurring in Alpine skiing. Fewer acute injuries occur in cross-country skiing, and those that do usually are the result of a sudden, compressive force from a seated fall. The prevalence of chronic spinal trauma in skiing is unknown. Both cross-country and Alpine skiers appear to have greater complaints of mild to moderate low back pain as compared with their nonskiing counterparts. These differences may be the result of a complex interaction between recreational and occupational activities. Theoretical analyses suggest a risk for low-grade torsional injury to the Alpine skier's spine, whereas in cross-country skiing significant shear forces are applied to lumbar discs during the kick but not the double-poling phase.

  3. [Effect of local hypothermia on H- and M-responses after spinal cord contusion in dogs].

    PubMed

    Iafarova, G G; Tumakaev, R F; Khazieva, A R; Baltina, T V

    2014-01-01

    In this study we investigated a motor-neuronal functional state based on H- and M-responses from m. quadratus plantae in dogs before and after experimental spinal cord contusion with and without following local intraoperative hypothermia. H- and M-responses from m. quadratus plantae were recorded during stimulation of the tibial nerve and results were compared between the groups. Our results demonstrate that local hypothermia applied after spinal cord contusion reduces amplitude of both M- and H-responses and also H(max)/M(max) ratio that may indicate depression of motorneurons excitability. After spinal cord contusion without following hypothermia the excitability of the spinal motorneurons during post-traumatic period, in opposite, was significantly increased. These results support a conclusion that intraoperative hypothermia after spinal cord contusion can delay development of functional excitability of the motoneurons and protect from further changes in H- and M-responses.

  4. A 'tool box' for deciphering neuronal circuits in the developing chick spinal cord.

    PubMed

    Hadas, Yoav; Etlin, Alex; Falk, Haya; Avraham, Oshri; Kobiler, Oren; Panet, Amos; Lev-Tov, Aharon; Klar, Avihu

    2014-10-29

    The genetic dissection of spinal circuits is an essential new means for understanding the neural basis of mammalian behavior. Molecular targeting of specific neuronal populations, a key instrument in the genetic dissection of neuronal circuits in the mouse model, is a complex and time-demanding process. Here we present a circuit-deciphering 'tool box' for fast, reliable and cheap genetic targeting of neuronal circuits in the developing spinal cord of the chick. We demonstrate targeting of motoneurons and spinal interneurons, mapping of axonal trajectories and synaptic targeting in both single and populations of spinal interneurons, and viral vector-mediated labeling of pre-motoneurons. We also demonstrate fluorescent imaging of the activity pattern of defined spinal neurons during rhythmic motor behavior, and assess the role of channel rhodopsin-targeted population of interneurons in rhythmic behavior using specific photoactivation.

  5. Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies

    PubMed Central

    Jordanova, Albena

    2014-01-01

    Hereditary spinal muscular atrophy is a motor neuron disorder characterized by muscle weakness and atrophy due to degeneration of the anterior horn cells of the spinal cord. Initially, the disease was considered purely as an autosomal recessive condition caused by loss-of-function SMN1 mutations on 5q13. Recent developments in next generation sequencing technologies, however, have unveiled a growing number of clinical conditions designated as non-5q forms of spinal muscular atrophy. At present, 16 different genes and one unresolved locus are associated with proximal non-5q forms, having high phenotypic variability and diverse inheritance patterns. This review provides an overview of the current knowledge regarding the phenotypes, causative genes, and disease mechanisms associated with proximal SMN1-negative spinal muscular atrophies. We describe the molecular and cellular functions enriched among causative genes, and discuss the challenges in the post-genomics era of spinal muscular atrophy research. PMID:24970098

  6. Extrinsic and Intrinsic Regulation of Axon Regeneration by MicroRNAs after Spinal Cord Injury

    PubMed Central

    Li, Ping; Teng, Zhao-Qian

    2016-01-01

    Spinal cord injury is a devastating disease which disrupts the connections between the brain and spinal cord, often resulting in the loss of sensory and motor function below the lesion site. Most injured neurons fail to regenerate in the central nervous system after injury. Multiple intrinsic and extrinsic factors contribute to the general failure of axonal regeneration after injury. MicroRNAs can modulate multiple genes' expression and are tightly controlled during nerve development or the injury process. Evidence has demonstrated that microRNAs and their signaling pathways play important roles in mediating axon regeneration and glial scar formation after spinal cord injury. This article reviews the role and mechanism of differentially expressed microRNAs in regulating axon regeneration and glial scar formation after spinal cord injury, as well as their therapeutic potential for promoting axonal regeneration and repair of the injured spinal cord.

  7. Caramiphen-induced block of sodium currents and spinal anesthesia.

    PubMed

    Leung, Yuk-Man; Tzeng, Jann-Inn; Gong, Chi-Li; Wang, Yu-Wen; Chen, Yu-Wen; Wang, Jhi-Joung

    2015-01-01

    The underlying mechanisms for the action of caramiphen used in local anesthesia are not well understood. The purpose of this study was to evaluate the block of caramiphen on voltage-gated Na⁺ channels and in spinal anesthesia. We investigated the effect of caramiphen on voltage-gated sodium channels in differentiated neuronal NG108-15 cells as well as on rat motor function, proprioception, and pain behavior (when administered intrathecally). In in vitro experiments, lidocaine produced concentration- and state-dependent effects on tonic block of voltage-gated Na⁺ currents (IC₅₀ of 66.2 and 212.9 µM at holding potentials of -70 and -100 mV, respectively). Caramiphen exhibited a milder state-dependence of block (IC₅₀ of 52.1 and 99.5 µM at holding potentials of -70 and -100 mV, respectively). Lidocaine showed a much stronger frequency-dependence of block than caramiphen: with high frequency stimulation (3.33 Hz), 50 µM caramiphen elicited an additional 20% blockade, whereas the same concentration of lidocaine produced 50% more block. In in vivo experiments, caramiphen with a more sensory-selective action over motor blockade was more potent than lidocaine (P<0.05) in spinal anesthesia. On an equipotent basis (25% effective dose (ED₂₅), ED₅₀, and ED₇₅), the duration of caramiphen at producing spinal anesthesia was longer than that of lidocaine (P<0.01). Our data revealed that caramiphen had a more potent, prolonged spinal blockade with a more sensory/nociceptive-selective action over motor blockade in comparison with lidocaine. Spinal anesthesia with caramiphen could be through the suppression of voltage-gated Na⁺ currents. PMID:25446426

  8. Changes in spinal alignment.

    PubMed

    Veintemillas Aráiz, M T; Beltrán Salazar, V P; Rivera Valladares, L; Marín Aznar, A; Melloni Ribas, P; Valls Pascual, R

    2016-04-01

    Spinal misalignments are a common reason for consultation at primary care centers and specialized departments. Misalignment has diverse causes and is influenced by multiple factors: in adolescence, the most frequent misalignment is scoliosis, which is idiopathic in 80% of cases and normally asymptomatic. In adults, the most common cause is degenerative. It is important to know the natural history and to detect factors that might predict progression. The correct diagnosis of spinal deformities requires specific imaging studies. The degree of deformity determines the type of treatment. The aim is to prevent progression of the deformity and to recover the flexibility and balance of the body.

  9. Emergence of Motor Circuit Activity

    PubMed Central

    Law, Chris; Paquet, Michel; Kania, Artur

    2014-01-01

    In the developing nervous system, ordered neuronal activity patterns can occur even in the absence of sensory input and to investigate how these arise, we have used the model system of the embryonic chicken spinal motor circuit, focusing on motor neurons of the lateral motor column (LMC). At the earliest stages of their molecular differentiation, we can detect differences between medial and lateral LMC neurons in terms of expression of neurotransmitter receptor subunits, including CHRNA5, CHRNA7, GRIN2A, GRIK1, HTR1A and HTR1B, as well as the KCC2 transporter. Using patch-clamp recordings we also demonstrate that medial and lateral LMC motor neurons have subtly different activity patterns that reflect the differential expression of neurotransmitter receptor subunits. Using a combination of patch-clamp recordings in single neurons and calcium-imaging of motor neuron populations, we demonstrate that inhibition of nicotinic, muscarinic or GABA-ergic activity, has profound effects of motor circuit activity during the initial stages of neuromuscular junction formation. Finally, by analysing the activity of large populations of motor neurons at different developmental stages, we show that the asynchronous, disordered neuronal activity that occurs at early stages of circuit formation develops into organised, synchronous activity evident at the stage of LMC neuron muscle innervation. In light of the considerable diversity of neurotransmitter receptor expression, activity patterns in the LMC are surprisingly similar between neuronal types, however the emergence of patterned activity, in conjunction with the differential expression of transmitter systems likely leads to the development of near-mature patterns of locomotor activity by perinatal ages. PMID:24722186

  10. Complete rat spinal cord transection as a faithful model of spinal cord injury for translational cell transplantation.

    PubMed

    Lukovic, Dunja; Moreno-Manzano, Victoria; Lopez-Mocholi, Eric; Rodriguez-Jiménez, Francisco Javier; Jendelova, Pavla; Sykova, Eva; Oria, Marc; Stojkovic, Miodrag; Erceg, Slaven

    2015-01-01

    Spinal cord injury (SCI) results in neural loss and consequently motor and sensory impairment below the injury. There are currently no effective therapies for the treatment of traumatic SCI in humans. Various animal models have been developed to mimic human SCI. Widely used animal models of SCI are complete or partial transection or experimental contusion and compression, with both bearing controversy as to which one more appropriately reproduces the human SCI functional consequences. Here we present in details the widely used procedure of complete spinal cord transection as a faithful animal model to investigate neural and functional repair of the damaged tissue by exogenous human transplanted cells. This injury model offers the advantage of complete damage to a spinal cord at a defined place and time, is relatively simple to standardize and is highly reproducible. PMID:25860664

  11. Complete rat spinal cord transection as a faithful model of spinal cord injury for translational cell transplantation.

    PubMed

    Lukovic, Dunja; Moreno-Manzano, Victoria; Lopez-Mocholi, Eric; Rodriguez-Jiménez, Francisco Javier; Jendelova, Pavla; Sykova, Eva; Oria, Marc; Stojkovic, Miodrag; Erceg, Slaven

    2015-04-10

    Spinal cord injury (SCI) results in neural loss and consequently motor and sensory impairment below the injury. There are currently no effective therapies for the treatment of traumatic SCI in humans. Various animal models have been developed to mimic human SCI. Widely used animal models of SCI are complete or partial transection or experimental contusion and compression, with both bearing controversy as to which one more appropriately reproduces the human SCI functional consequences. Here we present in details the widely used procedure of complete spinal cord transection as a faithful animal model to investigate neural and functional repair of the damaged tissue by exogenous human transplanted cells. This injury model offers the advantage of complete damage to a spinal cord at a defined place and time, is relatively simple to standardize and is highly reproducible.

  12. Prognostic value of cortical magnetic stimulation in spinal cord injury.

    PubMed

    Clarke, C E; Modarres-Sadeghi, H; Twomey, J A; Burt, A A

    1994-08-01

    Cortical magnetic stimulation was performed in a consecutive series of 10 patients presenting within 15 days of traumatic spinal cord injury. In those patients with complete paraplegia or quadriplegia, motor evoked potentials at presentation were absent below the level of the lesion. Six months after the injury, potentials had returned in the biceps brachii and abductor pollicis brevis muscles in some quadriplegic cases, but remained absent from the tibialis anterior in all of this group. None of those with a complete lesion made a significant functional recovery. Of the three patients with incomplete quadriplegia, two showed a significant recovery after 6 months. Motor evoked potentials were recordable below the level of the lesion at presentation in these cases, although the latencies were prolonged. In the remaining patient who failed to improve, potentials were unrecordable throughout the study. This small pilot study suggests that cortical magnetic stimulation may be useful in refining the prognosis in patients with an incomplete spinal cord injury. PMID:7970860

  13. Chondrolectin affects cell survival and neuronal outgrowth in in vitro and in vivo models of spinal muscular atrophy.

    PubMed

    Sleigh, James N; Barreiro-Iglesias, Antón; Oliver, Peter L; Biba, Angeliki; Becker, Thomas; Davies, Kay E; Becker, Catherina G; Talbot, Kevin

    2014-02-15

    Spinal muscular atrophy (SMA) is characterized by the selective loss of spinal motor neurons owing to reduced levels of survival motor neuron (Smn) protein. In addition to its well-established role in assembling constituents of the spliceosome, diverse cellular functions have been proposed for Smn, but the reason why low levels of this widely expressed protein result in selective motor neuron pathology is still debated. In longitudinal studies of exon-level changes in SMA mouse model tissues, designed to determine the contribution of splicing dysfunction to the disease, we have previously shown that a generalized defect in splicing is unlikely to play a causative role in SMA. Nevertheless, we identified a small subset of genes that were alternatively spliced in the spinal cord compared with control mice before symptom onset, indicating a possible mechanistic role in disease. Here, we have performed functional studies of one of these genes, chondrolectin (Chodl), known to be highly expressed in motor neurons and important for correct motor axon outgrowth in zebrafish. Using in vitro and in vivo models of SMA, we demonstrate altered expression of Chodl in SMA mouse spinal motor neurons, show that Chodl has distinct effects on cell survival and neurite outgrowth and that increasing the expression of chodl can rescue motor neuron outgrowth defects in Smn-depleted zebrafish. Our findings thus link the dysregulation of Chodl to the pathophysiology of motor neuron degeneration in SMA.

  14. Bone and Spinal Muscular Atrophy.

    PubMed

    Vai, Silvia; Bianchi, Maria Luisa; Moroni, Isabella; Mastella, Chiara; Broggi, Francesca; Morandi, Lucia; Arnoldi, Maria Teresa; Bussolino, Chiara; Baranello, Giovanni

    2015-10-01

    Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disease, leading to progressive denervation atrophy in the involved skeletal muscles. Bone status has been poorly studied. We assessed bone metabolism, bone mineral density (BMD) and fractures in 30 children (age range 15-171 months) affected by SMA types 2 and 3. Eighteen children (60%) had higher than normal levels of CTx (bone resorption marker); 25-OH vitamin D was in the lower range of normal (below 20 ng/ml in 9 children and below 12 ng/ml in 2). Lumbar spine BMAD (bone mineral apparent density) Z-score was below -1.5 in 50% of children. According to clinical records, four children had sustained four peripheral fractures; on spine X-rays, we observed 9 previously undiagnosed vertebral fractures in 7 children. There was a significant inverse regression between PTH and 25-OH D levels, and a significant regression between BMC and BMAD values and the scores of motor-functional tests. Even if this study could not establish the pathogenesis of bone derangements in SMA, its main findings - reduced bone density, low 25OH vitamin D levels, increased bone resorption markers and asymptomatic vertebral fractures also in very young patients - strongly suggest that even young subjects affected by SMA should be considered at risk of osteopenia and even osteoporosis and fractures. PMID:26055105

  15. THE LOCALIZED ACTION ON THE SPINAL CORD OF INTRAMUSCULARLY INJECTED TETANUS TOXIN

    PubMed Central

    Acheson, George H.; Ratnoff, Oscar D.; Schoenbach, Emanuel B.

    1942-01-01

    Local tetanus limited to one leg was studied in cats after intramuscular injection of tetanus toxin. 1. The electric and mechanical response of the affected muscle after a single stimulus to the intact sensory-motor nerve is greater in amplitude and duration than the response of the corresponding muscle of the unaffected leg (Fig. 1). 2. This augmented response of the muscle is associated with an augmented response arising from the ipsilateral portion of the spinal cord, while the contralateral part of the cord is unaffected, as demonstrated by electrographic records from the motor nerves (Figs. 2 to 5). 3. The augmented muscular response is abolished when the reflex arc is broken, but the augmented response in the spinal cord is independent of changes in the muscle, the neuromuscular junction, the afferent and efferent peripheral nerves, and the dorsal root ganglia. 4. The augmented spinal response develops in the absence of the peripheral signs of local tetanus. Hence the pathogenesis of the altered state in the spinal cord is independent of the peripheral effects of the toxin. 5. In local tetanus, therefore, the toxin injected intramuscularly acts selectively upon the segments of the spinal cord which supply the innervation of the injected area. 6. The augmented spinal response may be prevented by section of the nerve trunks supplying the area of injection prior to the injection of the toxin. 7. It is concluded that in local tetanus the toxin is carried to the spinal cord by way of peripheral nerves. PMID:19871198

  16. Neurosurgical approaches to spinal infections.

    PubMed

    Hazer, Derya Burcu; Ayhan, Selim; Palaoglu, Selcuk

    2015-05-01

    Spinal infection is rare. Clinical suspicion is important in patients with nonmechanical neck and/or back pain to make the proper diagnosis in early disease. Before planning surgery, a thorough evaluation of the spinal stability, alignment, and deformity is necessary. Timing of surgery, side of approach, appropriate surgical technique, and spinal instruments used are crucial. Biomechanical preservation of the spinal column during and after the infection is a significant issue. Postoperative spine infection is another entity of which spinal surgeons should be aware of. Proper septic conditions with meticulous planning of surgery are essential for successful spine surgery and better outcome. PMID:25952179

  17. Expression of the immunoglobulin superfamily cell adhesion molecules in the developing spinal cord and dorsal root ganglion.

    PubMed

    Gu, Zirong; Imai, Fumiyasu; Kim, In Jung; Fujita, Hiroko; Katayama, Kei ichi; Mori, Kensaku; Yoshihara, Yoshihiro; Yoshida, Yutaka

    2015-01-01

    Cell adhesion molecules belonging to the immunoglobulin superfamily (IgSF) control synaptic specificity through hetero- or homophilic interactions in different regions of the nervous system. In the developing spinal cord, monosynaptic connections of exquisite specificity form between proprioceptive sensory neurons and motor neurons, however, it is not known whether IgSF molecules participate in regulating this process. To determine whether IgSF molecules influence the establishment of synaptic specificity in sensory-motor circuits, we examined the expression of 157 IgSF genes in the developing dorsal root ganglion (DRG) and spinal cord by in situ hybridization assays. We find that many IgSF genes are expressed by sensory and motor neurons in the mouse developing DRG and spinal cord. For instance, Alcam, Mcam, and Ocam are expressed by a subset of motor neurons in the ventral spinal cord. Further analyses show that Ocam is expressed by obturator but not quadriceps motor neurons, suggesting that Ocam may regulate sensory-motor specificity in these sensory-motor reflex arcs. Electrophysiological analysis shows no obvious defects in synaptic specificity of monosynaptic sensory-motor connections involving obturator and quadriceps motor neurons in Ocam mutant mice. Since a subset of Ocam+ motor neurons also express Alcam, Alcam or other functionally redundant IgSF molecules may compensate for Ocam in controlling sensory-motor specificity. Taken together, these results reveal that IgSF molecules are broadly expressed by sensory and motor neurons during development, and that Ocam and other IgSF molecules may have redundant functions in controlling the specificity of sensory-motor circuits.

  18. Overexpression of survival motor neuron improves neuromuscular function and motor neuron survival in mutant SOD1 mice

    PubMed Central

    Turner, Bradley J.; Alfazema, Neza; Sheean, Rebecca K.; Sleigh, James N.; Davies, Kay E.; Horne, Malcolm K.; Talbot, Kevin

    2014-01-01

    Spinal muscular atrophy results from diminished levels of survival motor neuron (SMN) protein in spinal motor neurons. Low levels of SMN also occur in models of amyotrophic lateral sclerosis (ALS) caused by mutant superoxide dismutase 1 (SOD1) and genetic reduction of SMN levels exacerbates the phenotype of transgenic SOD1G93A mice. Here, we demonstrate that SMN protein is significantly reduced in the spinal cords of patients with sporadic ALS. To test the potential of SMN as a modifier of ALS, we overexpressed SMN in 2 different strains of SOD1G93A mice. Neuronal overexpression of SMN significantly preserved locomotor function, rescued motor neurons, and attenuated astrogliosis in spinal cords of SOD1G93A mice. Despite this, survival was not prolonged, most likely resulting from SMN mislocalization and depletion of gems in motor neurons of symptomatic mice. Our results reveal that SMN upregulation slows locomotor deficit onset and motor neuron loss in this mouse model of ALS. However, disruption of SMN nuclear complexes by high levels of mutant SOD1, even in the presence of SMN overexpression, might limit its survival promoting effects in this specific mouse model. Studies in emerging mouse models of ALS are therefore warranted to further explore the potential of SMN as a modifier of ALS. PMID:24210254

  19. Magnetoelectrical stimulation of motor cortex in children with motor disturbances.

    PubMed

    Müller, K; Hömberg, V; Aulich, A; Lenard, H G

    1992-04-01

    Transcranial magnetoelectrical stimulation (TMS) is now widely used as a diagnostic tool in adults. In this study we report our experiences with this technique in children with central motor disturbances. We used a Cadwell MES10 magnetoelectrical stimulator with a maximal magnetic field of 2 tesla. The stimulation procedure followed a standardized protocol, with the patients being as relaxed as possible in order to avoid contamination of parameters with different preinnervational levels. Stimulation data were compared to a data base obtained in 58 normal children. The first group of patients consisted of 20 children aged from 7 months to 16 years with hemiparesis of different etiologies. Neuroimaging data were correlated with the results of magnetoelectrical stimulation. In 13 patients a pathological pattern of TMS could be detected, and in 7 of these a corresponding lesion of the cortico-spinal tract was found in CT or MRI scans. In 7 children TMS was normal, in spite of a clear-cut lesion of the cortico-spinal tract in CT or MRI scans in 4 of them. The second group of patients consisted of 16 children with extrapyramidal disease, mostly of hereditary origin, such as DOPA-responsive dystonia or benign hereditary chorea. TMS showed a normal response pattern in this group. We discuss problems and possible pitfalls in TMS in childhood in evaluating the diagnostic value of TMS. At the moment the diagnostic usefulness of TMS in children with motor disturbances appears limited and calls for careful interpretation. PMID:1373370

  20. Spinal Cord Injury

    MedlinePlus

    ... How much do you know about taking good care of yourself? Links to more information girlshealth glossary girlshealth.gov home http://www.girlshealth.gov/ Home Illness & disability Types of ... Spinal cord injury Read advice from Dr. Jeffrey Rabin , a pediatric rehabilitation specialist at the Children’s National Medical Center. ...

  1. Maladaptive spinal plasticity opposes spinal learning and recovery in spinal cord injury

    PubMed Central

    Ferguson, Adam R.; Huie, J. Russell; Crown, Eric D.; Baumbauer, Kyle M.; Hook, Michelle A.; Garraway, Sandra M.; Lee, Kuan H.; Hoy, Kevin C.; Grau, James W.

    2012-01-01

    Synaptic plasticity within the spinal cord has great potential to facilitate recovery of function after spinal cord injury (SCI). Spinal plasticity can be induced in an activity-dependent manner even without input from the brain after complete SCI. A mechanistic basis for these effects is provided by research demonstrating that spinal synapses have many of the same plasticity mechanisms that are known to underlie learning and memory in the brain. In addition, the lumbar spinal cord can sustain several forms of learning and memory, including limb-position training. However, not all spinal plasticity promotes recovery of function. Central sensitization of nociceptive (pain) pathways in the spinal cord may emerge in response to various noxious inputs, demonstrating that plasticity within the spinal cord may contribute to maladaptive pain states. In this review we discuss interactions between adaptive and maladaptive forms of activity-dependent plasticity in the spinal cord below the level of SCI. The literature demonstrates that activity-dependent plasticity within the spinal cord must be carefully tuned to promote adaptive spinal training. Prior work from our group has shown that stimulation that is delivered in a limb position-dependent manner or on a fixed interval can induce adaptive plasticity that promotes future spinal cord learning and reduces nociceptive hyper-reactivity. On the other hand, stimulation that is delivered in an unsynchronized fashion, such as randomized electrical stimulation or peripheral skin injuries, can generate maladaptive spinal plasticity that undermines future spinal cord learning, reduces recovery of locomotor function, and promotes nociceptive hyper-reactivity after SCI. We review these basic phenomena, how these findings relate to the broader spinal plasticity literature, discuss the cellular and molecular mechanisms, and finally discuss implications of these and other findings for improved rehabilitative therapies after SCI. PMID

  2. Fibromyalgia and arachnoiditis presented as an acute spinal disorder

    PubMed Central

    Idris, Zamzuri; Ghazali, Faizul H.; Abdullah, Jafri M.

    2014-01-01

    Background: Adhesive arachnoiditis is a chronic, insidious condition that causes debilitating intractable pain and a range of other neurological problems. Its pathophysiology is not well understood. This manuscript discusses its presentations, which can mimic an acute spinal disorder, its hypothetical pathophysiology, treatment, and its relationship with fibromyalgia. Case Description: The authors present a case of a 47-year-old female who presented with clinical features mimicking an acute spinal disorder but later found to have an adhesive arachnoiditis. She was admitted following a trauma with complaints of back pain and paraplegia. On examination, there was marked tenderness over thoracolumbar spine with lower limbs upper motor neuron weakness. An urgent magnetic resonance imaging (MRI) of the spine revealed multiple lesions at her thoracic and lumbar spinal canals, which did not compress the spinal cord. Therefore, conservative management was initiated. Despite on regular therapies, her back and body pain worsened and little improvement in her limbs power was noted. Laminectomy was pursued and found to have spinal cord arachnoiditis. Subsequently, she was operated by other team members for multiple pelvic masses, which later proved to be benign. After gathering all the clinical information obtained at surgery and after taking detailed history inclusive of cognitive functions, diagnosis of an adhesive arachnoiditis syndrome was made. Currently, she is managed by neuropsychologist and pain specialist. Conclusion: This case report highlights the importance of knowing an adhesive arachnoiditis syndrome – a rarely discussed pathology by the neurosurgeon, which discloses a significant relationship between immune and nervous systems. PMID:25396073

  3. Frequency Mapping of Rat Spinal Cord at 7T

    NASA Astrophysics Data System (ADS)

    Chen, Evan; Rauscher, Alexander; Kozlowski, Piotr; Yung, Andrew

    2012-10-01

    The spinal cord is an integral part of the nervous system responsible for sensory, motor, and reflex control crucial to all bodily function. Due to its non-invasive nature, MRI is well matched for characterizing and imaging of spinal cord, and is used extensively for clinical applications. Recent developments in magnetic resonance imaging (MRI) at high field (7T) using phase represents a new approach of characterizing spinal cord myelin. Theory suggests that microstructure differences in myelinated white matter (WM) and non-myelinated gray matter (GM) affect MR phase, measurable frequency shifts. Data from pilot experiments using a multi-gradient echo (MGE) sequence to image rat spinal cords placed parallel to main magnetic field B0 has shown frequency shifts between not only between WM and GM, but also between specific WM tracts of the dorsal column, including the fasciculus gracilis, fasciculus cuneatus, and corticospinal tract. Using MGE, frequency maps at multiple echo times (TE) between 4ms and 22ms show a non-linear relationship between WM frequency, contrary to what was previously expected. These results demonstrate the effectiveness of MGE in revealing new information about spinal cord tissue microstructure, and lays important groundwork for in-vivo and human studies.

  4. Chronic generalized spinal muscular atrophy of infancy and childhood

    PubMed Central

    Pearn, J. H.; Wilson, J.

    1973-01-01

    Recent studies have shown that the acute fatal form of infantile spinal muscular atrophy (acute Werdnig-Hoffmann disease or spinal muscular atrophy Type I) is a distinct genetic and clinical entity. This has prompted clinical re-examination of the disease known as `arrested Werdnig-Hoffmann disease' which hitherto was thought to be a spectrum variant of the acute fatal form. A total of 18 such patients with the chronic generalized form of spinal muscular atrophy has been known to The Hospital for Sick Children over the past 10 years. Patients with this characteristic clinical syndrome comprise approximately one-fifth of children with chronic spinal muscular atrophy. Clinically, no patient was even able to crawl normally or progress further with motor milestones. Median age of clinical onset is 6 months of age, and life expectancy ranges from 2 years to the third decade. Inevitable spinal and joint deformities occur by the second decade of life. Management should be based on vigorous antibiotic therapy, orthopaedic and neurological surveillance, and a carefully planned educational programme aimed at realistic employment in late adolescence. ImagesFIG. 4p772-b PMID:4749680

  5. Motor cortex electrical stimulation augments sprouting of the corticospinal tract and promotes recovery of motor function

    PubMed Central

    Carmel, Jason B.; Martin, John H.

    2014-01-01

    The corticospinal system—with its direct spinal pathway, the corticospinal tract (CST) – is the primary system for controlling voluntary movement. Our approach to CST repair after injury in mature animals was informed by our finding that activity drives establishment of connections with spinal cord circuits during postnatal development. After incomplete injury in maturity, spared CST circuits sprout, and partially restore lost function. Our approach harnesses activity to augment this injury-dependent CST sprouting and to promote function. Lesion of the medullary pyramid unilaterally eliminates all CST axons from one hemisphere and allows examination of CST sprouting from the unaffected hemisphere. We discovered that 10 days of electrical stimulation of either the spared CST or motor cortex induces CST axon sprouting that partially reconstructs the lost CST. Stimulation also leads to sprouting of the cortical projection to the magnocellular red nucleus, where the rubrospinal tract originates. Coordinated outgrowth of the CST and cortical projections to the red nucleus could support partial re-establishment of motor systems connections to the denervated spinal motor circuits. Stimulation restores skilled motor function in our animal model. Lesioned animals have a persistent forelimb deficit contralateral to pyramidotomy in the horizontal ladder task. Rats that received motor cortex stimulation either after acute or chronic injury showed a significant functional improvement that brought error rate to pre-lesion control levels. Reversible inactivation of the stimulated motor cortex reinstated the impairment demonstrating the importance of the stimulated system to recovery. Motor cortex electrical stimulation is an effective approach to promote spouting of spared CST axons. By optimizing activity-dependent sprouting in animals, we could have an approach that can be translated to the human for evaluation with minimal delay. PMID:24994971

  6. Advanced Motors

    SciTech Connect

    Knoth, Edward A; Chelluri, Bhanumathi; Schumaker, Edward J

    2012-12-14

    vProject Summary Transportation energy usage is predicted to increase substantially by 2020. Hybrid vehicles and fuel cell powered vehicles are destined to become more prominent as fuel prices rise with the demand. Hybrid and fuel cell vehicle platforms are both dependent on high performance electric motors. Electric motors for transportation duty will require sizeable low-speed torque to accelerate the vehicle. As motor speed increases, the torque requirement decreases which results in a nearly constant power motor output. Interior permanent magnet synchronous motors (IPMSM) are well suited for this duty. , , These rotor geometries are configured in straight lines and semi circular arc shapes. These designs are of limited configurations because of the lack of availability of permanent magnets of any other shapes at present. We propose to fabricate rotors via a novel processing approach where we start with magnet powders and compact them into a net shape rotor in a single step. Using this approach, widely different rotor designs can be implemented for efficiency. The current limitation on magnet shape and thickness will be eliminated. This is accomplished by co-filling magnet and soft iron powders at specified locations in intricate shapes using specially designed dies and automatic powder filling station. The process fundamentals for accomplishing occurred under a previous Applied Technology Program titled, Motors and Generators for the 21st Century. New efficient motor designs that are not currently possible (or cost prohibitive) can be accomplished by this approach. Such an approach to motor fabrication opens up a new dimension in motor design. Feasibility Results We were able to optimize a IPMSM rotor to take advantage of the powder co-filling and DMC compaction processing methods. The minimum low speed torque requirement of 5 N-m can be met through an optimized design with magnet material having a Br capability of 0.2 T. This level of magnetic performance can

  7. A Pilot Clinical Study of Olfactory Mucosa Autograft for Chronic Complete Spinal Cord Injury

    PubMed Central

    IWATSUKI, Koichi; TAJIMA, Fumihiro; OHNISHI, Yu-ichiro; NAKAMURA, Takeshi; ISHIHARA, Masahiro; HOSOMI, Koichi; NINOMIYA, Koshi; MORIWAKI, Takashi; YOSHIMINE, Toshiki

    2016-01-01

    Recent studies of spinal cord axon regeneration have reported good long-term results using various types of tissue scaffolds. Olfactory tissue allows autologous transplantation and can easily be obtained by a simple biopsy that is performed through the external nares. We performed a clinical pilot study of olfactory mucosa autograft (OMA) for chronic complete spinal cord injury in eight patients according to the procedure outlined by Lima et al. Our results showed no serious adverse events and improvement in both the American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade and ASIA motor score in five patients. The preoperative post-rehabilitation ASIA motor score improved from 50 in all cases to 52 in case 2, 60 in case 4, 52 in case 6, 55 in case 7, and 58 in case 8 at 96 weeks after OMA. The AIS improved from A to C in four cases and from B to C in one case. Motor evoked potentials (MEPs) were also seen in one patient, reflecting conductivity in the central nervous system, including the corticospinal tract. The MEPs induced with transcranial magnetic stimulation allow objective assessment of the integrity of the motor circuitry comprising both the corticospinal tract and the peripheral motor nerves.We show the feasibility of OMA for chronic complete spinal cord injury. PMID:27053327

  8. [Histochemistry and choline acetyltransferase in cat spinal cord and spinal ganglia].

    PubMed

    Motavkin, P A; Okhotin, V E

    1978-09-01

    Cytochemical activity of choline acetyltransferase has been studied in the pericaryon of motor neurons of the spinal enlargement and sensitive neurocytes of the intervertebral ganglia in the cat by means of Burt's method. It has been demonstrated that cytoplasm of all motor neurons positively reacts with acetyl KoA. According to the activity of choline acetyltransferase, four groups of neurons have been determined. In cerebrospinal ganglia, the enzyme is present in 58% of pseudounipolar cells, which seem to be cholinergic neurocytes. It has been stated that for all nonspecific reactions the presence of massive and dense residue in all the neurons, walls of small blood vessels and sometimes in astrocytes is a characteristic feature. PMID:718431

  9. Immunotherapy strategies for spinal cord injury.

    PubMed

    Wang, Yong-Tang; Lu, Xiu-Min; Chen, Kai-Ting; Shu, Ya-Hai; Qiu, Chun-Hong

    2015-01-01

    Regeneration in the central nervous system (CNS) of adult mammalian after traumatic injury is limited, which often causes permanent functional motor and sensory loss. After spinal cord injury (SCI), the lack of regeneration is mainly attributed to the presence of a hostile microenvironment, glial scarring, and cavitation. Besides, inflammation has also been proved to play a crucial role in secondary degeneration following SCI. The more prominent treatment strategies in experimental models focus mainly on drugs and cell therapies, however, only a few strategies applied in clinical studies and therapies still have only limited effects on the repair of SCI. Recently, the interests in immunotherapy strategies for CNS are increasing in number and breadth. Immunotherapy strategies have made good progresses in treating many CNS degenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and multiple sclerosis (MS). However, the strategies begin to be considered to the treatment of SCI and other neurological disorders in recent years. Besides anti-inflamatory therapy, immunization with protein vaccines and DNA vaccines has emerged as a novel therapy strategy because of the simplicity of preparation and application. An inflammatory response followed by spinal cord injury, and is controled by specific signaling molecules, such as some cytokines playing a crucial role. As a result, appropriate immunoregulation, the expression of pro-inflammatory cytokines and anti-inflammatory cytokines may be an effective therapy strategy for earlier injury of spinal cord. In addition, myelinassociated inhibitors (MAIs) in the injured spinal cord, such as Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte- myelin glycoprotein (OMgp) are known to prevent axonal regeneration through their co-receptors, and to trigger demyelinating autoimmunity through T cell-mediated harmful autoimmune response. The antagonism of the MAIs through vaccinating with

  10. Different Modulation of Common Motor Information in Rat Primary and Secondary Motor Cortices

    PubMed Central

    Saiki, Akiko; Kimura, Rie; Samura, Toshikazu; Fujiwara-Tsukamoto, Yoko; Sakai, Yutaka; Isomura, Yoshikazu

    2014-01-01

    Rodents have primary and secondary motor cortices that are involved in the execution of voluntary movements via their direct and parallel projections to the spinal cord. However, it is unclear whether the rodent secondary motor cortex has any motor function distinct from the primary motor cortex to properly control voluntary movements. In the present study, we quantitatively examined neuronal activity in the caudal forelimb area (CFA) of the primary motor cortex and rostral forelimb area (RFA) of the secondary motor cortex in head-fixed rats performing forelimb movements (pushing, holding, and pulling a lever). We found virtually no major differences between CFA and RFA neurons, regardless of neuron subtypes, not only in their basal spiking properties but also in the time-course, amplitude, and direction preference of their functional activation for simple forelimb movements. However, the RFA neurons, as compared with the CFA neurons, showed obviously a greater susceptibility of their functional activation to an alteration in a behavioral situation, a 'rewarding' response that leads to reward or a 'consummatory' response that follows reward water, which might be accompanied by some internal adaptations without affecting the motor outputs. Our results suggest that, although the CFA and RFA neurons commonly process fundamental motor information to properly control forelimb movements, the RFA neurons may be functionally differentiated to integrate motor information with internal state information for an adaptation to goal-directed behaviors. PMID:24893154

  11. Motor neglect.

    PubMed Central

    Laplane, D; Degos, J D

    1983-01-01

    Motor neglect is characterised by an underutilisation of one side, without defects of strength, reflexes or sensibility. Twenty cases of frontal, parietal and thalamic lesions causing motor neglect, but all without sensory neglect, are reported. It is proposed that the cerebral structures involved in motor neglect are the same as those for sensory neglect and for the preparation of movement. As in sensory neglect, the multiplicity of the structures concerned suggests that this interconnection is necessary to maintain a sufficient level of activity. Predominance of left sided neglect by right sided lesions suggests that the left hemisphere is dominant for deliberate activity; hemispheric dominance could be applied to sensory neglect where conscious awareness would play the role of deliberate activity. PMID:6842219

  12. Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level.

    PubMed

    Brommer, Benedikt; Engel, Odilo; Kopp, Marcel A; Watzlawick, Ralf; Müller, Susanne; Prüss, Harald; Chen, Yuying; DeVivo, Michael J; Finkenstaedt, Felix W; Dirnagl, Ulrich; Liebscher, Thomas; Meisel, Andreas; Schwab, Jan M

    2016-03-01

    Pneumonia is the leading cause of death after acute spinal cord injury and is associated with poor neurological outcome. In contrast to the current understanding, attributing enhanced infection susceptibility solely to the patient's environment and motor dysfunction, we investigate whether a secondary functional neurogenic immune deficiency (spinal cord injury-induced immune deficiency syndrome, SCI-IDS) may account for the enhanced infection susceptibility. We applied a clinically relevant model of experimental induced pneumonia to investigate whether the systemic SCI-IDS is functional sufficient to cause pneumonia dependent on spinal cord injury lesion level and investigated whether findings are mirrored in a large prospective cohort study after human spinal cord injury. In a mouse model of inducible pneumonia, high thoracic lesions that interrupt sympathetic innervation to major immune organs, but not low thoracic lesions, significantly increased bacterial load in lungs. The ability to clear the bacterial load from the lung remained preserved in sham animals. Propagated immune susceptibility depended on injury of central pre-ganglionic but not peripheral postganglionic sympathetic innervation to the spleen. Thoracic spinal cord injury level was confirmed as an independent increased risk factor of pneumonia in patients after motor complete spinal cord injury (odds ratio = 1.35, P < 0.001) independently from mechanical ventilation and preserved sensory function by multiple regression analysis. We present evidence that spinal cord injury directly causes increased risk for bacterial infection in mice as well as in patients. Besides obvious motor and sensory paralysis, spinal cord injury also induces a functional SCI-IDS ('immune paralysis'), sufficient to propagate clinically relevant infection in an injury level dependent manner.

  13. Effect of melatonin on the functional recovery from experimental traumatic compression of the spinal cord

    PubMed Central

    Schiaveto-de-Souza, A.; da-Silva, C.A.; Defino, H.L.A.; Bel, E.A.Del

    2013-01-01

    Spinal cord injury is an extremely severe condition with no available effective therapies. We examined the effect of melatonin on traumatic compression of the spinal cord. Sixty male adult Wistar rats were divided into three groups: sham-operated animals and animals with 35 and 50% spinal cord compression with a polycarbonate rod spacer. Each group was divided into two subgroups, each receiving an injection of vehicle or melatonin (2.5 mg/kg, intraperitoneal) 5 min prior to and 1, 2, 3, and 4 h after injury. Functional recovery was monitored weekly by the open-field test, the Basso, Beattie and Bresnahan locomotor scale and the inclined plane test. Histological changes of the spinal cord were examined 35 days after injury. Motor scores were progressively lower as spacer size increased according to the motor scale and inclined plane test evaluation at all times of assessment. The results of the two tests were correlated. The open-field test presented similar results with a less pronounced difference between the 35 and 50% compression groups. The injured groups presented functional recovery that was more evident in the first and second weeks. Animals receiving melatonin treatment presented more pronounced functional recovery than vehicle-treated animals as measured by the motor scale or inclined plane. NADPH-d histochemistry revealed integrity of the spinal cord thoracic segment in sham-operated animals and confirmed the severity of the lesion after spinal cord narrowing. The results obtained after experimental compression of the spinal cord support the hypothesis that melatonin may be considered for use in clinical practice because of its protective effect on the secondary wave of neuronal death following the primary wave after spinal cord injury. PMID:23579633

  14. The validity of multimodal intraoperative monitoring (MIOM) in surgery of 109 spine and spinal cord tumors

    PubMed Central

    Eggspuehler, Andreas; Grob, Dieter; Jeszenszky, Dezsö; Benini, Arnaldo; Porchet, Francois; Mueller, Alfred; Dvorak, Jiri

    2007-01-01

    In a prospective study of 109 patients with tumor of the spine MIOM was performed during the surgical procedure between March 2000 and December 2005. To determine the sensitivity and specificity of MIOM techniques used to monitor spinal cord and nerve root function during surgical procedure of spinal tumors. MIOM become an integrated procedure during surgical approach to intramedullar and extramedullar spine tumors. The combination of monitoring ascending and descending pathways may provide more sensitive and specific results than SEP alone giving immediate feedback information regarding any neurological deficit during the operation. Intraoperative sensory spinal and cerebral evoked potential combined with EMG recordings and motor evoked potential of the spinal cord and muscles were evaluated and compared with postoperative clinical neurological changes. One hundred and nine consecutive patients with spinal tumors of different aetiologies were monitored by the means of MIOM during the entire surgical procedure. Eighty-two patients presented true negative findings while two patients monitored false negative, one false positive and 24 patients true positive findings where neurological deficits after the operation were present. All patients with neurological deficit recovered completely or to pre-existing neurological situation. The sensitivity of MIOM applied during surgery of spinal tumors has been calculated of 92% and specificity 99%. Based upon the results of the study MIOM is an effective method of monitoring the spinal cord and nerve root function during surgical approach of spinal tumors and consequently can reduce or prevent the occurrence of postoperative neurological deficit. PMID:17661095

  15. Multimodal intraoperative monitoring (MIOM) during surgical decompression of thoracic spinal stenosis in 36 patients

    PubMed Central

    Sutter, Martin A.; Grob, Dieter; Porchet, F.; Jeszenszky, Dezsö; Dvorak, Jiri

    2007-01-01

    A prospective study of 36 patients who received multimodal intraoperative monitoring (MIOM) during decompression of thoracic spinal stenosis between March 2000 and December 2005 was chosen as the study design. The objective was to determine the sensitivity and specificity of MIOM techniques used for monitoring spinal cord during surgical thoracic decompression. The background data revealed that the surgical decompression for thoracic spinal stenosis is less frequent than in other regions of the spine. However, due to the relative narrow spinal canal, neurological complications could be severe. The combination of monitoring ascending and descending pathways may provide an early alert to the surgeon in order to alter the surgical procedure, and avoid neurological complications. The methods involved evaluation of intraoperative somatosensory spinal and cerebral evoked potentials and motor evoked potentials of the spinal cord and muscles that were compared with post operative clinical neurological changes. 36 consecutive patients with thoracic spinal stenosis of different aetiologies were monitored by the means of MIOM during the surgical procedure. 31 patients had true negative while one patient had false positive findings. Three patients had true positive and one patient had false negative findings. This indicates a sensitivity of 75% and a specificity of 97%. The one case of false negative findings recovered completely within 3 months. In conclusion, the MIOM is an effective method of monitoring the spinal cord during surgical decompression of the thoracic spine. PMID:17610089