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Sample records for motor vehicle-related spinal

  1. Human Spinal Motor Control.

    PubMed

    Nielsen, Jens Bo

    2016-07-01

    Human studies in the past three decades have provided us with an emerging understanding of how cortical and spinal networks collaborate to ensure the vast repertoire of human behaviors. Humans have direct cortical connections to spinal motoneurons, which bypass spinal interneurons and exert a direct (willful) muscle control with the aid of a context-dependent integration of somatosensory and visual information at cortical level. However, spinal networks also play an important role. Sensory feedback through spinal circuitries is integrated with central motor commands and contributes importantly to the muscle activity underlying voluntary movements. Regulation of spinal interneurons is used to switch between motor states such as locomotion (reciprocal innervation) and stance (coactivation pattern). Cortical regulation of presynaptic inhibition of sensory afferents may focus the central motor command by opening or closing sensory feedback pathways. In the future, human studies of spinal motor control, in close collaboration with animal studies on the molecular biology of the spinal cord, will continue to document the neural basis for human behavior. PMID:27023730

  2. Tribal motor vehicle injury prevention programs for reducing disparities in motor vehicle-related injuries.

    PubMed

    West, Bethany A; Naumann, Rebecca B

    2014-04-18

    A previous analysis of National Vital Statistics System data for 2003-2007 that examined disparities in rates of motor vehicle-related death by race/ethnicity and sex found that death rates for American Indians/Alaska Natives were two to four times the rates of other races/ethnicities. To address the disparity in motor vehicle-related injuries and deaths among American Indians/Alaska Natives, CDC funded four American Indian tribes during 2004-2009 to tailor, implement, and evaluate evidence-based road safety interventions. During the implementation of these four motor vehicle-related injury prevention pilot programs, seat belt and child safety seat use increased and alcohol-impaired driving decreased. Four American Indian/Alaska Native tribal communities-the Tohono O'odham Nation, the Ho-Chunk Nation, the White Mountain Apache Tribe, and the San Carlos Apache Tribe-implemented evidence-based road safety interventions to reduce motor vehicle-related injuries and deaths. Each community selected interventions from the Guide to Community Preventive Services and implemented them during 2004-2009. Furthermore, each community took a multifaceted approach by incorporating several strategies, such as school and community education programs, media campaigns, and collaborations with law enforcement officers into their programs. Police data and direct observational surveys were the main data sources used to assess results of the programs. Results included increased use of seat belts and child safety seats, increased enforcement of alcohol-impaired driving laws, and decreased motor vehicle crashes involving injuries or deaths. CDC's Office of Minority Health and Health Equity selected the intervention analysis and discussion as an example of a program that might be effective for reducing motor vehicle-related injury disparities in the United States. The Guide to Community Preventive Services recognizes these selected interventions as effective; this report examines the

  3. 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…

  4. 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

  5. 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

  6. 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

  7. 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.

  8. Construction equipment and motor vehicle related injuries on construction sites in Turkey.

    PubMed

    Gürcanli, G Emre; Müngen, Ugur; Akad, Murat

    2008-08-01

    Research on occupational accidents on construction sites in Turkey is very few. Moreover, research on motor vehicle and equipment accidents also do not exist. Investigation in the scope of this study shows that after falls and contact with electricity, accidents involving heavy equipment and motor vehicles rank third and fourth, respectively. This study aims to reveal the characteristics of these types of accidents, deduct the prominent causes that lead to fatalities as well as permanent disabilities using the present data. With the aid of obtained results, recommendations are made for safety experts on how to derive data from insufficient sources in Turkey and to evaluate these data for prevention and mitigation of the risks that construction workers are exposed to. 168 fatal and 38 non-fatal traffic accident-caused incidents as well as 206 fatal and 97 non-fatal construction equipment accidents, which were selected from official statistics and expert reports, were taken into consideration. Analysis and classification of these accidents were done according to the way they happened, the type of construction site and the occupation of the victims. Moreover, the leading causes of fatal and non-fatal injuries, to which drivers, operators and co-operators are exposed, are presented. Critical findings concerning prominent ways of occurrence, type of construction work and occupation are presented; and a number of measures for reducing the present risks are suggested. Some approaches for analysing relevant data are proposed for further research. PMID:18716386

  9. 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

    ... 41 Public Contracts and Property Management 3 2012-01-01 2012-01-01 false What Government-issued charge cards may I use to purchase fuel and motor vehicle related services? 102-34.320 Section 102-34.320 Public Contracts and Property Management Federal Property Management Regulations System (Continued) FEDERAL MANAGEMENT REGULATION...

  10. 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

    ... 41 Public Contracts and Property Management 3 2014-01-01 2014-01-01 false What Government-issued charge cards may I use to purchase fuel and motor vehicle related services? 102-34.320 Section 102-34.320 Public Contracts and Property Management Federal Property Management Regulations System (Continued) FEDERAL MANAGEMENT REGULATION...

  11. Spatial organization of cortical and spinal neurons controlling motor behavior

    PubMed Central

    Levine, Ariel J; Lewallen, Kathryn A; Pfaff, Samuel L

    2013-01-01

    A major task of the central nervous system (CNS) is to control behavioral actions, which necessitates a precise regulation of muscle activity. The final components of the circuitry controlling muscles are the motorneurons, which settle into pools in the ventral horn of the spinal cord in positions that mirror the musculature organization within the body. This ‘musculotopic’ motor-map then becomes the internal CNS reference for the neuronal circuits that control motor commands. This review describes recent progress in defining the neuroanatomical organization of the higher-order motor circuits in the cortex and spinal cord, and our current understanding of the integrative features that contribute to complex motor behaviors. We highlight emerging evidence that cortical and spinal motor command centers are loosely organized with respect to the musculotopic spatial-map, but these centers also incorporate organizational features that associate with the function of different muscle groups during commonly enacted behaviors. PMID:22841417

  12. Changes in corticospinal facilitation of lower limb spinal motor neurons after spinal cord lesions.

    PubMed Central

    Brouwer, B; Bugaresti, J; Ashby, P

    1992-01-01

    The projections from the cortex to the motor neurons of lower limb muscles were examined in 33 normal subjects and 16 patients with incomplete spinal cord lesions. Corticospinal neurons were excited by transcranial magnetic stimulation and the effects on single spinal motor neurons determined from peristimulus time histograms (PSTHs) of single tibialis anterior (TA) and soleus (SOL) motor units. In normal subjects magnetic stimulation produced a short latency facilitation of TA motor units but had little or no effect on SOL motor units. In the patients with spinal cord lesions magnetic stimulation also produced facilitation of TA but not SOL motor units; however, the mean latency of the TA facilitation was significantly longer (by about 14 ms) in the patient group. The F wave latencies were normal in all patients tested, suggesting that central rather than peripheral conduction was slowed. The duration of the period of increased firing probability (in TA motor units) was also significantly longer in the patients with spinal cord lesions. These changes may reflect the slowing of conduction and dispersal of conduction velocities in the corticospinal pathways as a consequence of the spinal cord lesion. No significant correlations were found between the delay of the TA facilitation and the clinical deficits in this group of patients. Images PMID:1312579

  13. 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

  14. 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

  15. Motor imagery and cortico-spinal excitability: A review.

    PubMed

    Grosprêtre, Sidney; Ruffino, Célia; Lebon, Florent

    2016-01-01

    Motor imagery (MI) has received a lot of interest during the last decades as its chronic or acute use has demonstrated several effects on improving sport performances or skills. The development of neuroimagery techniques also helped further our understanding of the neural correlates underlying MI. While some authors showed that MI, motor execution and action observation activated similar motor cortical regions, transcranial magnetic stimulation (TMS) studies brought great insights on the role of the primary motor cortex and on the activation of the cortico-spinal pathway during MI. After defining MI and describing the TMS technique, a short report of MI activities only at cortical level is provided. Then, a main focus on the specificities of cortico-spinal modulations during MI, investigated by TMS, is provided. Finally, a brief overview of sub-cortical mechanisms gives importance to the activation of peripheral neural structures during MI. PMID:25830411

  16. Motor imagery muscle contraction strength influences spinal motor neuron excitability and cardiac sympathetic nerve activity

    PubMed Central

    Bunno, Yoshibumi; Suzuki, Toshiaki; Iwatsuki, Hiroyasu

    2015-01-01

    [Purpose] The aim of this study was to investigate the changes in spinal motor neuron excitability and autonomic nervous system activity during motor imagery of isometric thenar muscle activity at 10% and 50% maximal voluntary contraction (MVC). [Methods] The F-waves and low frequency/high frequency (LF/HF) ratio were recorded at rest, during motor imagery, and post-trial. For motor imagery trials, subjects were instructed to imagine thenar muscle activity at 10% and 50% MVC while holding the sensor of a pinch meter for 5 min. [Results] The F-waves and LF/HF ratio during motor imagery at 50% MVC were significantly increased compared with those at rest, whereas those during motor imagery at 10% MVC were not significantly different from those at rest. The relative values of the F/M amplitude ratio during motor imagery at 50% MVC were significantly higher than those at 10% MVC. The relative values of persistence and the LF/HF ratio during motor imagery were similar during motor imagery at the two muscle contraction strengths. [Conclusion] Motor imagery can increase the spinal motor neuron excitability and cardiac sympathetic nerve activity. Motor imagery at 50% MVC may be more effective than motor imagery at 10% MVC. PMID:26834354

  17. 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.

  18. Decreased spinal synaptic inputs to phrenic motor neurons elicit localized inactivity-induced phrenic motor facilitation

    PubMed Central

    Streeter, K.A.; Baker-Herman, T.L.

    2014-01-01

    Phrenic motor neurons receive rhythmic synaptic inputs throughout life. Since even brief disruption in phrenic neural activity is detrimental to life, on-going neural activity may play a key role in shaping phrenic motor output. To test the hypothesis that spinal mechanisms sense and respond to reduced phrenic activity, anesthetized, ventilated rats received micro-injections of procaine in the C2 ventrolateral funiculus (VLF) to transiently (~30 min) block axon conduction in bulbospinal axons from medullary respiratory neurons that innervate one phrenic motor pool; during procaine injections, contralateral phrenic neural activity was maintained. Once axon conduction resumed, a prolonged increase in phrenic burst amplitude was observed in the ipsilateral phrenic nerve, demonstrating inactivity-induced phrenic motor facilitation (iPMF). Inhibition of tumor necrosis factor alpha (TNFα) and atypical PKC (aPKC) activity in spinal segments containing the phrenic motor nucleus impaired ipsilateral iPMF, suggesting a key role for spinal TNFα and aPKC in iPMF following unilateral axon conduction block. A small phrenic burst amplitude facilitation was also observed contralateral to axon conduction block, indicating crossed spinal phrenic motor facilitation (csPMF). csPMF was independent of spinal TNFα and aPKC. Ipsilateral iPMF and csPMF following unilateral withdrawal of phrenic synaptic inputs were associated with proportional increases in phrenic responses to chemoreceptor stimulation (hypercapnia), suggesting iPMF and csPMF increase phrenic dynamic range. These data suggest that local, spinal mechanisms sense and respond to reduced synaptic inputs to phrenic motor neurons. We hypothesize that iPMF and csPMF may represent compensatory mechanisms that assure adequate motor output is maintained in a physiological system in which prolonged inactivity ends life. PMID:24681155

  19. Decreased spinal synaptic inputs to phrenic motor neurons elicit localized inactivity-induced phrenic motor facilitation.

    PubMed

    Streeter, K A; Baker-Herman, T L

    2014-06-01

    Phrenic motor neurons receive rhythmic synaptic inputs throughout life. Since even brief disruption in phrenic neural activity is detrimental to life, on-going neural activity may play a key role in shaping phrenic motor output. To test the hypothesis that spinal mechanisms sense and respond to reduced phrenic activity, anesthetized, ventilated rats received micro-injections of procaine in the C2 ventrolateral funiculus (VLF) to transiently (~30min) block axon conduction in bulbospinal axons from medullary respiratory neurons that innervate one phrenic motor pool; during procaine injections, contralateral phrenic neural activity was maintained. Once axon conduction resumed, a prolonged increase in phrenic burst amplitude was observed in the ipsilateral phrenic nerve, demonstrating inactivity-induced phrenic motor facilitation (iPMF). Inhibition of tumor necrosis factor alpha (TNFα) and atypical PKC (aPKC) activity in spinal segments containing the phrenic motor nucleus impaired ipsilateral iPMF, suggesting a key role for spinal TNFα and aPKC in iPMF following unilateral axon conduction block. A small phrenic burst amplitude facilitation was also observed contralateral to axon conduction block, indicating crossed spinal phrenic motor facilitation (csPMF). csPMF was independent of spinal TNFα and aPKC. Ipsilateral iPMF and csPMF following unilateral withdrawal of phrenic synaptic inputs were associated with proportional increases in phrenic responses to chemoreceptor stimulation (hypercapnia), suggesting iPMF and csPMF increase phrenic dynamic range. These data suggest that local, spinal mechanisms sense and respond to reduced synaptic inputs to phrenic motor neurons. We hypothesize that iPMF and csPMF may represent compensatory mechanisms that assure adequate motor output is maintained in a physiological system in which prolonged inactivity ends life. PMID:24681155

  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. Profound motor blockade with epidural ropivacaine following spinal bupivacaine.

    PubMed

    Buggy, D J; Allsager, C M; Coley, S

    1999-09-01

    Ropivacaine, a relatively new amide local anaesthetic, reputedly produces less motor block than equivalent doses of bupivacaine, potentially combining high-quality analgesia with the ability to ambulate. We report two cases of prolonged, profound motor block with patient-controlled epidural analgesia using 0.1% ropivacaine, following spinal bupivacaine for Caesarean section. As there was no evidence of inadvertent intrathecal ropivacaine administration or of any neurological injury, we hypothesise that epidural ropivacaine may interact with intrathecal bupivacaine to prolong its effect. PMID:10460566

  2. Spinal motor neuron excitability during the cutaneous silent period.

    PubMed

    Leis, A A; Stĕtkárová, I; Berić, A; Stokić, D S

    1995-12-01

    The physiologic mechanisms generating the cutaneous silent period (CSP) remain uncertain. It is not known whether the CSP occurs because of inexcitability of the spinal motor neuron. We therefore, assessed excitability of the motor neuron during the CSP using F-wave responses. H-reflexes were also elicited during the CSP. Electrical stimulation to the fifth digit produced the CSP in the voluntarily contracting abductor pollicis brevis muscle (APB). Median nerve stimulation at the wrist elicited control F or H responses during isometric APB contraction (condition 1) and in resting muscle (condition 2). Control amplitudes were compared to those elicited in the midst of the CSP. In Condition 1, F-wave amplitudes and frequency during the CSP were unchanged compared with controls. However, F-waves were increased in amplitude and frequency during the CSP (P < 0.001) relative to responses elicited in resting muscle (condition 2). H-reflexes during the CSP were suppressed (P < 0.001) compared with controls elicited during contraction (condition 1), but facilitated relative to the resting state (condition 2) in which no H-reflexes were elicitable. We conclude that spinal motor neurons remain excitable to antidromic volleys at the same time that the corticospinal volley is inhibited to produce the CSP. Moreover, motor neuron excitability appears to be increased during the CSP compared to the relaxed state. PMID:7477071

  3. Anatomical changes in human motor cortex and motor pathways following complete thoracic spinal cord injury.

    PubMed

    Wrigley, P J; Gustin, S M; Macey, P M; Nash, P G; Gandevia, S C; Macefield, V G; Siddall, P J; Henderson, L A

    2009-01-01

    A debilitating consequence of complete spinal cord injury (SCI) is the loss of motor control. Although the goal of most SCI treatments is to re-establish neural connections, a potential complication in restoring motor function is that SCI may result in anatomical and functional changes in brain areas controlling motor output. Some animal investigations show cell death in the primary motor cortex following SCI, but similar anatomical changes in humans are not yet established. The aim of this investigation was to use voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) to determine if SCI in humans results in anatomical changes within motor cortices and descending motor pathways. Using VBM, we found significantly lower gray matter volume in complete SCI subjects compared with controls in the primary motor cortex, the medial prefrontal, and adjacent anterior cingulate cortices. DTI analysis revealed structural abnormalities in the same areas with reduced gray matter volume and in the superior cerebellar cortex. In addition, tractography revealed structural abnormalities in the corticospinal and corticopontine tracts of the SCI subjects. In conclusion, human subjects with complete SCI show structural changes in cortical motor regions and descending motor tracts, and these brain anatomical changes may limit motor recovery following SCI. PMID:18483004

  4. Spinal muscular atrophy patient-derived motor neurons exhibit hyperexcitability

    PubMed Central

    Liu, Huisheng; Lu, Jianfeng; Chen, Hong; Du, Zhongwei; Li, Xue-Jun; Zhang, Su-Chun

    2015-01-01

    Spinal muscular atrophy (SMA) presents severe muscle weakness with limited motor neuron (MN) loss at an early stage, suggesting potential functional alterations in MNs that contribute to SMA symptom presentation. Using SMA induced pluripotent stem cells (iPSCs), we found that SMA MNs displayed hyperexcitability with increased membrane input resistance, hyperpolarized threshold, and larger action potential amplitude, which was mimicked by knocking down full length survival motor neuron (SMN) in non-SMA MNs. We further discovered that SMA MNs exhibit enhanced sodium channel activities with increased current amplitude and facilitated recovery, which was corrected by restoration of SMN1 in SMA MNs. Together we propose that SMN reduction results in MN hyperexcitability and impaired neurotransmission, the latter of which exacerbate each other via a feedback loop, thus contributing to severe symptoms at an early stage of SMA. PMID:26190808

  5. 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. PMID:26314089

  6. Intraoperative monitoring of spinal cord function using motor evoked potentials via transcutaneous epidural electrode during anterior cervical spinal surgery.

    PubMed

    Gokaslan, Z L; Samudrala, S; Deletis, V; Wildrick, D M; Cooper, P R

    1997-08-01

    Because false-positive results are not infrequent when monitoring somatosensory evoked potentials during surgery, monitoring of motor evoked potentials (MEPs) has been proposed and successfully used during the removal of spinal cord tumors. However, this often requires direct visual placement of an epidural electrode after a laminectomy. We evaluated the use of MEPs, recorded via a transcutaneously placed epidural electrode, to monitor motor pathway functional integrity during surgery on the anterior cervical spine. Sixteen patients underwent anterior cervical vertebral decompression and fusion for cervical myelopathy and/or radiculopathy. Before surgery, an epidural monitoring electrode was placed transcutaneously at the midthoracic level and was used to record MEPs after transcranial cortical electrical stimulation. Electrode placement was successful in all patients but one, and satisfactory baseline spinal MEPs were obtained except for one patient who had cerebral palsy with significant motor dysfunction. Patients showed no significant changes in spinal MEPs during surgery, and all had baseline or better motor function postoperatively. None had complications from epidural electrode placement or electrical stimulation. We conclude that motor pathways can be monitored safely during anterior cervical spinal surgery using spinal MEPs recorded via a transcutaneously placed epidural electrode, that MEP preservation during surgery correlates with good postoperative motor function, and that cerebral palsy patients may possess too few functional motor fibers to allow MEP recording. PMID:9278914

  7. 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

  8. 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

  9. 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

  10. Excitability of spinal motor neurons during motor imagery of thenar muscle activity under maximal voluntary contractions of 50% and 100%

    PubMed Central

    Bunno, Yoshibumi; Onigata, Chieko; Suzuki, Toshiaki

    2015-01-01

    [Purpose] We often perform physical therapy using motor imagery of muscle contraction to improve motor function for healthy subjects and central nerve disorders. This study aimed to determine the differences in the excitability of spinal motor neurons during motor imagery of a muscle contraction at different contraction strengths. [Subjects] We recorded the F-wave in 15 healthy subjects. [Methods] In resting trial, the muscle was relaxed during F-wave recording. For motor imagery trial, subjects were instructed to imagine maximal voluntary contractions of 50% and 100% while holding the sensor of a pinch meter, and F-waves were recorded for each contraction. The F-wave was recorded immediately after motor imagery. [Results] Persistence and F/M amplitude ratio during motor imagery under maximal voluntary contractions of 50% and 100% were significantly higher than that at rest. In addition, the relative values of persistence, F/M amplitude ratio, and latency were similar during motor imagery under the two muscle contraction strengths. [Conclusion] Motor imagery under maximal voluntary contractions of 50% and 100% can increase the excitability of spinal motor neurons. Differences in the imagined muscle contraction strengths are not involved in changes in the excitability of spinal motor neurons. PMID:26504291

  11. 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

  12. Body machine interface: remapping motor skills after spinal cord injury.

    PubMed

    Casadio, M; Pressman, A; Acosta, S; Danzinger, Z; Fishbach, A; Mussa-Ivaldi, F A; Muir, K; Tseng, H; Chen, D

    2011-01-01

    The goal of a body-machine interface (BMI) is to map the residual motor skills of the users into efficient patterns of control. The interface is subject to two processes of learning: while users practice controlling the assistive device, the interface modifies itself based on the user's residual abilities and preferences. In this study, we combined virtual reality and movement capture technologies to investigate the reorganization of movements that occurs when individuals with spinal cord injury (SCI) are allowed to use a broad spectrum of body motions to perform different tasks. Subjects, over multiple sessions, used their upper body movements to engage in exercises that required different operational functions such as controlling a keyboard for playing a videogame, driving a simulated wheelchair in a virtual reality (VR) environment, and piloting a cursor on a screen for reaching targets. In particular, we investigated the possibility of reducing the dimensionality of the control signals by finding repeatable and stable correlations of movement signals, established both by the presence of biomechanical constraints and by learned patterns of coordination. The outcomes of these investigations will provide guidance for further studies of efficient remapping of motor coordination for the control of assistive devices and are a basis for a new training paradigm in which the burden of learning is significantly removed from the impaired subjects and shifted to the devices. PMID:22275588

  13. 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

    ... Public Contracts and Property Management Federal Property Management Regulations System (Continued) FEDERAL MANAGEMENT REGULATION PERSONAL PROPERTY 34-MOTOR VEHICLE MANAGEMENT Motor Vehicle Fueling § 102-34... 41 Public Contracts and Property Management 3 2011-01-01 2011-01-01 false What...

  14. 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

    ... Public Contracts and Property Management Federal Property Management Regulations System (Continued) FEDERAL MANAGEMENT REGULATION PERSONAL PROPERTY 34-MOTOR VEHICLE MANAGEMENT Motor Vehicle Fueling § 102-34... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false What...

  15. 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

    ... Public Contracts and Property Management Federal Property Management Regulations System (Continued) FEDERAL MANAGEMENT REGULATION PERSONAL PROPERTY 34-MOTOR VEHICLE MANAGEMENT Motor Vehicle Fueling § 102-34... 41 Public Contracts and Property Management 3 2013-07-01 2013-07-01 false What...

  16. 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

  17. 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

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

    PubMed Central

    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. PMID:24860484

  19. Intrathecal amantadine for prolonged spinal blockade of sensory and motor functions in rats.

    PubMed

    Tzeng, Jann-Inn; Kan, Chung-Dann; Wang, Jieh-Neng; Wang, Jhi-Joung; Lin, Heng-Teng; Hung, Ching-Hsia

    2016-08-01

    We aimed to compare the hypothesized local anesthetic action of amantadine (1-adamantanamine) with that of the known local anesthetic mepivacaine. Motor, proprioceptive, and nociceptive functions were evaluated in rats after intrathecal administration. Amantadine elicited spinal anesthesia in a dose-related fashion and produced a better sensory-selective action over motor blockade (P < 0.01). On the 50% effective dose (ED50 ) basis, the rank of potency on spinal motor, proprioceptive, and nociceptive block was mepivacaine > amantadine (P < 0.01 for the differences). Amantadine (63.5 μmol/kg) and mepivacaine (7.1 μmol/kg) produced complete spinal block of motor function, proprioception, and nociception. On an equipotent basis (ED25 , ED50 , and ED75 ), the duration of amantadine was longer (P < 0.01) than that of mepivacaine on spinal motor, proprioceptive, and nociceptive block. Our preclinical data demonstrated that amantadine was less potent than mepivacaine at producing spinal anesthesia. The spinal block duration produced by amantadine was greater than that produced by mepivacaine. Both amantadine and mepivacaine produced a markedly nociceptive-specific blockade. PMID:27011292

  20. Distinct roles for secreted semaphorin signaling in spinal motor axon guidance.

    PubMed

    Huber, Andrea B; Kania, Artur; Tran, Tracy S; Gu, Chenghua; De Marco Garcia, Natalia; Lieberam, Ivo; Johnson, Dontais; Jessell, Thomas M; Ginty, David D; Kolodkin, Alex L

    2005-12-22

    Neuropilins, secreted semaphorin coreceptors, are expressed in discrete populations of spinal motor neurons, suggesting they provide critical guidance information for the establishment of functional motor circuitry. We show here that motor axon growth and guidance are impaired in the absence of Sema3A-Npn-1 signaling. Motor axons enter the limb precociously, showing that Sema3A controls the timing of motor axon in-growth to the limb. Lateral motor column (LMC) motor axons within spinal nerves are defasciculated as they grow toward the limb and converge in the plexus region. Medial and lateral LMC motor axons show dorso-ventral guidance defects in the forelimb. In contrast, Sema3F-Npn-2 signaling guides the axons of a medial subset of LMC neurons to the ventral limb, but plays no major role in regulating their fasciculation. Thus, Sema3A-Npn-1 and Sema3F-Npn-2 signaling control distinct steps of motor axon growth and guidance during the formation of spinal motor connections. PMID:16364899

  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. Assessment of corticospinal function in spinal cord injury using transcranial motor cortex stimulation: a review.

    PubMed

    McKay, W B; Stokic, D S; Dimitrijevic, M R

    1997-08-01

    Other than clinical examination, few methods exist for assessing the functional condition of descending long tracts of the spinal cord in humans. This review covers neurophysiological examination of the corticospinal system using transcranial electrical and magnetic motor cortex stimulation. The neurophysiological basis for the motor evoked potentials (MEPs) and the differences between the two methods are discussed followed by a review of their use in individuals with spinal cord injury (SCI). Transcranial motor cortex stimulation is used to monitor descending spinal cord tract condition during spinal surgeries and could be useful for assessing central nervous system trauma, especially in the unconscious multitrauma patient. In the chronic phase of SCI, recordings of MEPs have enabled the estimation of central conduction times that relate to the condition of axons passing through the injured segment of the spinal cord. They were found to correlate well with clinical examination scores but as predictors of outcome, the reports have been mixed. The use of transcranial motor cortex stimulation to modify segmental reflexes and in combination with volitional attempts have also provided evidence of conduction across the lesion in paralyzed SCI subjects. However, MEPs can be absent in some SCI individuals who may be able to volitionally activate muscles below the level of the spinal cord lesion. Such findings are useful in elucidating the neural mechanisms underlying the performance of a volitional movement and may serve to guide and monitor the effects of future treatments for paralysis in SCI and other neurological disorders. PMID:9300564

  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. 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

  5. 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

  6. Respiratory Motor Control Disrupted by Spinal Cord Injury: Mechanisms, Evaluation, and Restoration

    PubMed Central

    Terson de Paleville, Daniela G. L.; McKay, William B.; Folz, Rodney J.

    2012-01-01

    Pulmonary complications associated with persistent respiratory muscle weakness, paralysis, and spasticity are among the most important problems faced by patients with spinal cord injury when lack of muscle strength and disorganization of reciprocal respiratory muscle control lead to breathing insufficiency. This review describes the mechanisms of the respiratory motor control and its change in individuals with spinal cord injury, methods by which respiratory function is measured, and rehabilitative treatment used to restore respiratory function in those who have experienced such injury. PMID:22408690

  7. 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

  8. 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

  9. Circuits for grasping: spinal dI3 interneurons mediate cutaneous control of motor behavior.

    PubMed

    Bui, Tuan V; Akay, Turgay; Loubani, Osama; Hnasko, Thomas S; Jessell, Thomas M; Brownstone, Robert M

    2013-04-10

    Accurate motor performance depends on the integration in spinal microcircuits of sensory feedback information. Hand grasp is a skilled motor behavior known to require cutaneous sensory feedback, but spinal microcircuits that process and relay this feedback to the motor system have not been defined. We sought to define classes of spinal interneurons involved in the cutaneous control of hand grasp in mice and to show that dI3 interneurons, a class of dorsal spinal interneurons marked by the expression of Isl1, convey input from low threshold cutaneous afferents to motoneurons. Mice in which the output of dI3 interneurons has been inactivated exhibit deficits in motor tasks that rely on cutaneous afferent input. Most strikingly, the ability to maintain grip strength in response to increasing load is lost following genetic silencing of dI3 interneuron output. Thus, spinal microcircuits that integrate cutaneous feedback crucial for paw grip rely on the intermediary role of dI3 interneurons. PMID:23583114

  10. 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

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

    PubMed Central

    Huxtable, Adrianne G.; Smith, Stephanie M.C.; Peterson, Timothy J.; Watters, Jyoti J.

    2015-01-01

    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). PMID:25926462

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

    PubMed

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

    2016-05-01

    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

  13. 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

  14. 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

  15. Longitudinal Evaluation of Residual Cortical and Subcortical Motor Evoked Potentials in Spinal Cord Injured Rats.

    PubMed

    Redondo-Castro, Elena; Navarro, Xavier; García-Alías, Guillermo

    2016-05-15

    We have applied transcranial electrical stimulation to rats with spinal cord injury and selectively tested the motor evoked potentials (MEPs) conveyed by descending motor pathways with cortical and subcortical origin. MEPs were elicited by electrical stimulation to the brain and recorded on the tibialis anterior muscles. Stimulation parameters were characterized and changes in MEP responses tested in uninjured rats, in rats with mild or moderate contusion, and in animals with complete transection of the spinal cord. All injuries were located at the T8 vertebral level. Two peaks, termed N1 and N2, were obtained when changing from single pulse stimulation to trains of 9 pulses at 9 Hz. Selective injuries to the brain or spinal cord funiculi evidenced the subcortical origin of N1 and the cortical origin of N2. Animals with mild contusion showed small behavioral deficits and abolished N1 but maintained small amplitude N2 MEPs. Substantial motor deficits developed in rats with moderate contusion, and these rats had completely eliminated N1 and N2 MEPs. Animals with complete cord transection had abolished N1 and N2 and showed severe impairment of locomotion. The results indicate the reliability of MEP testing to longitudinally evaluate over time the degree of impairment of cortical and subcortical spinal pathways after spinal cord injuries of different severity. PMID:26560177

  16. 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

  17. Glycoconjugates Distribution during Developing Mouse Spinal Cord Motor Organizers

    PubMed Central

    Vojoudi, Elham; Ebrahimi, Vahid; Ebrahimzadeh-Bideskan, Alireza; Fazel, Alireza

    2015-01-01

    Background: The aim of this research was to study the distribution and changes of glycoconjugates particularly their terminal sugars by using lectin histochemistry during mouse spinal cord development. Methods: Formalin-fixed sections of mouse embryo (10-16 fetal days) were processed for lectin histochemical method. In this study, two groups of horseradish peroxidase-labeled specific lectins were used: N-acetylgalactosamine, including Dolichos biflorus, Wisteria floribunda agglutinin (WFA), Vicia villosa, Glycine max as well as focuse-binding lectins, including tetragonolobus, Ulex europaeus, and Orange peel fungus (OFA). All sections were counterstained with alcian blue (pH 2.5). Results: Our results showed that only WFA and OFA reacted strongly with the floor plate cells from early to late embryonic period of developing spinal cord. The strongest reactions were related to the 14, 15, and 16 days of tissue sections incubated with OFA and WFA lectins. Conclusion: The present study demonstrated that cellular and molecular differentiation of the spinal cord organizers is a wholly regulated process, and α-L-fucose, α-D-GalNAc, and α/β-D-GalNAc terminal sugars play a significant role during the prenatal spinal cord development. PMID:25605492

  18. Immediate plasticity in the motor pathways after spinal cord hemisection: implications for transcranial magnetic motor-evoked potentials.

    PubMed

    Fujiki, Minoru; Kobayashi, Hidenori; Inoue, Ryo; Ishii, Keisuke

    2004-06-01

    The present study evaluates motor functional recovery after C2 spinal cord hemisection with or without contralateral brachial root transection, which causes a condition that is similar to the crossed phrenic phenomenon on rats. Descending motor pathways, including the reticulospinal extrapyramidal tract and corticospinal pyramidal tracts, were evaluated by transcranial magnetic motor-evoked potentials (mMEPs) and direct cortical electrical motor-evoked potentials (eMEP), respectively. All MEPs recorded from the left forelimb were abolished immediately after the left C2 hemisection. Left mMEPs recovered dramatically immediately after contralateral right brachial root transection. Corticospinal eMEPs never recovered, regardless of transection. The facilitation of mMEPs in animals that had undergone combined contralateral root transection was well correlated with open-field behavioral motor performance. Both electrophysiological and neurological facilitations were significantly attenuated by the selective serotonin synthesis inhibitor para-chlorophenylalanine (p-CPA). These results suggest that serotonergic reticulospinal fibers located contralateral to hemisection contribute to the behavioral and electrophysiological improvement that immediately follows spinal cord injury (SCI). PMID:15144873

  19. 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

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

    PubMed Central

    Strey, K.A.; Nichols, N.L.; Baertsch, N.A.; Broytman, O.; Baker-Herman, T.L.

    2012-01-01

    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/p62 in spinal regions associated with the phrenic motor pool. Although PKCζ/Ι activity is necessary for iPMF, spinal aPKC 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 where prolonged inactivity ends life. PMID:23152633

  1. 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

  2. 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

  3. 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

  4. Spinal segment-specific transcutaneous stimulation differentially shapes activation pattern among motor pools in humans.

    PubMed

    Sayenko, Dimitry G; Atkinson, Darryn A; Dy, Christine J; Gurley, Katelyn M; Smith, Valerie L; Angeli, Claudia; Harkema, Susan J; Edgerton, V Reggie; Gerasimenko, Yury P

    2015-06-01

    Transcutaneous and epidural electrical spinal cord stimulation techniques are becoming more valuable as electrophysiological and clinical tools. Recently, we observed selective activation of proximal and distal motor pools during epidural spinal stimulation. In the present study, we hypothesized that the characteristics of recruitment curves obtained from leg muscles will reflect a relative preferential activation of proximal and distal motor pools based on their arrangement along the lumbosacral enlargement. The purpose was to describe the electrophysiological responses to transcutaneous stimulation in leg muscles innervated by motoneurons from different segmental levels. Stimulation delivered along the rostrocaudal axis of the lumbosacral enlargement in the supine position resulted in a selective topographical recruitment of proximal and distal leg muscles, as described by threshold intensity, slope of the recruitment curves, and plateau point intensity and magnitude. Relatively selective recruitment of proximal and distal motor pools can be titrated by optimizing the site and intensity level of stimulation to excite a given combination of motor pools. The slope of the recruitment of particular muscles allows characterization of the properties of afferents projecting to specific motoneuron pools, as well as to the type and size of the motoneurons. The location and intensity of transcutaneous spinal electrical stimulation are critical to target particular neural structures across different motor pools in investigation of specific neuromodulatory effects. Finally, the asymmetry in bilateral evoked potentials is inevitable and can be attributed to both anatomical and functional peculiarities of individual muscles or muscle groups. PMID:25814642

  5. 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

  6. 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

  7. Stem cell-derived motor neurons from spinal and bulbar muscular atrophy patients.

    PubMed

    Grunseich, Christopher; Zukosky, Kristen; Kats, Ilona R; Ghosh, Laboni; Harmison, George G; Bott, Laura C; Rinaldi, Carlo; Chen, Ke-lian; Chen, Guibin; Boehm, Manfred; Fischbeck, Kenneth H

    2014-10-01

    Spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is a motor neuron disease caused by polyglutamine repeat expansion in the androgen receptor. Although degeneration occurs in the spinal cord and muscle, the exact mechanism is not clear. Induced pluripotent stem cells from spinal and bulbar muscular atrophy patients provide a useful model for understanding the disease mechanism and designing effective therapy. Stem cells were generated from six patients and compared to control lines from three healthy individuals. Motor neurons from four patients were differentiated from stem cells and characterized to understand disease-relevant phenotypes. Stem cells created from patient fibroblasts express less androgen receptor than control cells, but show androgen-dependent stabilization and nuclear translocation. The expanded repeat in several stem cell clones was unstable, with either expansion or contraction. Patient stem cell clones produced a similar number of motor neurons compared to controls, with or without androgen treatment. The stem cell-derived motor neurons had immunoreactivity for HB9, Isl1, ChAT, and SMI-32, and those with the largest repeat expansions were found to have increased acetylated α-tubulin and reduced HDAC6. Reduced HDAC6 was also found in motor neuron cultures from two other patients with shorter repeats. Evaluation of stably transfected mouse cells and SBMA spinal cord showed similar changes in acetylated α-tubulin and HDAC6. Perinuclear lysosomal enrichment, an HDAC6 dependent process, was disrupted in motor neurons from two patients with the longest repeats. SBMA stem cells present new insights into the disease, and the observations of reduced androgen receptor levels, repeat instability, and reduced HDAC6 provide avenues for further investigation of the disease mechanism and development of effective therapy. PMID:24925468

  8. Increased atypical PKC expression and activity in the phrenic motor nucleus following cervical spinal injury

    PubMed Central

    Guenther, C.H.; Windelborn, J.A.; Tubon, T.C.; Yin, J.C.P.; Mitchell, G.S.

    2012-01-01

    Atypical protein kinase C (aPKC) isoforms are expressed in phrenic motor neurons, a group of motor neurons critical for breathing. Following C2 cervical hemisection (C2HS), spontaneous plasticity occurs in crossed-spinal synaptic pathways to phrenic motor neurons, at least partially restoring inspiratory phrenic activity below the injury. Since aPKCs are necessary for synaptic plasticity in other systems, we tested the hypothesis that C2HS increases aPKC expression and activity in spinal regions associated with the phrenic motor nucleus. C2 laminectomy (sham) or C2HS was performed on adult, male Lewis rats. Ventral spinal segments C3–5 were harvested 1, 3 or 28 days post-surgery, and prepared for aPKC enzyme activity assays and immunoblots. Ventral cervical aPKC activity was elevated 1 and 28, but not 3, days post-C2HS (1 day: 63% vs sham ipsilateral to injury; p<0.05; 28 day: 426% vs sham; p<0.05; no difference in ipsilateral vs contralateral response). Total PKCζ/ι protein expression was unchanged by C2HS, but total and phosphorylated PKMζ (constitutively active PKCζ isoform) increased ipsilateral to injury 28 days post-C2HS (p<0.05). Ipsilateral aPKC activity and expression were strongly correlated (r2=0.675, p<0.001). In a distinct group of rats, immunohistochemistry confirmed that aPKCs are expressed in neurons 28 days post-C2HS, including large, presumptive phrenic motor neurons; aPKCs were not detected in adjacent microglia (OX-42 positive cells) or astrocytes (GFAP positive cells). Changes in aPKC expression in the phrenic motor nucleus following C2HS suggests that aPKCs may contribute to functional recovery following cervical spinal injury. PMID:22329943

  9. Spinal adenosine A2a receptor activation elicits long-lasting phrenic motor facilitation.

    PubMed

    Golder, Francis J; Ranganathan, Lavanya; Satriotomo, Irawan; Hoffman, Michael; Lovett-Barr, Mary Rachael; Watters, Jyoti J; Baker-Herman, Tracy L; Mitchell, Gordon S

    2008-02-27

    Acute intermittent hypoxia elicits a form of spinal, brain-derived neurotrophic factor (BDNF)-dependent respiratory plasticity known as phrenic long-term facilitation. Ligands that activate G(s)-protein-coupled receptors, such as the adenosine 2a receptor, mimic the effects of neurotrophins in vitro by transactivating their high-affinity receptor tyrosine kinases, the Trk receptors. Thus, we hypothesized that A2a receptor agonists would elicit phrenic long-term facilitation by mimicking the effects of BDNF on TrkB receptors. Here we demonstrate that spinal A2a receptor agonists transactivate TrkB receptors in the rat cervical spinal cord near phrenic motoneurons, thus inducing long-lasting (hours) phrenic motor facilitation. A2a receptor activation increased phosphorylation and new synthesis of an immature TrkB protein, induced TrkB signaling through Akt, and strengthened synaptic pathways to phrenic motoneurons. RNA interference targeting TrkB mRNA demonstrated that new TrkB protein synthesis is necessary for A2a-induced phrenic motor facilitation. A2a receptor activation also increased breathing in unanesthetized rats, and improved breathing in rats with cervical spinal injuries. Thus, small, highly permeable drugs (such as adenosine receptor agonists) that transactivate TrkB receptors may provide an effective therapeutic strategy in the treatment of patients with ventilatory control disorders, such as obstructive sleep apnea, or respiratory insufficiency after spinal injury or during neurodegenerative diseases. PMID:18305238

  10. 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

  11. Acute lower motor neuron syndrome and spinal cord gray matter hyperintensities in HIV infection

    PubMed Central

    Wilson, Michael R.; Chad, David A.; Venna, Nagagopal

    2015-01-01

    Objective: To describe a novel manifestation of lower motor neuron disease in patients with well-controlled HIV infection. Methods: A retrospective study was performed to identify HIV-positive individuals with acute, painful lower motor neuron diseases. Results: Six patients were identified with HIV and lower motor neuron disease. Two patients met the inclusion criteria of well-controlled, chronic HIV infection and an acute, painful, unilateral lower motor neuron paralytic syndrome affecting the distal portion of the upper limb. These patients had segmental T2-hyperintense lesions in the central gray matter of the cervical spinal cord on MRI. One patient stabilized and the second patient improved with immunomodulatory therapy. Conclusions: This newly described syndrome expands the clinical spectrum of lower motor neuron diseases in HIV. PMID:26015990

  12. 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

  13. Mitochondrial Dysfunction during the Early Stages of Excitotoxic Spinal Motor Neuron Degeneration in Vivo.

    PubMed

    Santa-Cruz, Luz Diana; Guerrero-Castillo, Sergio; Uribe-Carvajal, Salvador; Tapia, Ricardo

    2016-07-20

    Glutamate excitotoxicity and mitochondrial dysfunction are involved in motor neuron degeneration process during amyotrophic lateral sclerosis (ALS). We have previously shown that microdialysis perfusion of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) in the lumbar region of the rat spinal cord produces permanent paralysis of the ipsilateral hindlimb and death of motor neurons by a Ca(2+)-dependent mechanism, in a process that starts 2-3 h after AMPA perfusion. Co-perfusion with different energy metabolic substrates, mainly pyruvate, prevented the paralysis and motor neuron degeneration induced by AMPA, suggesting that mitochondrial energetic deficiencies are involved in this excitotoxic motor neuron death. To test this, in the present work, we studied the functional and ultrastructural characteristics of mitochondria isolated from the ventral horns of lumbar spinal cords of rats, at the beginning of the AMPA-induced degeneration process, when motor neurons are still alive. Animals were divided in four groups: perfused with AMPA, AMPA + pyruvate, and pyruvate alone and Krebs-Ringer medium as controls. Mitochondria from the AMPA-treated group showed decreased oxygen consumption rates, respiratory controls, and transmembrane potentials. Additionally, activities of the respiratory chain complexes I and IV were significantly decreased. Electron microscopy showed that mitochondria from AMPA-treated rats presented swelling, disorganized cristae and disrupted membranes. Remarkably, in the animals co-perfused with AMPA and pyruvate all these abnormalities were prevented. We conclude that mitochondrial dysfunction plays a crucial role in spinal motor neuron degeneration induced by overactivation of AMPA receptors in vivo. These mechanisms could be involved in ALS motor neuron degeneration. PMID:27090876

  14. Temporal course of motor recovery after Brown-Sequard spinal cord injuries.

    PubMed

    Little, J W; Halar, E

    1985-02-01

    Recovery of voluntary motor function after incomplete spinal cord injuries is attributed to a variety of physiological mechanisms, such as resolution of conduction block in injured axons, and neuroplasticity mechanisms in spared axons. To better understand these recovery mechanisms, we have examined motor recovery in one type of incomplete cord injury, the Brown-Sequard Syndrome. This syndrome is observed in patients with unilateral injury of the spinal cord and is manifested as asymmetric weakness and pain/temperature sensory loss contralateral to the weakest extremity. We have followed the course of motor recovery in two patients and reviewed the literature in an additional 59. Common features of this motor recovery include: 1) recovery of ipsilateral proximal extensor muscles before ipsilateral distal flexors, 2) recovery of any weakness in the extremity with pain/temperature sensory loss before the opposite extremity, and 3) recovery of voluntary motor strength and a functional gait by 1 to 6 months. We discuss these observations with respect to three hypotheses to explain motor recovery and suggest that neuroplasticity mechanisms functioning in spared descending axons may mediate much of the observed recovery after Brown-Sequard cord lesions. PMID:3982846

  15. 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

  16. Spinal TNFα is necessary for inactivity-induced phrenic motor facilitation

    PubMed Central

    Broytman, Oleg; Baertsch, Nathan A; Baker-Herman, Tracy L

    2013-01-01

    A prolonged reduction in central neural respiratory activity elicits a form of plasticity known as inactivity-induced phrenic motor facilitation (iPMF), a ‘rebound’ increase in phrenic burst amplitude apparent once respiratory neural activity is restored. iPMF requires atypical protein kinase C (aPKC) activity within spinal segments containing the phrenic motor nucleus to stabilize an early transient increase in phrenic burst amplitude and to form long-lasting iPMF following reduced respiratory neural activity. Upstream signal(s) leading to spinal aPKC activation are unknown. We tested the hypothesis that spinal tumour necrosis factor-α (TNFα) is necessary for iPMF via an aPKC-dependent mechanism. Anaesthetized, ventilated rats were exposed to a 30 min neural apnoea; upon resumption of respiratory neural activity, a prolonged increase in phrenic burst amplitude (42 ± 9% baseline; P < 0.05) was apparent, indicating long-lasting iPMF. Pretreatment with recombinant human soluble TNF receptor 1 (sTNFR1) in the intrathecal space at the level of the phrenic motor nucleus prior to neural apnoea blocked long-lasting iPMF (2 ± 8% baseline; P > 0.05). Intrathecal TNFα without neural apnoea was sufficient to elicit long-lasting phrenic motor facilitation (pMF; 62 ± 7% baseline; P < 0.05). Similar to iPMF, TNFα-induced pMF required spinal aPKC activity, as intrathecal delivery of a ζ-pseudosubstrate inhibitory peptide (PKCζ-PS) 35 min following intrathecal TNFα arrested TNFα-induced pMF (28 ± 8% baseline; P < 0.05). These data demonstrate that: (1) spinal TNFα is necessary for iPMF; and (2) spinal TNFα is sufficient to elicit pMF via a similar aPKC-dependent mechanism. These data are consistent with the hypothesis that reduced respiratory neural activity elicits iPMF via a TNFα-dependent increase in spinal aPKC activity. PMID:23878370

  17. Spinal TNF is necessary for inactivity-induced phrenic motor facilitation.

    PubMed

    Broytman, Oleg; Baertsch, Nathan A; Baker-Herman, Tracy L

    2013-11-15

    A prolonged reduction in central neural respiratory activity elicits a form of plasticity known as inactivity-induced phrenic motor facilitation (iPMF), a 'rebound' increase in phrenic burst amplitude apparent once respiratory neural activity is restored. iPMF requires atypical protein kinase C (aPKC) activity within spinal segments containing the phrenic motor nucleus to stabilize an early transient increase in phrenic burst amplitude and to form long-lasting iPMF following reduced respiratory neural activity. Upstream signal(s) leading to spinal aPKC activation are unknown. We tested the hypothesis that spinal tumour necrosis factor-α (TNFα) is necessary for iPMF via an aPKC-dependent mechanism. Anaesthetized, ventilated rats were exposed to a 30 min neural apnoea; upon resumption of respiratory neural activity, a prolonged increase in phrenic burst amplitude (42 ± 9% baseline; P < 0.05) was apparent, indicating long-lasting iPMF. Pretreatment with recombinant human soluble TNF receptor 1 (sTNFR1) in the intrathecal space at the level of the phrenic motor nucleus prior to neural apnoea blocked long-lasting iPMF (2 ± 8% baseline; P > 0.05). Intrathecal TNFα without neural apnoea was sufficient to elicit long-lasting phrenic motor facilitation (pMF; 62 ± 7% baseline; P < 0.05). Similar to iPMF, TNFα-induced pMF required spinal aPKC activity, as intrathecal delivery of a ζ-pseudosubstrate inhibitory peptide (PKCζ-PS) 35 min following intrathecal TNFα arrested TNFα-induced pMF (28 ± 8% baseline; P < 0.05). These data demonstrate that: (1) spinal TNFα is necessary for iPMF; and (2) spinal TNFα is sufficient to elicit pMF via a similar aPKC-dependent mechanism. These data are consistent with the hypothesis that reduced respiratory neural activity elicits iPMF via a TNFα-dependent increase in spinal aPKC activity. PMID:23878370

  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. 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

  20. 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

  1. Extraction of motor activity from the cervical spinal cord of behaving rats

    NASA Astrophysics Data System (ADS)

    Prasad, Abhishek; Sahin, Mesut

    2006-12-01

    Injury at the cervical region of the spinal cord results in the loss of the skeletal muscle control from below the shoulders and hence causes quadriplegia. The brain-computer interface technique is one way of generating a substitute for the lost command signals in these severely paralyzed individuals using the neural signals from the brain. In this study, we are investigating the feasibility of an alternative method where the volitional signals are extracted from the cervical spinal cord above the point of injury. A microelectrode array assembly was implanted chronically at the C5-C6 level of the spinal cord in rats. Neural recordings were made during the face cleaning behavior with forelimbs as this task involves cyclic forelimb movements and does not require any training. The correlation between the volitional motor signals and the elbow movements was studied. Linear regression technique was used to reconstruct the arm movement from the rectified-integrated version of the principal neural components. The results of this study demonstrate the feasibility of extracting the motor signals from the cervical spinal cord and using them for reconstruction of the elbow movements.

  2. Extraction of motor activity from the cervical spinal cord of behaving rats.

    PubMed

    Prasad, Abhishek; Sahin, Mesut

    2006-12-01

    Injury at the cervical region of the spinal cord results in the loss of the skeletal muscle control from below the shoulders and hence causes quadriplegia. The brain-computer interface technique is one way of generating a substitute for the lost command signals in these severely paralyzed individuals using the neural signals from the brain. In this study, we are investigating the feasibility of an alternative method where the volitional signals are extracted from the cervical spinal cord above the point of injury. A microelectrode array assembly was implanted chronically at the C5-C6 level of the spinal cord in rats. Neural recordings were made during the face cleaning behavior with forelimbs as this task involves cyclic forelimb movements and does not require any training. The correlation between the volitional motor signals and the elbow movements was studied. Linear regression technique was used to reconstruct the arm movement from the rectified-integrated version of the principal neural components. The results of this study demonstrate the feasibility of extracting the motor signals from the cervical spinal cord and using them for reconstruction of the elbow movements. PMID:17124332

  3. 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

  4. 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

  5. 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

  6. Cathodal transcutaneous spinal direct current stimulation (tsDCS) improves motor unit recruitment in healthy subjects.

    PubMed

    Bocci, Tommaso; Vannini, Beatrice; Torzini, Antonio; Mazzatenta, Andrea; Vergari, Maurizio; Cogiamanian, Filippo; Priori, Alberto; Sartucci, Ferdinando

    2014-08-22

    Transcutaneous spinal direct current stimulation (tsDCS) is a new promising technique for modulating spinal cord function in humans. However, its effects on corticospinal pathways and lower motorneuron excitability are poorly understood. We studied the effects of tsDCS on motor unit recruitment by evaluating changes in motor unit number (MUNE) and peripheral silent period (PSP) after sham (s-tsDCS), anodal (a-tsDCS) and cathodal (c-tsDCS) tsDCS applied either over the cervical or the lower thoracic spinal cord in healthy subjects. For the calculation of MUNE we used the multipoint incremental technique recording from either the ulnar nerve innervated abductor digiti minimi (ADM) or the median nerve innervated abductor pollicis brevis (APB) muscle. c-tsDCS dramatically increases MUNE values following cervical polarization, while sham and anodal polarization have no significant effect (APB: F(4,99)=26.4, p<0.001, two-way repeated measures ANOVA with "time" and "stimulation" as factors; ADM: F(4,99)=22.1, p<0.0001). At the same time, c-tsDCS dampened PSP respect to sham and anodal conditions (p<0.0001). Interestingly, also thoracic c-tsDCS significantly improved motor unit recruitment compared with both s-tsDCS and a-tsDCS (APB: F(4,99)=20.1, p<0.0001; ADM: F(4,99)=16.6, p<0.0001). Our data in healthy subjects suggest that tsDCS, possibly also through supraspinal effects, could provide a novel therapeutic tool in managing several pathological conditions characterized by reduced motor unit recruitment, such as stroke and spinal cord injuries. PMID:24970753

  7. 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

  8. Prolonged Minocycline Treatment Impairs Motor Neuronal Survival and Glial Function in Organotypic Rat Spinal Cord Cultures

    PubMed Central

    Pinkernelle, Josephine; Fansa, Hisham; Ebmeyer, Uwe; Keilhoff, Gerburg

    2013-01-01

    Background Minocycline, a second-generation tetracycline antibiotic, exhibits anti-inflammatory and neuroprotective effects in various experimental models of neurological diseases, such as stroke, Alzheimer’s disease, amyotrophic lateral sclerosis and spinal cord injury. However, conflicting results have prompted a debate regarding the beneficial effects of minocycline. Methods In this study, we analyzed minocycline treatment in organotypic spinal cord cultures of neonatal rats as a model of motor neuron survival and regeneration after injury. Minocycline was administered in 2 different concentrations (10 and 100 µM) at various time points in culture and fixed after 1 week. Results Prolonged minocycline administration decreased the survival of motor neurons in the organotypic cultures. This effect was strongly enhanced with higher concentrations of minocycline. High concentrations of minocycline reduced the number of DAPI-positive cell nuclei in organotypic cultures and simultaneously inhibited microglial activation. Astrocytes, which covered the surface of the control organotypic cultures, revealed a peripheral distribution after early minocycline treatment. Thus, we further analyzed the effects of 100 µM minocycline on the viability and migration ability of dispersed primary glial cell cultures. We found that minocycline reduced cell viability, delayed wound closure in a scratch migration assay and increased connexin 43 protein levels in these cultures. Conclusions The administration of high doses of minocycline was deleterious for motor neuron survival. In addition, it inhibited microglial activation and impaired glial viability and migration. These data suggest that especially high doses of minocycline might have undesired affects in treatment of spinal cord injury. Further experiments are required to determine the conditions for the safe clinical administration of minocycline in spinal cord injured patients. PMID:23967343

  9. Effects of baclofen on motor units paralysed by chronic cervical spinal cord injury

    PubMed Central

    Häger-Ross, Charlotte K.; Klein, Cliff S.

    2010-01-01

    Baclofen, a gamma-aminobutyric acid receptorB agonist, is used to reduce symptoms of spasticity (hyperreflexia, increases in muscle tone, involuntary muscle activity), but the long-term effects of sustained baclofen use on skeletal muscle properties are unclear. The aim of our study was to evaluate whether baclofen use and paralysis due to cervical spinal cord injury change the contractile properties of human thenar motor units more than paralysis alone. Evoked electromyographic activity and force were recorded in response to intraneural stimulation of single motor axons to thenar motor units. Data from three groups of motor units were compared: 23 paralysed units from spinal cord injured subjects who take baclofen and have done so for a median of 7 years, 25 paralysed units from spinal cord injured subjects who do not take baclofen (median: 10 years) and 45 units from uninjured control subjects. Paralysed motor unit properties were independent of injury duration and level. With paralysis and baclofen, the median motor unit tetanic forces were significantly weaker, twitch half-relaxation times longer and half maximal forces reached at lower frequencies than for units from uninjured subjects. The median values for these same parameters after paralysis alone were comparable to control data. Axon conduction velocities differed across groups and were slowest for paralysed units from subjects who were not taking baclofen and fastest for units from the uninjured. Greater motor unit weakness with long-term baclofen use and paralysis will make the whole muscle weaker and more fatigable. Significantly more paralysed motor units need to be excited during patterned electrical stimulation to produce any given force over time. The short-term benefits of baclofen on spasticity (e.g. management of muscle spasms that may otherwise hinder movement or social interactions) therefore have to be considered in relation to its possible long-term effects on muscle rehabilitation

  10. Spinal cord stimulation alleviates motor deficits in a primate model of Parkinson disease.

    PubMed

    Santana, Maxwell B; Halje, Pär; Simplício, Hougelle; Richter, Ulrike; Freire, Marco Aurelio M; Petersson, Per; Fuentes, Romulo; Nicolelis, Miguel A L

    2014-11-19

    Although deep brain electrical stimulation can alleviate the motor symptoms of Parkinson disease (PD), just a small fraction of patients with PD can take advantage of this procedure due to its invasive nature. A significantly less invasive method--epidural spinal cord stimulation (SCS)--has been suggested as an alternative approach for symptomatic treatment of PD. However, the mechanisms underlying motor improvements through SCS are unknown. Here, we show that SCS reproducibly alleviates motor deficits in a primate model of PD. Simultaneous neuronal recordings from multiple structures of the cortico-basal ganglia-thalamic loop in parkinsonian monkeys revealed abnormal highly synchronized neuronal activity within each of these structures and excessive functional coupling among them. SCS disrupted this pathological circuit behavior in a manner that mimics the effects caused by pharmacological dopamine replacement therapy or deep brain stimulation. These results suggest that SCS should be considered as an additional treatment option for patients with PD. PMID:25447740

  11. Variability analyses suggest that supraspino-spinal interactions provide dynamic stability in motor control.

    PubMed

    Wang, H; Jung, R

    2002-03-15

    Effects of supraspino-spinal feedforward-feedback (FF-FB) interactions on variability in locomotor rhythm and coordination were examined in in vitro brain-spinal cord lamprey preparations. Spinal locomotor networks were activated by applying 0.2 mM N-methyl-DL-aspartate (NMA) to three spinal pools: gill, rostral and caudal. Bathing the brain with zero Ca(2+) saline altered supraspinal-spinal drive and FF-FB interaction while spino-supraspinal feedback was changed by applying NMA to the caudal pool only. Wavelet analyses indicated a non-uniform energy distribution in ventral root (VR) activity that shifted between frequency bands on FF-FB interruption. Wavelet analysis was used to extract 300-s long epochs of low frequency burst rhythm. These were analyzed using a sliding-window time-varying covariance method. From the autocovariance in each window, the cycle period and height of the first side lobe peak were determined. Rostral VR variability (determined from standard deviation and coefficient of variation of all cycle periods and the mean peak height) was significantly higher than caudal VR variability. FF-FB interruption significantly decreased the rostral VR cycle period and variability but the rostro-caudal gradient remained. The intersegmental delay was also affected. The caudal VR rhythm with NMA in the caudal pool only was slower but more variable than with NMA over the entire cord. These results indicate that the locomotor rhythm in the presence of supraspino-spinal interactions is slower but has a higher variability. The higher variability may reflect a dynamic stability of the system. Additionally, differences in local neural organization likely contribute to rostro-caudal differences in variability of the motor output. PMID:11879799

  12. Magnetic motor evoked potentials (MEP) in diseases of the spinal cord.

    PubMed

    Linden, D; Berlit, P

    1994-11-01

    Transcranial magnetic stimulation (TMS) is a non-invasive diagnostic method particularly suited to investigation of the long motor tracts. The clinical value of this method in many cortical and subcortical diseases has been well established, but comparable studies for most spinal cord diseases have still to be made. Forty patients in whom spinal cord disease was established by clinical examination, cerebrospinal fluid examination, and magnetic resonance imaging (MRI) were studied by means of somatosensory evoked potentials (SEP, median and tibial nerve stimulation) and magnetic motor evoked potentials (MEP, first dorsal interosseus and tibialis anterior muscle recordings after transcranial and spinal stimulation). The underlying pathology was neoplastic (n = 16), inflammatory (n = 15) or ischemic (n = 9). Clinical signs and symptoms ranged from slight sensory disturbances to complete paraplegia and had developed within minutes (ischemia) or over many years (benign neoplastic disease). The overall frequency of pathological SEP was slightly higher than that of MEP (78% vs 68%) which was statistically not significant (p > 0.05). This was also true for the subgroups, except for pure motor disorders, which gave the same yield for both methods. Decreased amplitudes or absence of MEP were more frequent in neoplastic than in inflammatory lesions (75% vs 33%, p < 0.05). In the latter, however, MEP more often occurred with increased latencies (40% vs 31%, p > 0.05, n.s.). Pathological SEP were found in 75% of patients presenting with pure motor abnormalities, while pathological MEP were found in 30% of patients with pure sensory disturbances.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7887135

  13. 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

  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. PMID:27051566

  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. Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

    PubMed

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

    2016-03-01

    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 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. 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 has been demonstrated that non-motor neuronal cells are also involved in disease pathogenesis and could have important therapeutic implications. For these reasons it will be crucial to take this evidence into account for the clinical translation of the novel therapeutic approaches. PMID:26681261

  17. Premotor spinal network with balanced excitation and inhibition during motor patterns has high resilience to structural division.

    PubMed

    Petersen, Peter C; Vestergaard, Mikkel; Jensen, Kristian H R; Berg, Rune W

    2014-02-19

    Direct measurements of synaptic inhibition (I) and excitation (E) to spinal motoneurons can provide an important insight into the organization of premotor networks. Such measurements of flexor motoneurons participating in motor patterns in turtles have recently demonstrated strong concurrent E and I as well as stochastic membrane potentials and irregular spiking in the adult turtle spinal cord. These findings represent a departure from the widespread acceptance of feedforward reciprocal rate models for spinal motor function. The apparent discrepancy has been reviewed as an experimental artifact caused by the distortion of local networks in the transected turtle spinal cord. We tested this assumption in the current study by performing experiments to assess the integrity of motor functions in the intact spinal cord and the cord transected at segments D9/D10. Excitatory and inhibitory synaptic inputs to motoneurons were estimated during rhythmic motor activity and demonstrated primarily intense inputs that consisted of qualitatively similar mixed E/I before and after the transection. To understand this high functional resilience, we used mathematical modeling of networks with recurrent connectivity that could potentially explain the balanced E/I. Both experimental and modeling data support the concept of a locally balanced premotor network consisting of recurrent E/I connectivity, in addition to the well known reciprocal network activity. The multifaceted synaptic connections provide spinal networks with a remarkable ability to remain functional after structural divisions. PMID:24553920

  18. 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

  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. Osteopontin is an alpha motor neuron marker in the mouse spinal cord.

    PubMed

    Misawa, Hidemi; Hara, Mayumi; Tanabe, Shogo; Niikura, Mamiko; Moriwaki, Yasuhiro; Okuda, Takashi

    2012-04-01

    Motor neurons (MNs) are designated as alpha/gamma and fast/slow based on their target sites and the types of muscle fibers innervated; however, few molecular markers that distinguish between these subtypes are available. Here we report that osteopontin (OPN) is a selective marker of alpha MNs in the mouse spinal cord. OPN was detected in approximately 70% of postnatal choline acetyltransferase (ChAT)-positive MNs with relatively large somas, but not in those with smaller somas. OPN+/ChAT+ MNs were also positive for NeuN, an alpha MN marker, but were negative for Err3, a gamma MN marker. The size distribution of OPN+/ChAT+ cells was nearly identical to that of NeuN+/ChAT+ alpha MNs. Group Ia proprioceptive terminals immunoreactive for vesicular glutamate transporter-1 were selectively detected on the OPN+/ChAT+ cells. OPN staining was also detected at motor axon terminals at neuromuscular junctions, where the OPN+ terminals were positive or negative for SV2A, a marker distinguishing fast/slow motor endplates. Finally, retrograde labeling following intramuscular injection of fast blue indicated that OPN is expressed in both fast and slow MNs. Collectively, our findings show that OPN is an alpha MN marker present in both the soma and the endplates of alpha MNs in the postnatal mouse spinal cord. PMID:22420030

  1. Influence of Baclofen on Laryngeal and Spinal Motor Drive During Cough in the Anesthetized Cat

    PubMed Central

    Castillo, Daniel; Pitts, Teresa

    2016-01-01

    Objectives/Hypothesis The antitussive properties of (±) baclofen on laryngeal muscle activities have not been determined. The hypothesis of this study was that administration of (±) baclofen would suppress upper airway muscle motor activity in a dose-dependent manner during cough. Study Design This is a prospective, preclinical, hypothesis-driven, paired design. Methods Electromyograms of the parasternal, rectus abdominis, thyroarytenoid, posterior cricoarytenoid, and thyrohyoid were measured, along with esophageal pressure. Cough was elicited by mechanical stimulation of the lumen of the intrathoracic trachea in spontaneously breathing cats. Results Baclofen (±) (3–10 µg kg−1 i.a.) induced decreases in the electromyogram amplitude of the rectus abdominis motor drive during coughing, the inspiratory and active expiratory (E1) phases of cough, and cough number per epoch. There was no effect of (±) baclofen on the EMG amplitudes of any of the laryngeal muscles, the parasternal, or the duration of the passive expiratory (E2) phase. Conclusions Results from the present study indicate differential control mechanisms for laryngeal and inspiratory motor drive during cough, providing evidence of a control system regulating laryngeal activity and inspiratory spinal drive that is divergent from the control of expiratory spinal motoneurons. PMID:23670824

  2. The Impact of Sacral Sensory Sparing in Motor Complete Spinal Cord Injury

    PubMed Central

    Kirshblum, Steven; Botticello, Amanda; Lammertse, Daniel P.; Marino, Ralph J.; Chiodo, Anthony E.; Jha, Amitabh

    2013-01-01

    Objective To determine the effect of sensory sparing in motor complete persons with spinal cord injury (SCI) on completion of rehabilitation on neurologic, functional, and social outcomes reported at 1 year. Design Secondary analysis of longitudinal data collected by using prospective survey-based methods. Setting Data submitted to the National SCI Statistical Center Database. Participants Of persons (N=4106) enrolled in the model system with a motor complete injury (American Spinal Injury Association Impairment Scale [AIS] grade A or B) at the time of discharge between 1997 and 2007, a total of 2331 (56.8%) completed a 1-year follow-up interview (Form II) and 1284 (31.3%) had complete data for neurologic (eg, AIS grade, injury level) variables at 1 year. Interventions Not applicable. Main Outcome Measures AIS grade (A vs B) at 1 year, bladder management, hospitalizations, perceived health status, motor FIM items, Satisfaction With Life Scale, depressive symptoms, and social participation. Results Compared with persons with AIS grade A at discharge, persons with AIS grade B were less likely to require indwelling catheterization and be hospitalized and more likely to perceive better health, report greater functional independence (ie, self-care, sphincter control, mobility, locomotion), and report social participation in the first year postinjury. A greater portion of individuals with AIS grade B at discharge had improved neurologic recovery at 1 year postinjury than those with AIS grade A. Significant AIS group differences in 1-year outcomes related to physical health were maintained after excluding persons who improved to motor incomplete status for only bladder management and change in perceived health status. This recognition of differences between persons with motor complete injuries (AIS grade A vs B) has important ramifications for the field of SCI rehabilitation and research. PMID:21353822

  3. Reorganization and Preservation of Motor Control of the Brain in Spinal Cord Injury: A Systematic Review

    PubMed Central

    Kokotilo, Kristen J; Eng, Janice J; Curt, Armin

    2011-01-01

    Reorganization of brain function in people with CNS damage has been identified as one of the fundamental mechanisms involved in the recovery of sensori-motor function. Spinal cord injury (SCI) brain mapping studies during motor tasks aim for assessing the reorganization and preservation of brain networks involved in motor control. Revealing the activation of cortical and sub-cortical brain areas in people with SCI can indicate principal patterns of brain reorganization when the neurotrauma is distal to the brain. This review assessed brain activation after SCI in terms of intensity, volume, and somatotopic localization, as well as preservation of activation during attempted and/or imagined movements. Twenty-five studies meeting the inclusion criteria could be identified in MEDLINE (1980 to January 2008). Relevant characteristics of studies (level of lesion, time after injury, motor task) and mapping techniques varied widely. Changes in brain activation were found in both cortical and subcortical areas of individuals with SCI. In addition, several studies described a shift in the region of brain activation. These patterns appeared to be dynamic and influenced by the level, completeness and time after injury, as well as extent of clinical recovery. In addition, several aspects of reorganization of brain function following SCI resembled those reported in stroke. This review demonstrates that brain networks involved in different demands of motor control remain responsive even in chronic paralysis. These findings imply that therapeutic strategies aiming for restoring spinal cord function even in people with chronic SCI can build on a preserved competent brain control. PMID:19604097

  4. SRC family kinases are required for limb trajectory selection by spinal motor axons.

    PubMed

    Kao, Tzu-Jen; Palmesino, Elena; Kania, Artur

    2009-04-29

    Signal relay by guidance receptors at the axonal growth cone is a process essential for the assembly of a functional nervous system. We investigated the in vivo function of Src family kinases (SFKs) as growth cone guidance signaling intermediates in the context of spinal lateral motor column (LMC) motor axon projection toward the ventral or dorsal limb mesenchyme. Using in situ mRNA detection we determined that Src and Fyn are expressed in LMC motor neurons of chick and mouse embryos at the time of limb trajectory selection. Inhibition of SFK activity by C-terminal Src kinase (Csk) overexpression in chick LMC axons using in ovo electroporation resulted in LMC axons selecting the inappropriate dorsoventral trajectory within the limb mesenchyme, with medial LMC axon projecting into the dorsal and ventral limb nerve with apparently random incidence. We also detected LMC axon trajectory choice errors in Src mutant mice demonstrating a nonredundant role for Src in motor axon guidance in agreement with gain and loss of Src function in chick LMC neurons which led to the redirection of LMC axons. Finally, Csk-mediated SFK inhibition attenuated the retargeting of LMC axons caused by EphA or EphB over-expression, implying the participation of SFKs in Eph-mediated LMC motor axon guidance. In summary, our findings demonstrate that SFKs are essential for motor axon guidance and suggest that they play an important role in relaying ephrin:Eph signals that mediate the selection of motor axon trajectory in the limb. PMID:19403835

  5. 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

  6. 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

  7. 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

  8. 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

  9. Ryk controls remapping of motor cortex during functional recovery after spinal cord injury.

    PubMed

    Hollis, Edmund R; Ishiko, Nao; Yu, Ting; Lu, Chin-Chun; Haimovich, Ariela; Tolentino, Kristine; Richman, Alisha; Tury, Anna; Wang, Shih-Hsiu; Pessian, Maysam; Jo, Euna; Kolodkin, Alex; Zou, Yimin

    2016-05-01

    Limited functional recovery can be achieved through rehabilitation after incomplete spinal cord injury. Eliminating the function of a repulsive Wnt receptor, Ryk, in mice and rats by either conditional knockout in the motor cortex or monoclonal antibody infusion resulted in increased corticospinal axon collateral branches with presynaptic puncta in the spinal cord and enhanced recovery of forelimb reaching and grasping function following a cervical dorsal column lesion. Using optical stimulation, we observed that motor cortical output maps underwent massive changes after injury and that hindlimb cortical areas were recruited to control the forelimb over time. Furthermore, a greater cortical area was dedicated to controlling the forelimb in Ryk conditional knockout mice than in controls (wild-type or heterozygotes). In the absence of weekly task-specific training, recruitment of ectopic cortical areas was greatly reduced and there was no significant functional recovery even in Ryk conditional knockout mice. Our study provides evidence that maximal circuit reorganization and functional recovery can be achieved by combining molecular manipulation and targeted rehabilitation. PMID:27065364

  10. Radial glia inhibit peripheral glial infiltration into the spinal cord at motor exit point transition zones.

    PubMed

    Smith, Cody J; Johnson, Kimberly; Welsh, Taylor G; Barresi, Michael J F; Kucenas, Sarah

    2016-07-01

    In the mature vertebrate nervous system, central and peripheral nervous system (CNS and PNS, respectively) GLIA myelinate distinct motor axon domains at the motor exit point transition zone (MEP TZ). How these cells preferentially associate with and myelinate discrete, non-overlapping CNS versus PNS axonal segments, is unknown. Using in vivo imaging and genetic cell ablation in zebrafish, we demonstrate that radial glia restrict migration of PNS glia into the spinal cord during development. Prior to development of radial glial endfeet, peripheral cells freely migrate back and forth across the MEP TZ. However, upon maturation, peripherally located cells never enter the CNS. When we ablate radial glia, peripheral glia ectopically migrate into the spinal cord during developmental stages when they would normally be restricted. These findings demonstrate that radial glia contribute to both CNS and PNS development and control the unidirectional movement of glial cell types across the MEP TZ early in development. GLIA 2016. GLIA 2016;64:1138-1153. PMID:27029762

  11. Spinal cord injury affects I-wave facilitation in human motor cortex.

    PubMed

    Nardone, Raffaele; Höller, Yvonne; Bathke, Arne C; Orioli, Andrea; Schwenker, Kerstin; Frey, Vanessa; Golaszewski, Stefan; Brigo, Francesco; Trinka, Eugen

    2015-07-01

    Transcranial magnetic stimulation (TMS) is a useful non-invasive approach for studying cortical physiology. To further clarify the mechanisms of cortical reorganization after spinal cord injury (SCI), we used a non-invasive paired TMS protocol for the investigation of the corticospinal I-waves, the so-called I-wave facilitation, in eight patients with cervical SCI. We found that the pattern of I-wave facilitation significantly differs between SCI patients with normal and abnormal central motor conduction (CMCT), and healthy controls. The group with normal CMCT showed increased I-wave facilitation, while the group with abnormal CMCT showed lower I-wave facilitation compared to a control group. The facilitatory I-wave interaction occurs at the level of the motor cortex, and the mechanisms responsible for the production of I-waves are under control of GABA-related inhibition. Therefore, the findings of our small sample preliminary study provide further physiological evidence of increased motor cortical excitability in patients with preserved corticospinal projections. This is possibly due to decreased GABAergic intracortical inhibition. The excitability of networks producing short-interval intracortical facilitation could increase after SCI as a mechanism to enhance activation of residual corticospinal tract pathways and thus compensate for the impaired ability of the motor cortex to generate appropriate voluntary movements. Finally, the I-wave facilitation technique could be used in clinical neurorehabilitation as an additional method of assessing and monitoring function in SCI. PMID:26151771

  12. 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

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

    PubMed

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

    2015-01-01

    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

  14. 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

  15. Mechanism of Forelimb Motor Function Restoration after Cervical Spinal Cord Hemisection in Rats: A Comparison of Juveniles and Adults

    PubMed Central

    Hasegawa, Atsushi; Takahashi, Masahito; Satomi, Kazuhiko; Ohne, Hideaki; Takeuchi, Takumi; Sato, Shunsuke; Ichimura, Shoichi

    2016-01-01

    The aim of this study was to investigate forelimb motor function after cervical spinal cord injury in juvenile and adult rats. Both rats received a left segmental hemisection of the spinal cord after C3-C4 laminectomy. Behavioral evaluation of motor function was monitored and assessed using the New Rating Scale (NRS) and Forelimb Locomotor Scale (FLS) and by measuring the range of motion (ROM) of both the elbow and wrist. Complete left forelimb motor paralysis was observed in both rats. The NRS showed motor function recovery restored to 50.2 ± 24.7% in juvenile rats and 34.0 ± 19.8% in adult rats. FLS was 60.4 ± 26.8% in juvenile rats and 46.5 ± 26.9% in adult rats. ROM of the elbow and wrist were 88.9 ± 20.6% and 44.4 ± 24.1% in juvenile rats and 70.0 ± 29.2% and 40.0 ± 21.1% in adult rats. Thus, the NRS and ROM of the elbow showed a significant difference between age groups. These results indicate that left hemisection of the cervical spinal cord was not related to right-sided motor functions. Moreover, while motor paralysis of the left forelimb gradually recovered in both groups, the improvement was greater in juvenile rats. PMID:27065569

  16. Effect of transgenic human insulin-like growth factor-1 on spinal motor neurons following peripheral nerve injury

    PubMed Central

    GU, JIAXIANG; LIU, HONGJUN; ZHANG, NAICHEN; TIAN, HENG; PAN, JUNBO; ZHANG, WENZHONG; WANG, JINGCHENG

    2015-01-01

    The aim of the present study was to observe the protective effect of exogenous human insulin-like growth factor-1 (hIGF-1) on spinal motor neurons, following its local transfection into an area of peripheral nerve injury. A total of 90 male Wistar rats that had been established as sciatic nerve crush injury models were randomly divided into three groups: hIGF-1 treatment, sham-transfected control and blank control groups. The different phases of hIGF-1 expression were observed in the spinal cord via postoperative immunostaining and the apoptosis of motor neurons was observed using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method. Pathological changes of the motor neurons and Nissl bodies within cell bodies were observed via Marsland and Luxol fast blue double staining, while changes in the neuropil of the spinal cord anterior horn were investigated via ultrastructural observation. It was found that hIGF-1, locally transfected into an area of peripheral nerve injury, was expressed in the spinal anterior horn following axoplasmic transport; the peak hIGF-1 expression occurred approximately a week following transfection. The number of apoptotic spinal cord motor neurons observed in the hIGF-1 treatment group was fewer than that in the sham-transfected and blank control groups at days 7, 14 and 21 following transfection (P<0.01). Furthermore, the quantity of motor neuron cells in the anterior horn of the spinal cord in the hIGF-1 treatment group was higher compared with those in the sham-transfected and blank control groups at days 2, 7, 14 and 28 following transfection (P<0.01). The degenerative changes of Nissl bodies within the cytoplasm of the hIGF-1 treatment group were less severe compared with those of the sham-transfected and blank control groups. At day 56 following transfection, the spinal anterior horn neuropil ultrastructure in the hIGF-1 treatment group was generally normal, while the sham-transfected and blank control

  17. 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

  18. 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

  19. 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

  20. 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

  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. 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

  3. 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

  4. 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

  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. Genetic circuitry of Survival motor neuron, the gene underlying spinal muscular atrophy

    PubMed Central

    Sen, Anindya; Dimlich, Douglas N.; Guruharsha, K. G.; Kankel, Mark W.; Hori, Kazuya; Yokokura, Takakazu; Brachat, Sophie; Richardson, Delwood; Loureiro, Joseph; Sivasankaran, Rajeev; Curtis, Daniel; Davidow, Lance S.; Rubin, Lee L.; Hart, Anne C.; Van Vactor, David; Artavanis-Tsakonas, Spyros

    2013-01-01

    The clinical severity of the neurodegenerative disorder spinal muscular atrophy (SMA) is dependent on the levels of functional Survival Motor Neuron (SMN) protein. Consequently, current strategies for developing treatments for SMA generally focus on augmenting SMN levels. To identify additional potential therapeutic avenues and achieve a greater understanding of SMN, we applied in vivo, in vitro, and in silico approaches to identify genetic and biochemical interactors of the Drosophila SMN homolog. We identified more than 300 candidate genes that alter an Smn-dependent phenotype in vivo. Integrating the results from our genetic screens, large-scale protein interaction studies, and bioinformatic analysis, we define a unique interactome for SMN that provides a knowledge base for a better understanding of SMA. PMID:23757500

  7. Differences in recruitment order of motor units in phasic and tonic flexion reflex in `spinal man'

    PubMed Central

    Grimby, Lennart; Hannerz, Jan

    1970-01-01

    The recruitment order of motoneurones in muscle contractions has been held to be largely constant and determined by the size of the cell. However, as shown in a previous investigation using electromyographic techniques, the order in which different motor units are activated during voluntary muscle contractions changes in normal human subjects on shifts from phasic to tonic contraction. In order to investigate these two types of activity also in cases in which the cerebral influence on the motoneurone pool is blocked, an analysis was made of the recruitment order in phasic and tonic flexion reflexes in 10 patients with total interruption of the spinal cord. The following four principles were found to apply and presumed to be generally valid for the isolated human spinal cord: (1) in the phasic exteroceptive reflex, the order of recruitment varies despite application of a standardized stimulus; (2) in the tonic reflex, the first unit to be recruited is usually the same even with widely different types of stimuli; (3) a shift from phasic to tonic reflex activation may result in considerable changes in recruitment order; (4) after facilitation by a subliminal long-lasting stimulus, the first unit to be recruited in the phasic reflex is also the first to be recruited in the tonic reflex. It is suggested that a tonic influence on the motoneurone pool is required for the presupposed constancy of the recruitment order. Images PMID:5478941

  8. Chronic uranium contamination alters spinal motor neuron integrity via modulation of SMN1 expression and microglia recruitment.

    PubMed

    Saint-Marc, Brice; Elie, Christelle; Manens, Line; Tack, Karine; Benderitter, Marc; Gueguen, Yann; Ibanez, Chrystelle

    2016-07-01

    Consequences of uranium contamination have been extensively studied in brain as cognitive function impairments were observed in rodents. Locomotor disturbances have also been described in contaminated animals. Epidemiological studies have revealed increased risk of motor neuron diseases in veterans potentially exposed to uranium during their military duties. To our knowledge, biological response of spinal cord to uranium contamination has not been studied even though it has a crucial role in locomotion. Four groups of rats were contaminated with increasing concentrations of uranium in their drinking water compared to a control group to study cellular mechanisms involved in locomotor disorders. Nissl staining of spinal cord sections revealed the presence of chromatolytic neurons in the ventral horn. This observation was correlated with a decreased number of motor neurons in the highly contaminated group and a decrease of SMN1 protein expression (Survival of Motor Neuron 1). While contamination impairs motor neuron integrity, an increasing number of microglial cells indicates the trigger of a neuroinflammation process. Potential overexpression of a microglial recruitment chemokine, MCP-1 (Monocyte Chimioattractant Protein 1), by motor neurons themselves could mediate this process. Studies on spinal cord appear to be relevant for risk assessment of population exposed via contaminated food and water. PMID:27153795

  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. 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. PMID:25948267

  11. 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

  12. Effects of anodal transcranial direct current stimulation over the leg motor area on lumbar spinal network excitability in healthy subjects.

    PubMed

    Roche, N; Lackmy, A; Achache, V; Bussel, B; Katz, R

    2011-06-01

    In recent years, two techniques have become available for the non-invasive stimulation of human motor cortex: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). The effects of TMS and tDCS when applied over motor cortex should be considered with regard not only to cortical circuits but also to spinal motor circuits. The different modes of action and specificity of TMS and tDCS suggest that their effects on spinal network excitability may be different from that in the cortex. Until now, the effects of tDCS on lumbar spinal network excitability have never been studied. In this series of experiments, on healthy subjects, we studied the effects of anodal tDCS over the lower limb motor cortex on (i) reciprocal Ia inhibition projecting from the tibialis anterior muscle (TA) to the soleus (SOL), (ii) presynaptic inhibition of SOL Ia terminals, (iii) homonymous SOL recurrent inhibition, and (iv) SOL H-reflex recruitment curves. The results show that anodal tDCS decreases reciprocal Ia inhibition, increases recurrent inhibition and induces no modification of presynaptic inhibition of SOL Ia terminals and of SOL-H reflex recruitment curves. Our results indicate therefore that the effects of tDCS are the opposite of those previously described for TMS on spinal network excitability. They also indicate that anodal tDCS induces effects on spinal network excitability similar to those observed during co-contraction suggesting that anodal tDCS activates descending corticospinal projections mainly involved in co-contractions. PMID:21502292

  13. 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

  14. Contact-Mediated Inhibition Between Oligodendrocyte Progenitor Cells and Motor Exit Point Glia Establishes the Spinal Cord Transition Zone

    PubMed Central

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

    2014-01-01

    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. PMID:25268888

  15. Metamorphosis-induced changes in the coupling of spinal thoraco-lumbar motor outputs during swimming in Xenopus laevis.

    PubMed

    Beyeler, Anna; Métais, Charles; Combes, Denis; Simmers, John; Le Ray, Didier

    2008-09-01

    Anuran metamorphosis includes a complete remodeling of the animal's biomechanical apparatus, requiring a corresponding functional reorganization of underlying central neural circuitry. This involves changes that must occur in the coordination between the motor outputs of different spinal segments to harmonize locomotor and postural functions as the limbs grow and the tail regresses. In premetamorphic Xenopus laevis tadpoles, axial motor output drives rostrocaudally propagating segmental myotomal contractions that generate propulsive body undulations. During metamorphosis, the anterior axial musculature of the tadpole progressively evolves into dorsal muscles in the postmetamorphic froglet in which some of these back muscles lose their implicit locomotor function to serve exclusively in postural control in the adult. To understand how locomotor and postural systems interact during locomotion in juvenile Xenopus, we have investigated the coordination between postural back and hindlimb muscle activity during free forward swimming. Axial/dorsal muscles, which contract in bilateral alternation during undulatory swimming in premetamorphic tadpoles, change their left-right coordination to become activated in phase with bilaterally synchronous hindlimb extensions in locomoting juveniles. Based on in vitro electrophysiological experiments as well as specific spinal lesions in vivo, a spinal cord region was delimited in which propriospinal interactions are directly responsible for the coordination between leg and back muscle contractions. Our findings therefore indicate that dynamic postural adjustments during adult Xenopus locomotion are mediated by local intraspinal pathways through which the lumbar generator for hindlimb propulsive kicking provides caudorostral commands to thoracic spinal circuitry controlling the dorsal trunk musculature. PMID:18596184

  16. Time-of-Flight Secondary Ion Mass Spectrometry based Molecular Histology of Human Spinal Cord Tissue and Motor Neurons

    PubMed Central

    Hanrieder, Jörg; Malmberg, Per; Lindberg, Olle R.; Fletcher, John S.; Ewing, Andrew G.

    2013-01-01

    Secondary ion mass spectrometry is a powerful method for imaging biological samples with high spatial resolution. Whole section ToF SIMS scans and multivariate data analysis have been performed on human spinal cord in order to delineate anatomical regions of interest based on their chemical distribution pattern. ToF SIMS analysis of thoracic spinal cord sections was performed at 5µm resolution within 2 hours. Multivariate image analysis by means of principal component analysis and maximum auto correlation factor analysis resulted in detection of more than 400 m/z peaks that were found to be significantly changed. Here, the results show characteristic biochemical distributions that are well in line with major histological regions, including grey and white matter. As an approach for iterative segmentation, we further evaluated previously outlined regions of interest as identified by multivariate image analysis. Here, further discrimination of the grey matter into ventral, lateral and dorsal neuroanatomical regions was observed. TOF SIMS imaging has been carried out at submicron resolution obtaining localization and characterization of spinal motor neurons based on their chemical fingerprint, including neurotransmitter precursors that serve as molecular indicators for motor neuron integrity. Thus, TOF SIMS can be used as an approach for chemical histology and pathology. SIMS holds immense potential for investigating the subcellular mechanisms underlying spinal cord related diseases including chronic pain and amyotrophic lateral sclerosis. PMID:23947367

  17. Role of proteasomes in the formation of neurofilamentous inclusions in spinal motor neurons of aluminum-treated rabbits.

    PubMed

    Kimura, Noriyuki; Kumamoto, Toshihide; Ueyama, Hidetsugu; Horinouchi, Hideo; Ohama, Eisaku

    2007-12-01

    We examined the role of the 20S proteasome in pathologic changes, including abnormal aggregation of phosphorylated neurofilaments, of spinal motor nerve cells from aluminum-treated rabbits. Immunohistochemistry for the 20S proteasome revealed that many lumbar spinal motor neurons without intracytoplasmic neurofilamentous inclusions or with small inclusions were more intensely stained in aluminum-treated rabbits than in controls, whereas the immunoreactivity was greatly decreased in some enlarged neurons containing large neurofilamentous inclusions. Proteasome activity in whole spinal cord extracts was significantly increased in aluminum-treated rabbits compared with controls. Furthermore, Western blot analysis indicated that the 20S proteasome degraded non-phosphorylated high molecular weight neurofilament (neurofilament-H) protein in vitro. These results suggest that aluminum does not inhibit 20S proteasome activity, and the 20S proteasome degrades neurofilament-H protein. We propose that abnormal aggregation of phosphorylated neurofilaments is induced directly by aluminum, and is not induced by the proteasome inhibition in the aluminum-treated rabbits. Proteasome activation might be involved in intracellular proteolysis, especially in the earlier stages of motor neuron degeneration in aluminum-treated rabbits. PMID:18021372

  18. 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

  19. 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

  20. FK1706, a novel non-immunosuppressant neurophilin ligand, ameliorates motor dysfunction following spinal cord injury through its neuroregenerative action.

    PubMed

    Yamaji, Takayuki; Yamazaki, Shunji; Li, Jiyao; Price, Raymond D; Matsuoka, Nobuya; Mutoh, Seitaro

    2008-09-01

    Injured spinal cord axons fail to regenerate in part due to a lack of trophic support. While various methods for replacing neurotrophins have been pursued, clinical uses of these methods face significant barriers. FK1706, a non-immunosuppressant neurophilin ligand, potentiates nerve growth factor signaling, suggesting therapeutic potential for functional deficits following spinal cord injury. Here, we demonstrate that FK1706 significantly improves behavioral outcomes in animal models of spinal cord hemisection and contusion injuries in rats. Furthermore, we show that FK1706 is effective even if administration is delayed until 1 week after injury, suggesting that FK1706 has a reasonable therapeutic time-window. Morphological analysis of injured axons in the dorsal corticospinal tract showed an increase in the radius and perimeter of stained axons, which were reduced by FK1706 treatment, suggesting that axonal swelling and retraction balls observed in injured spinal cord were improved by the neurotrophic effect of FK1706. Taken together, FK1706 improves both behavioral motor function and the underlying morphological changes, suggesting that FK1706 may have therapeutic potential in meeting the significant unmet needs in spinal cord injury. PMID:18602914

  1. 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

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

    PubMed

    Streeter, K A; Baker-Herman, T L

    2014-10-01

    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

  3. 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

  4. Combined Muscle Motor and Somatosensory Evoked Potentials for Intramedullary Spinal Cord Tumour Surgery

    PubMed Central

    Choi, Il; Hyun, Seung-Jae; Kang, Joong-Koo

    2014-01-01

    Purpose To evaluate whether intraoperative neurophysiologic monitoring (IONM) with combined muscle motor evoked potentials (mMEPs) and somatosensory evoked potentials is useful for more aggressive and safe resection in intramedullary spinal cord tumour (IMSCT) surgery. Materials and Methods We reviewed data from consecutive patients who underwent surgery for IMSCT between 1998 and April 2012. The patients were divided into two groups based on whether or not IONM was applied. In the monitored group, the procedures were performed under IONM using 75% muscle amplitude decline weaning criteria. The control group was comprised of patients who underwent IMSCT surgery without IONM. The primary outcome was the rate of gross total excision of the tumour on magnetic resonance imaging at one week after surgery. The secondary outcome was the neurologic outcome based on the McCormick Grade scale. Results The two groups had similar demographics. The total gross removal tended to increase when intraoperative neurophysiologic monitoring was used, but this tendency did not reach statistical significance (76% versus 58%; univariate analysis, p=0.049; multivariate regression model, p=0.119). The serial McCormick scale score was similar between the two groups (based on repeated measure ANOVA). Conclusion Our study evaluated combined IONM of trans-cranial electrical (Tce)-mMEPs and SEPs for IMSCT. During IMSCT surgery, combined Tce-mMEPs and SEPs using 75% muscle amplitude weaning criteria did not result in significant improvement in the rate of gross total excision of the tumour or neurologic outcome. PMID:24954338

  5. The response to paired motor cortical stimuli is abolished at a spinal level during human muscle fatigue

    PubMed Central

    McNeil, Chris J; Martin, Peter G; Gandevia, Simon C; Taylor, Janet L

    2009-01-01

    During maximal exercise, supraspinal fatigue contributes significantly to the decline in muscle performance but little is known about intracortical inhibition during such contractions. Long-interval inhibition is produced by a conditioning motor cortical stimulus delivered via transcranial magnetic stimulation (TMS) 50–200 ms prior to a second test stimulus. We aimed to delineate changes in this inhibition during a sustained maximal voluntary contraction (MVC). Eight subjects performed a 2 min MVC of elbow flexors. Single test and paired (conditioning–test interval of 100 ms) stimuli were delivered via TMS over the motor cortex every 7–8 s throughout the effort and during intermittent MVCs in the recovery period. To determine the role of spinal mechanisms, the protocol was repeated but the TMS test stimulus was replaced by cervicomedullary stimulation which activates the corticospinal tract. TMS motor evoked potentials (MEPs) and cervicomedullary motor evoked potentials (CMEPs) were recorded from biceps brachii. Unconditioned MEPs increased progressively with fatigue, whereas CMEPs increased initially but returned to the control value in the final 40 s of contraction. In contrast, both conditioned MEPs and CMEPs decreased rapidly with fatigue and were virtually abolished within 30 s. In recovery, unconditioned responses required <30 s but conditioned MEPs and CMEPs required ∼90 s to return to control levels. Thus, long-interval inhibition increased markedly as fatigue progressed. Contrary to expectations, subcortically evoked CMEPs were inhibited as much as MEPs. This new phenomenon was also observed in the first dorsal interosseous muscle. Tested with a high intensity conditioning stimulus during a fatiguing maximal effort, long-interval inhibition of MEPs was increased primarily by spinal rather than motor cortical mechanisms. The spinal mechanisms exposed here may contribute to the development of central fatigue in human muscles. PMID:19805743

  6. 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

  7. Motor axon exit from the mammalian spinal cord is controlled by the homeodomain protein Nkx2.9 via Robo-Slit signaling

    PubMed Central

    Bravo-Ambrosio, Arlene; Mastick, Grant; Kaprielian, Zaven

    2012-01-01

    Mammalian motor circuits control voluntary movements by transmitting signals from the central nervous system (CNS) to muscle targets. To form these circuits, motor neurons (MNs) must extend their axons out of the CNS. Although exit from the CNS is an indispensable phase of motor axon pathfinding, the underlying molecular mechanisms remain obscure. Here, we present the first identification of a genetic pathway that regulates motor axon exit from the vertebrate spinal cord, utilizing spinal accessory motor neurons (SACMNs) as a model system. SACMNs are a homogeneous population of spinal MNs with axons that leave the CNS through a discrete lateral exit point (LEP) and can be visualized by the expression of the cell surface protein BEN. We show that the homeodomain transcription factor Nkx2.9 is selectively required for SACMN axon exit and identify the Robo2 guidance receptor as a likely downstream effector of Nkx2.9; loss of Nkx2.9 leads to a reduction in Robo2 mRNA and protein within SACMNs and SACMN axons fail to exit the spinal cord in Robo2-deficient mice. Consistent with short-range interactions between Robo2 and Slit ligands regulating SACMN axon exit, Robo2-expressing SACMN axons normally navigate through LEP-associated Slits as they emerge from the spinal cord, and fail to exit in Slit-deficient mice. Our studies support the view that Nkx2.9 controls SACMN axon exit from the mammalian spinal cord by regulating Robo-Slit signaling. PMID:22399681

  8. 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. PMID:26888285

  9. 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

  10. 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. PMID:1773774

  11. Time-related changes of motor unit properties in the rat medial gastrocnemius muscle after the spinal cord injury. II. Effects of a spinal cord hemisection.

    PubMed

    Celichowski, Jan; Kryściak, Katarzyna; Krutki, Piotr; Majczyński, Henryk; Górska, Teresa; Sławińska, Urszula

    2010-06-01

    The contractile properties of motor units (MUs) were investigated in the medial gastrocnemius (MG) muscle in rats after the spinal cord hemisection at a low thoracic level. Hemisected animals were divided into 4 groups: 14, 30, 90 and 180 days after injury. Intact rats formed a control group. The mass of the MG muscle did not change significantly after spinal cord hemisection, hind limb locomotor pattern was almost unchanged starting from two weeks after injury, but contractile properties of MUs were however altered. Contraction time (CT) and half-relaxation time (HRT) of MUs were prolonged in all investigated groups of hemisected rats. The twitch-to-tetanus ratio (Tw/Tet) of fast MUs after the spinal cord hemisection increased. For slow MUs Tw/Tet values did not change in the early stage after the injury, but significantly decreased in rats 90 and 180 days after hemisection. As a result of hemisection the fatigue resistance especially of slow and fast resistant MU types was reduced, as well as fatigue index (Fat I) calculated for the whole examined population of MUs decreased progressively with the time. After spinal cord hemisection a reduced number of fast MUs presented the sag at frequencies 30 and 40 Hz, however more of them revealed sag in 20 Hz tetanus in comparison to control group. Due to considerable changes in twitch contraction time and disappearance of sag effect in unfused tetani of some MUs in hemisected animals, the classification of MUs in all groups of rats was based on the 20 Hz tetanus index (20 Hz Tet I) but not on the standard criteria usually applied for MUs classification. MU type differentiations demonstrated some clear changes in MG muscle composition in hemisected animals consisting of an increase in the proportion of slow MUs (likely due to an increased participation of the studied muscle in tonic antigravity activity) together with an increase in the percentage of fast fatigable MUs. PMID:19679495

  12. The effects of anodal transcranial direct current stimulation and patterned electrical stimulation on spinal inhibitory interneurons and motor function in patients with spinal cord injury.

    PubMed

    Yamaguchi, Tomofumi; Fujiwara, Toshiyuki; Tsai, Yun-An; Tang, Shuen-Chang; Kawakami, Michiyuki; Mizuno, Katsuhiro; Kodama, Mitsuhiko; Masakado, Yoshihisa; Liu, Meigen

    2016-06-01

    Supraspinal excitability and sensory input may play an important role for the modulation of spinal inhibitory interneurons and functional recovery among patients with incomplete spinal cord injury (SCI). Here, we investigated the effects of anodal transcranial direct current stimulation (tDCS) combined with patterned electrical stimulation (PES) on spinal inhibitory interneurons in patients with chronic incomplete SCI and in healthy individuals. Eleven patients with incomplete SCI and ten healthy adults participated in a single-masked, sham-controlled crossover study. PES involved stimulating the common peroneal nerve with a train of ten 100 Hz pulses every 2 s for 20 min. Anodal tDCS (1 mA) was simultaneously applied to the primary motor cortex that controls the tibialis anterior muscle. We measured reciprocal inhibition and presynaptic inhibition of a soleus H-reflex by stimulating the common peroneal nerve prior to tibial nerve stimulation, which elicits the H-reflex. The inhibition was assessed before, immediately after, 10 min after and 20 min after the stimulation. Compared with baseline, simultaneous application of anodal tDCS with PES significantly increased changes in disynaptic reciprocal inhibition and long-latency presynaptic inhibition in both healthy and SCI groups for at least 20 min after the stimulation (all, p < 0.001). In patients with incomplete SCI, anodal tDCS with PES significantly increased the number of ankle movements in 10 s at 20 min after the stimulation (p = 0.004). In conclusion, anodal tDCS combined with PES could induce spinal plasticity and improve ankle movement in patients with incomplete SCI. PMID:26790423

  13. Effects of A Voltage Sensitive Calcium Channel Blocker and A Sodium-Calcium Exchanger Inhibitor on Apoptosis of Motor Neurons in Adult Spinal Cord Slices

    PubMed Central

    Momeni, Hamid Reza; Jarahzadeh, Mahsa

    2012-01-01

    Objective: The apoptosis of motor neurons is a critical phenomenon in spinal cord injuries. Adult spinal cord slices were used to investigate whether voltage sensitive calcium channels and Na+/Ca2+ exchangers play a role in the apoptosis of motor neurons. Materials and Methods: In this experimental research, the thoracic region of the adult mouse spinal cord was sliced using a tissue chopper and the slices were incubated in a culture medium in the presence or absence of N/L type voltage sensitive calcium channels blocker (loperamide, 100 µM) or Na+/Ca2+ exchangers inhibitor(bepridil, 20 µM) for 6 hours. 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyl tetrazolium (MTT) staining was used to assess slice viability while morphological features of apoptosis in motor neurons were studied using fluorescent staining. Results: After 6 hours in culture, loperamideand bepridil not only increased slice viability, but also prevented motor neuron apoptosis and significantly increased the percentage of viable motor neurons in the ventral horns of the spinal cord. Conclusion: The results of this study suggest that voltage sensitive calcium channels and Na+/Ca2+ exchanger might be involved in the apoptosis of motor neurons in adult spinal cord slices. PMID:23508879

  14. 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. PMID:18598683

  15. 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

  16. A Simple Experimentally Based Model Using Proprioceptive Regulation of Motor Primitives Captures Adjusted Trajectory Formation in Spinal Frogs

    PubMed Central

    Kargo, William J.; Ramakrishnan, Arun; Hart, Corey B.; Rome, Lawrence C.

    2010-01-01

    Spinal circuits may organize trajectories using pattern generators and synergies. In frogs, prior work supports fixed-duration pulses of fixed composition synergies, forming primitives. In wiping behaviors, spinal frogs adjust their motor activity according to the starting limb position and generate fairly straight and accurate isochronous trajectories across the workspace. To test whether a compact description using primitives modulated by proprioceptive feedback could reproduce such trajectory formation, we built a biomechanical model based on physiological data. We recorded from hindlimb muscle spindles to evaluate possible proprioceptive input. As movement was initiated, early skeletofusimotor activity enhanced many muscle spindles firing rates. Before movement began, a rapid estimate of the limb position from simple combinations of spindle rates was possible. Three primitives were used in the model with muscle compositions based on those observed in frogs. Our simulations showed that simple gain and phase shifts of primitives based on published feedback mechanisms could generate accurate isochronous trajectories and motor patterns that matched those observed. Although on-line feedback effects were omitted from the model after movement onset, our primitive-based model reproduced the wiping behavior across a range of starting positions. Without modifications from proprioceptive feedback, the model behaviors missed the target in a manner similar to that in deafferented frogs. These data show how early proprioception might be used to make a simple estimate initial limb state and to implicitly plan a movement using observed spinal motor primitives. Simulations showed that choice of synergy composition played a role in this simplicity. To generate froglike trajectories, a hip flexor synergy without sartorius required motor patterns with more proprioceptive knee flexor control than did patterns built with a more natural synergy including sartorius. Such synergy

  17. Early phrenic motor neuron loss and transient respiratory abnormalities after unilateral cervical spinal cord contusion.

    PubMed

    Nicaise, Charles; Frank, David M; Hala, Tamara J; Authelet, Michèle; Pochet, Roland; Adriaens, Dominique; Brion, Jean-Pierre; Wright, Megan C; Lepore, Angelo C

    2013-06-15

    Contusion-type cervical spinal cord injury (SCI) is one of the most common forms of SCI observed in patients. In particular, injuries targeting the C3-C5 region affect the pool of phrenic motor neurons (PhMNs) that innervates the diaphragm, resulting in significant and often chronic respiratory dysfunction. Using a previously described rat model of unilateral midcervical C4 contusion with the Infinite Horizon Impactor, we have characterized the early time course of PhMN degeneration and consequent respiratory deficits following injury, as this knowledge is important for designing relevant treatment strategies targeting protection and plasticity of PhMN circuitry. PhMN loss (48% of the ipsilateral pool) occurred almost entirely during the first 24 h post-injury, resulting in persistent phrenic nerve axonal degeneration and denervation at the diaphragm neuromuscular junction (NMJ). Reduced diaphragm compound muscle action potential amplitudes following phrenic nerve stimulation were observed as early as the first day post-injury (30% of pre-injury maximum amplitude), with slow functional improvement over time that was associated with partial reinnervation at the diaphragm NMJ. Consistent with ipsilateral diaphragmatic compromise, the injury resulted in rapid, yet only transient, changes in overall ventilatory parameters measured via whole-body plethysmography, including increased respiratory rate, decreased tidal volume, and decreased peak inspiratory flow. Despite significant ipsilateral PhMN loss, the respiratory system has the capacity to quickly compensate for partially impaired hemidiaphragm function, suggesting that C4 hemicontusion in rats is a model of SCI that manifests subacute respiratory abnormalities. Collectively, these findings demonstrate significant and persistent diaphragm compromise in a clinically relevant model of midcervical contusion SCI; however, the therapeutic window for PhMN protection is restricted to early time points post-injury. On

  18. Locomotor step training with body weight support improves respiratory motor function in individuals with chronic spinal cord injury

    PubMed Central

    de Paleville, Daniela Terson; McKay, William; Aslan, Sevda; Folz, Rodney; Sayenko, Dimitry; Ovechkin, Alexander V.

    2013-01-01

    This prospective case-controlled clinical study was undertaken to investigate to what extent the manually assisted treadmill stepping Locomotor Training with body weight support (LT) can change respiratory function in individuals with chronic Spinal Cord Injury (SCI). Pulmonary function outcomes (Forced Vital Capacity /FVC/, Forced Expiratory Volume one second /FEV1/, Maximum Inspiratory Pressure /PImax/, Maximum Expiratory Pressure /PEmax/) and surface electromyographic (sEMG) measures of respiratory muscles activity during respiratory taskswere obtained from eight individuals with chronic C3-T12 SCI before and after 62±10 (Mean ± SD) sessions of the LT. FVC, FEV1, PImax, PEmax, amount of overall sEMG activity and rate of motor unit recruitment were significantly increased after LT (p<0.05) These results suggest that these improvements induced by the LT are likely the result of neuroplastic changes in spinal neural circuitry responsible for the activation of respiratory muscles preserved after injury. PMID:23999001

  19. Grafted Human Embryonic Progenitors Expressing Neurogenin-2 Stimulate Axonal Sprouting and Improve Motor Recovery after Severe Spinal Cord Injury

    PubMed Central

    Perrin, Florence E.; Lonjon, Nicolas; Serre, Angeline; Prieto, Monica; Mallet, Jacques; Privat, Alain

    2010-01-01

    Background Spinal cord injury (SCI) is a widely spread pathology with currently no effective treatment for any symptom. Regenerative medicine through cell transplantation is a very attractive strategy and may be used in different non-exclusive ways to promote functional recovery. We investigated functional and structural outcomes after grafting human embryonic neural progenitors (hENPs) in spinal cord-lesioned rats. Methods and Principal Findings With the objective of translation to clinics we have chosen a paradigm of delayed grafting, i.e., one week after lesion, in a severe model of spinal cord compression in adult rats. hENPs were either naïve or engineered to express Neurogenin 2 (Ngn2). Moreover, we have compared integrating and non-integrating lentiviral vectors, since the latter present reduced risks of insertional mutagenesis. We show that transplantation of hENPs transduced to express Ngn2 fully restore weight support and improve functional motor recovery after severe spinal cord compression at thoracic level. This was correlated with partial restoration of serotonin innervations at lumbar level, and translocation of 5HT1A receptors to the plasma membrane of motoneurons. Since hENPs were not detectable 4 weeks after grafting, transitory expression of Ngn2 appears sufficient to achieve motor recovery and to permit axonal regeneration. Importantly, we also demonstrate that transplantation of naïve hENPs is detrimental to functional recovery. Conclusions and Significance Transplantation and short-term survival of Ngn2-expressing hENPs restore weight support after SCI and partially restore serotonin fibers density and 5HT1A receptor pattern caudal to the lesion. Moreover, grafting of naïve-hENPs was found to worsen the outcome versus injured only animals, thus pointing to the possible detrimental effect of stem cell-based therapy per se in SCI. This is of major importance given the increasing number of clinical trials involving cell grafting developed for

  20. Spinal dorsal horn neuron response to mechanical stimuli is decreased by electrical stimulation of the primary motor cortex.

    PubMed

    Senapati, Arun K; Huntington, Paula J; Peng, Yuan B

    2005-03-01

    Motor cortex stimulation (MCS) has been used clinically as a tool for the control for central post-stroke pain and neuropathic facial pain. The underlying mechanisms involved in the antinociceptive effect of MCS are not clearly understood. We hypothesize that the antinociceptive effect is through the modulation of the spinal dorsal horn neuron activity. Thirty-two wide dynamic range spinal dorsal horn neurons were recorded, in response to graded mechanical stimulation (brush, pressure, and pinch) at their respective receptive fields, while a stepwise electrical stimulation was applied simultaneously in the motor cortex. The responses to brush at control, 10 V, 20 V, and 30 V, and recovery were 11.5+/-1.6, 12.1+/-2.6, 11.1+/-2.2, 10.5+/-2.1, and 13.2+/-2.5 spikes/s, respectively. The responses to pressure at control, 10 V, 20 V, and 30 V, and recovery were 33.2+/-6.1, 22.9+/-5.3, 20.5+/-5.0, 17.3+/-3.8, and 27.0+/-4.0 spikes/s, respectively. The responses to pinch at control, 10 V, 20 V, and 30 V, and recovery were 37.2+/-6.4, 26.3+/-4.7, 25.9+/-4.7, 22.5+/-4.3, and 35.0+/-6.2 spikes/s, respectively. It is concluded that, in the rat, electrical stimulation of the motor cortex produces significant transient inhibition of the responses of spinal cord dorsal horn neurons to higher intensity mechanical stimuli without affecting their response to an innocuous stimulus. PMID:15725415

  1. 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

  2. Safe transcranial electric stimulation motor evoked potential monitoring during posterior spinal fusion in two patients with cochlear implants.

    PubMed

    Yellin, Joseph L; Wiggins, Cheryl R; Franco, Alier J; Sankar, Wudbhav N

    2016-08-01

    Transcranial electric stimulation (TES) motor evoked potentials (MEPs) have become a regular part of intraoperative neurophysiologic monitoring (IONM) for posterior spinal fusion (PSF) surgery. Almost all of the relative contraindications to TES have come and gone. One exception is in the case of patients with a cochlear implant (CI). Herein we illustrate two cases of pediatric patients with CIs who underwent PSF using TES MEPs as part of IONM. In both instances the patients displayed no untoward effects from TES, and post-operatively both CIs were intact and functioning as they were prior to surgery. PMID:26103915

  3. Motor recovery at 6 months after admission is related to structural and functional reorganization of the spine and brain in patients with spinal cord injury.

    PubMed

    Hou, Jingming; Xiang, Zimin; Yan, Rubing; Zhao, Ming; Wu, Yongtao; Zhong, Jianfeng; Guo, Lei; Li, Haitao; Wang, Jian; Wu, Jixiang; Sun, Tiansheng; Liu, Hongliang

    2016-06-01

    This study aimed to explore structural and functional reorganization of the brain in the early stages of spinal cord injury (SCI) and identify brain areas that contribute to motor recovery. We studied 25 patients with SCI, including 10 with good motor recovery and 15 with poor motor recovery, along with 25 matched healthy controls. The mean period post-SCI was 9.2 ± 3.5 weeks in good recoverers and 8.8 ± 2.6 weeks in poor recoverers. All participants underwent structural and functional MRI on a 3-T magnetic resonance system. We evaluated differences in cross-sectional spinal cord area at the C2/C3 level, brain cortical thickness, white matter microstructure, and functional connectivity during the resting state among the three groups. We also evaluated associations between structural and functional reorganization and the rate of motor recovery. After SCI, compared with good recoverers, poor recoverers had a significantly decreased cross-sectional spinal cord area, cortical thickness in the right supplementary motor area and premotor cortex, and fractional anisotropy (FA) in the right primary motor cortex and posterior limb of the internal capsule. Meanwhile, poor recoverers showed decreased functional connectivity between the primary motor cortex and higher order motor areas (supplementary motor area and premotor cortex), while good recoverers showed increased functional connectivity among these regions. The structural and functional reorganization of the spine and brain was associated with motor recovery rate in all SCI patients. In conclusion, structural and functional reorganization of the spine and brain directly affected the motor recovery of SCI. Less structural atrophy and enhanced functional connectivity are associated with good motor recovery in patients with SCI. Multimodal imaging has the potential to predict motor recovery in the early stage of SCI. Hum Brain Mapp 37:2195-2209, 2016. © 2016 Wiley Periodicals, Inc. PMID:26936834

  4. Lateralization of cervical spinal cord activity during an isometric upper extremity motor task with functional magnetic resonance imaging.

    PubMed

    Weber, Kenneth A; Chen, Yufen; Wang, Xue; Kahnt, Thorsten; Parrish, Todd B

    2016-01-15

    The purpose of this study was to use an isometric upper extremity motor task to detect activity induced blood oxygen level dependent signal changes in the cervical spinal cord with functional magnetic resonance imaging. Eleven healthy volunteers performed six 5minute runs of an alternating left- and right-sided isometric wrist flexion task, during which images of the cervical spinal cord were acquired with a reduced field-of-view T2*-weighted gradient-echo echo-planar-imaging sequence. Spatial normalization to a standard spinal cord template was performed, and group average activation maps were generated in a mixed-effects analysis. The task activity significantly exceeded that of the control analyses. The activity was lateralized to the hemicord ipsilateral to the task and reliable across the runs at the group and subject level. Finally, a multi-voxel pattern analysis was able to successfully decode the left and right tasks at the C6 and C7 vertebral levels. PMID:26488256

  5. 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

  6. Spatacsin and spastizin act in the same pathway required for proper spinal motor neuron axon outgrowth in zebrafish.

    PubMed

    Martin, Elodie; Yanicostas, Constantin; Rastetter, Agnès; Alavi Naini, Seyedeh Maryam; Maouedj, Alissia; Kabashi, Edor; Rivaud-Péchoux, Sophie; Brice, Alexis; Stevanin, Giovanni; Soussi-Yanicostas, Nadia

    2012-12-01

    Hereditary spastic paraplegias (HSPs) are rare neurological conditions caused by degeneration of the long axons of the cerebrospinal tracts, leading to locomotor impairment and additional neurological symptoms. There are more than 40 different causative genes, 24 of which have been identified, including SPG11 and SPG15 mutated in complex clinical forms. Since the vast majority of the causative mutations lead to loss of function of the corresponding proteins, we made use of morpholino-oligonucleotide (MO)-mediated gene knock-down to generate zebrafish models of both SPG11 and SPG15 and determine how invalidation of the causative genes (zspg11 and zspg15) during development might contribute to the disease. Micro-injection of MOs targeting each gene caused locomotor impairment and abnormal branching of spinal cord motor neurons at the neuromuscular junction. More severe phenotypes with abnormal tail developments were also seen. Moreover, partial depletion of both proteins at sub-phenotypic levels resulted in the same phenotypes, suggesting for the first time, in vivo, a genetic interaction between these genes. In conclusion, the zebrafish orthologues of the SPG11 and SPG15 genes are important for proper development of the axons of spinal motor neurons and likely act in a common pathway to promote their proper path finding towards the neuromuscular junction. PMID:22801083

  7. 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

  8. DL-Homocysteic acid application disrupts calcium homeostasis and induces degeneration of spinal motor neurons in vivo.

    PubMed

    Adalbert, Róbert; Engelhardt, József I; Siklós, László

    2002-05-01

    Excitotoxicity, autoimmunity and free radicals have been postulated to play a role in the pathomechanism of amyotrophic lateral sclerosis (ALS), the most frequent motor neuron disease. Altered calcium homeostasis has already been demonstrated in Cu/Zn superoxide dismutase transgenic animals, suggesting a role for free radicals in the pathogenesis of ALS, and in passive transfer experiments, modeling autoimmunity. These findings also suggested that yet-confined pathogenic insults, associated with ALS, could trigger the disruption of calcium homeostasis of motor neurons. To test the possibility that excitotoxic processes may also be able to increase calcium in motor neurons, we applied the glutamate analogue DL-homocysteic acid to the spinal cord of rats in vivo and analyzed the calcium distribution of the motor neurons over a 24-h survival period by electron microscopy. Initially, an elevated cytoplasmic calcium level, with no morphological sign of degeneration, was noticed. Later, increasing calcium accumulation was seen in different cellular compartments with characteristic features of alteration at different survival times. This calcium accumulation in organelles was paralleled by their progressive degeneration, which culminated in cell death by the end of the observation time. These findings confirm that increased calcium also plays a role in excitotoxic lesion of motor neurons, in line with previous studies documenting the involvement of calcium ions in motor neuronal injury in other models of the disease as well as elevated calcium in biopsy samples from ALS patients. We suggest that intracellular calcium might be responsible for the interplay between the different pathogenic processes resulting in a uniform clinicopathological picture of the disease. PMID:11935257

  9. 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

  10. 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

  11. Surgical and conservative methods for restoring impaired motor function - facial nerve, spinal accessory nerve, hypoglossal nerve (not including vagal nerve or swallowing)

    PubMed Central

    Laskawi, R.; Rohrbach, S.

    2005-01-01

    The present review gives a survey of rehabilitative measures for disorders of the motor function of the mimetic muscles (facial nerve), and muscles innervated by the spinal accessory and hypoglossal nerves. The dysfunction can present either as paralysis or hyperkinesis (hyperkinesia). Conservative and surgical treatment options aimed at restoring normal motor function and correcting the movement disorders are described. Static reanimation techniques are not dealt with. The final section describes the use of botulinum toxin in the therapy of dysphagia. PMID:22073058

  12. AMPA Receptor Phosphorylation and Synaptic Colocalization on Motor Neurons Drive Maladaptive Plasticity below Complete Spinal Cord Injury1,2,3

    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

  13. Overexpression of the astrocyte glutamate transporter GLT1 exacerbates phrenic motor neuron degeneration, diaphragm compromise, and forelimb motor dysfunction following cervical contusion spinal cord injury.

    PubMed

    Li, Ke; Nicaise, Charles; Sannie, Daniel; Hala, Tamara J; Javed, Elham; Parker, Jessica L; Putatunda, Rajarshi; Regan, Kathleen A; Suain, Valérie; Brion, Jean-Pierre; Rhoderick, Fred; Wright, Megan C; Poulsen, David J; Lepore, Angelo C

    2014-05-28

    A major portion of spinal cord injury (SCI) cases affect midcervical levels, the location of the phrenic motor neuron (PhMN) pool that innervates the diaphragm. While initial trauma is uncontrollable, a valuable opportunity exists in the hours to days following SCI for preventing PhMN loss and consequent respiratory dysfunction that occurs during secondary degeneration. One of the primary causes of secondary injury is excitotoxic cell death due to dysregulation of extracellular glutamate homeostasis. GLT1, mainly expressed by astrocytes, is responsible for the vast majority of functional uptake of extracellular glutamate in the CNS, particularly in spinal cord. We found that, in bacterial artificial chromosome-GLT1-enhanced green fluorescent protein reporter mice following unilateral midcervical (C4) contusion SCI, numbers of GLT1-expressing astrocytes in ventral horn and total intraspinal GLT1 protein expression were reduced soon after injury and the decrease persisted for ≥6 weeks. We used intraspinal delivery of adeno-associated virus type 8 (AAV8)-Gfa2 vector to rat cervical spinal cord ventral horn for targeting focal astrocyte GLT1 overexpression in areas of PhMN loss. Intraspinal delivery of AAV8-Gfa2-GLT1 resulted in transduction primarily of GFAP(+) astrocytes that persisted for ≥6 weeks postinjury, as well as increased intraspinal GLT1 protein expression. Surprisingly, we found that astrocyte-targeted GLT1 overexpression increased lesion size, PhMN loss, phrenic nerve axonal degeneration, and diaphragm neuromuscular junction denervation, and resulted in reduced functional diaphragm innervation as assessed by phrenic nerve-diaphragm compound muscle action potential recordings. These results demonstrate that GLT1 overexpression via intraspinal AAV-Gfa2-GLT1 delivery exacerbates neuronal damage and increases respiratory impairment following cervical SCI. PMID:24872566

  14. Effects of Pain and Pain Management on Motor Recovery of Spinal Cord-Injured Patients: A Longitudinal Study.

    PubMed

    Cragg, Jacquelyn J; Haefeli, Jenny; Jutzeler, Catherine R; Röhrich, Frank; Weidner, Norbert; Saur, Marion; Maier, Doris D; Kalke, Yorck B; Schuld, Christian; Curt, Armin; Kramer, John K

    2016-09-01

    Background Approximately 60% of patients suffering from acute spinal cord injury (SCI) develop pain within days to weeks after injury, which ultimately persists into chronic stages. To date, the consequences of pain after SCI have been largely examined in terms of interfering with quality of life. Objective The objective of this study was to examine the effects of pain and pain management on neurological recovery after SCI. Methods We analyzed clinical data in a prospective multicenter observational cohort study in patients with SCI. Using mixed effects regression techniques, total motor and sensory scores were modelled at 1, 3, 6, and 12 months postinjury. Results A total of 225 individuals were included in the study (mean age: 45.8 ± 18 years, 80% male). At 1 month postinjury, 28% of individuals with SCI reported at- or below-level neuropathic pain. While pain classification showed no effect on neurological outcomes, individuals administered anticonvulsant medications at 1 month postinjury showed significant reductions in pain intensity (2 points over 1 year; P < .05) and greater recovery in total motor scores (7.3 points over 1 year; P < .05). This drug effect on motor recovery remained significant after adjustment for injury level and injury severity, pain classification, and pain intensity. Conclusion While initial pain classification and intensity did not reveal an effect on motor recovery following acute SCI, anticonvulsants conferred a significant beneficial effect on motor outcomes. Early intervention with anticonvulsants may have effects beyond pain management and warrant further studies to evaluate the therapeutic effectiveness in human SCI. PMID:26747127

  15. The contractile properties of the medial gastrocnemius motor units innervated by L4 and L5 spinal nerves in the rat.

    PubMed

    Celichowski, Jan; Taborowska, Malwina

    2011-01-01

    When a muscle innervation originates from more than one spinal cord segment, the injury of one of the respective ventral roots evokes an overload, and alters the activity and properties of the remaining motor units. However, it is not well documented if the three types of motor units are equally represented within the innervating ventral roots. Single motor units in the rat medial gastrocnemius muscle were studied and their contractile properties as well as distribution of different types of motor units belonging to subpopulations innervated by axons in L4 and L5 ventral roots were analyzed. The composition of the three physiological types of motor units in the two subpopulations was similar. Force parameters were similar for motor units belonging to the two subpopulations. However, the twitch time parameters were slightly longer in L4 in comparison to L5 motor units although the difference was significant only for fast resistant to fatigue motor units. The force-frequency relationships in the two subpopulations of motor units were not different. Concluding, the two subpopulations of motor units in the studied muscle differ in the number of motor units, but contain similar proportions of the three physiological types of these units and their contractile properties are similar. Therefore, the injury of one ventral root evokes various degrees of muscle denervation, but is non-selective in relation to the three types of motor units. PMID:21846299

  16. 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

  17. 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

  18. Role of Neurotrophins in Recovery of Phrenic Motor Function Following Spinal Cord Injury

    PubMed Central

    Sieck, Gary C.; Mantilla, Carlos B.

    2009-01-01

    Many individuals who sustain a cervical spinal cord injury are unable to maintain adequate ventilation due to diaphragm muscle paralysis. These patients become dependent on mechanical ventilators and this situation is associated with ongoing problems with pulmonary clearance, infections, and lung injury leading to significant morbidity and reduced life expectancy. Therefore, functional recovery of rhythmic phrenic activity and the ability to generate expulsive forces would dramatically affect the quality of life of patients with cervical spinal cord injury. Neurotrophins are very promising in that they have been shown to play an important role in modulating functional neuroplasticity. Specifically, brain-derived neurotrophic factor (BDNF) acting via the tropomyosin-related kinase receptor type B (TrkB) has been implicated in neuroplasticity following spinal cord injury. Our central hypothesis is that functional recovery of rhythmic phrenic activity after cervical spinal cord injury is enhanced by an increase in BDNF/TrkB signaling in phrenic motoneurons, providing a novel therapeutic target for patients. PMID:19703592

  19. Motor strategies used by rats spinalized at birth to maintain stance in response to imposed perturbations

    PubMed Central

    Giszter, Simon F; Davies, Michelle R; Graziani, Virginia

    2010-01-01

    Some rats spinalized P1/P2 achieve autonomous weight supported locomotion and quiet stance as adults. We used force platforms and robot applied perturbations to test such spinalized rats (n=6) which exhibited both weight supporting locomotion and stance, and also normal rats (n=8). Ground reaction forces in individual limbs, and the animals’ center of pressure were examined. In normal rats, both forelimbs and hindlimbs participated actively to control horizontal components of ground reaction forces. Rostral perturbations increased forelimb ground reaction forces, and caudal perturbations increased hindlimb ground reaction forces. Operate rats carried 60% body weight on the forelimbs and had a more rostral center of pressure placement. Normal rats pattern was to carry significantly more weight on the hindlimbs in quiet stance (~60%). Operate rats strategy of compensation for perturbations was entirely in forelimbs; as a result, the hind-limbs were largely isolated from the perturbation. Stiffness magnitude of the whole body was measured: its magnitude was hourglass shaped, with the principal axis oriented rostrocaudally. Operate rats were significantly less stiff; only 60-75% of normal rats’ stiffness. The injured rats adopt a stance strategy that isolates the hindlimbs from perturbation and may thus prevent hindlimb loadings. Such loadings could initiate reflex stepping, which we observed. This might activate lumbar pattern generators used in their locomotion. Adult spinalized rats never achieve independent hindlimb weight supported stance. The stance strategy of the P1 spinalized rats differed strongly from the behavior of intact rats and may be difficult for rats spinalized as adults to master. PMID:17287444

  20. 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

  1. Effect of dexmedetomidine-etomidate-fentanyl combined anesthesia on somatosensory- and motor-evoked potentials in patients undergoing spinal surgery

    PubMed Central

    LIN, SHENG; DAI, NA; CHENG, ZHENGYAN; SHAO, WEI; FU, ZHIJIAN

    2014-01-01

    This aim of the present study was to evaluate the effects of dexmedetomidine (DEX) on the intraoperative monitoring of somatosensory-evoked potentials (SEPs) and motor-evoked potentials (MEPs) in patients undergoing spinal surgery. A total of 36 patients who received spinal surgery under general anesthesia were randomly divided into two groups (n=18 per group), group C, the test group and group D, the control group, and these groups were subjected to a matching anesthesia induction. In brief, the anesthesia was administered via injection of etomidate and fentanyl; once the patients were unconscious, a laryngeal mask airway (LMA) was inserted, SEPs and MEPs were monitored and the collected data were considered to be basic data. Cisatracurium was subsequently injected and an endotracheal tube (7#) was inserted to replace the LMA. The following procedures were conducted for anesthesia maintenance: Group C, the anesthesia was maintained via target-controlled infusion of etomidate and intermittent injection of fentanyl; and group D, DEX (0.5 μg/kg) was injected over a duration of 10 min and then pumped at a rate of 0.5 μg/kg/h. In the two groups, all of the other drugs used were the same and a muscle relaxant was not administered. The bispectral index was maintained between 45 and 55 during surgery, and the SEPs and MEPs were monitored continuously until the surgery was completed. No significant difference in duration and amplitude of the SEPs (P15-N20) was identified between group C and D (P>0.05). Furthermore, the MEPs were monitored in the two groups at specific durations and no significant difference was observed between the two groups (P>0.05). The SEPs and MEPs were maintained in the patients who were administered with the DEX-etomidate-fentanyl combined anesthesia during spinal surgery. PMID:24940443

  2. 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. PMID:27299569

  3. Activation of the unfolded protein response enhances motor recovery after spinal cord injury

    PubMed Central

    Valenzuela, V; Collyer, E; Armentano, D; Parsons, G B; Court, F A; Hetz, C

    2012-01-01

    Spinal cord injury (SCI) is a major cause of paralysis, and involves multiple cellular and tissular responses including demyelination, inflammation, cell death and axonal degeneration. Recent evidence suggests that perturbation on the homeostasis of the endoplasmic reticulum (ER) is observed in different SCI models; however, the functional contribution of this pathway to this pathology is not known. Here we demonstrate that SCI triggers a fast ER stress reaction (1–3 h) involving the upregulation of key components of the unfolded protein response (UPR), a process that propagates through the spinal cord. Ablation of X-box-binding protein 1 (XBP1) or activating transcription factor 4 (ATF4) expression, two major UPR transcription factors, leads to a reduced locomotor recovery after experimental SCI. The effects of UPR inactivation were associated with a significant increase in the number of damaged axons and reduced amount of oligodendrocytes surrounding the injury zone. In addition, altered microglial activation and pro-inflammatory cytokine expression were observed in ATF4 deficient mice after SCI. Local expression of active XBP1 into the spinal cord using adeno-associated viruses enhanced locomotor recovery after SCI, and was associated with an increased number of oligodendrocytes. Altogether, our results demonstrate a functional role of the UPR in SCI, offering novel therapeutic targets to treat this invalidating condition. PMID:22337234

  4. Riluzole promotes motor and respiratory recovery associated with enhanced neuronal survival and function following high cervical spinal hemisection.

    PubMed

    Satkunendrarajah, K; Nassiri, F; Karadimas, S K; Lip, A; Yao, G; Fehlings, M G

    2016-02-01

    Cervical spinal cord injury (SCI) can result in devastating functional deficits that involve the respiratory and hand function. The mammalian spinal cord has limited ability to regenerate and restore meaningful functional recovery following SCI. Riluzole, 2-amino-6-trifluoromethoxybenzothiazole, an anti-glutamatergic drug has been shown to reduce excitotoxicity and confer neuroprotection at the site of injury following experimental SCI. Based on promising preclinical studies, riluzole is currently under Phase III clinical trial for the treatment of SCI (ClinicalTrials.gov: NCT01597518). Riluzole's anti-glutamatergic role has the potential to regulate neuronal function and provide neuroprotection and influence glutamatergic connections distal to the initial injury leading to enhanced functional recovery following SCI. In order to investigate this novel role of riluzole we used a high cervical hemisection model of SCI, which interrupts all descending input to motoneurons innervating the ipsilateral forelimb and diaphragm muscles. Following C2 spinal cord hemisection, animals were placed into one of two groups: one group received riluzole (8 mg/kg) 1 h after injury and every 12 h thereafter for 7 days at 6 mg/kg, while the second group of injured rats received vehicle solution for the same duration of time. A third group of sham injured rats underwent a C2 laminectomy without hemisection and served as uninjured control rats. Interestingly, this study reports a significant loss of motoneurons within the cervical spinal cord caudal to C2 hemisection injury. Disruption of descending input led to a decrease in glutamatergic synapses and motoneurons caudal to the injury while riluzole treatment significantly limited this decline. Functionally, Hoffmann reflex recordings revealed an increase in the excitability of the remaining ipsilateral cervical motoneurons and significant improvements in skilled and unskilled forelimb function and respiratory motor function in the

  5. Substantially elevating the levels of αB-crystallin in spinal motor neurons of mutant SOD1 mice does not significantly delay paralysis or attenuate mutant protein aggregation

    PubMed Central

    Xu, Guilian; Fromholt, Susan; Ayers, Jacob I.; Brown, Hilda; Siemienski, Zoe; Crosby, Keith W.; Mayer, Christopher A.; Janus, Christopher; Borchelt, David R.

    2015-01-01

    There has been great interest in enhancing endogenous protein maintenance pathways such as the heat-shock chaperone response, as it is postulated that enhancing clearance of misfolded proteins could have beneficial disease modifying effects in ALS and other neurodegenerative disorders. In cultured cell models of mutant SOD1 aggregation, co-expression of αB-crystallin (αB-crys) has been shown to inhibit the formation of detergent-insoluble forms of mutant protein. Here, we describe the generation of a new line of transgenic mice that express αB-crys at >6-fold the normal level in spinal cord, with robust increases in immunoreactivity throughout the spinal cord grey matter and, specifically, in spinal motor neurons. Surprisingly, spinal cords of mice expressing αB-crys alone contained 20% more motor neurons per section than littermate controls. Raising αB-crys by these levels in mice transgenic for either G93A or L126Z mutant SOD1 had no effect on the age at which paralysis developed. In the G93A mice, which showed the most robust degree of motor neuron loss, the number of these cells declined by the same proportion as in mice expressing the mutant SOD1 alone. In paralyzed bigenic mice, the levels of detergent-insoluble, misfolded, mutant SOD1 were similar to those of mice expressing mutant SOD1 alone. These findings indicate that raising the levels of αB-crys in spinal motor neurons by 6-fold does not produce the therapeutic effects predicted by cell culture models of mutant SOD1 aggregation. PMID:25557022

  6. 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. PMID:9419055

  7. Spinal muscular atrophy and a model for survival of motor neuron protein function in axonal ribonucleoprotein complexes.

    PubMed

    Rossoll, Wilfried; Bassell, Gary J

    2009-01-01

    Spinal muscular atrophy (SMA) is a neurodegenerative disease that results from loss of function of the SMN1 gene, encoding the ubiquitously expressed survival of motor neuron (SMN) protein, a protein best known for its housekeeping role in the SMN-Gemin multiprotein complex involved in spliceosomal small nuclear ribonucleoprotein (snRNP) assembly. However, numerous studies reveal that SMN has many interaction partners, including mRNA binding proteins and actin regulators, suggesting its diverse role as a molecular chaperone involved in mRNA metabolism. This review focuses on studies suggesting an important role of SMN in regulating the assembly, localization, or stability of axonal messenger ribonucleoprotein (mRNP) complexes. Various animal models for SMA are discussed, and phenotypes described that indicate a predominant function for SMN in neuronal development and synapse formation. These models have begun to be used to test different therapeutic strategies that have the potential to restore SMN function. Further work to elucidate SMN mechanisms within motor neurons and other cell types involved in neuromuscular circuitry hold promise for the potential treatment of SMA. PMID:19343312

  8. 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

  9. 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 ...

  10. 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

  11. Neuroprotective Effects of Toll-Like Receptor 4 Antagonism in Spinal Cord Cultures and in a Mouse Model of Motor Neuron Degeneration

    PubMed Central

    De Paola, Massimiliano; Mariani, Alessandro; Bigini, Paolo; Peviani, Marco; Ferrara, Giovanni; Molteni, Monica; Gemma, Sabrina; Veglianese, Pietro; Castellaneta, Valeria; Boldrin, Valentina; Rossetti, Carlo; Chiabrando, Chiara; Forloni, Gianluigi; Mennini, Tiziana; Fanelli, Roberto

    2012-01-01

    Sustained inflammatory reactions are common pathological events associated with neuron loss in neurodegenerative diseases. Reported evidence suggests that Toll-like receptor 4 (TLR4) is a key player of neuroinflammation in several neurodegenerative diseases. However, the mechanisms by which TLR4 mediates neurotoxic signals remain poorly understood. We investigated the role of TLR4 in in vitro and in vivo settings of motor neuron degeneration. Using primary cultures from mouse spinal cords, we characterized both the proinflammatory and neurotoxic effects of TLR4 activation with lipopolysaccharide (activation of microglial cells, release of proinflammatory cytokines and motor neuron death) and the protective effects of a cyanobacteria-derived TLR4 antagonist (VB3323). With the use of TLR4-deficient cells, a critical role of the microglial component with functionally active TLR4 emerged in this setting. The in vivo experiments were carried out in a mouse model of spontaneous motor neuron degeneration, the wobbler mouse, where we preliminarily confirmed a protective effect of TLR4 antagonism. Compared with vehicle- and riluzole-treated mice, those chronically treated with VB3323 showed a decrease in microglial activation and morphological alterations of spinal cord neurons and a better performance in the paw abnormality and grip-strength tests. Taken together, our data add new understanding of the role of TLR4 in mediating neurotoxicity in the spinal cord and suggest that TLR4 antagonists could be considered in future studies as candidate protective agents for motor neurons in degenerative diseases. PMID:22562723

  12. The control of rostrocaudal pattern in the developing spinal cord: specification of motor neuron subtype identity is initiated by signals from paraxial mesoderm.

    PubMed

    Ensini, M; Tsuchida, T N; Belting, H G; Jessell, T M

    1998-03-01

    The generation of distinct classes of motor neurons is an early step in the control of vertebrate motor behavior. To study the interactions that control the generation of motor neuron subclasses in the developing avian spinal cord we performed in vivo grafting studies in which either the neural tube or flanking mesoderm were displaced between thoracic and brachial levels. The positional identity of neural tube cells and motor neuron subtype identity was assessed by Hox and LIM homeodomain protein expression. Our results show that the rostrocaudal identity of neural cells is plastic at the time of neural tube closure and is sensitive to positionally restricted signals from the paraxial mesoderm. Such paraxial mesodermal signals appear to control the rostrocaudal identity of neural tube cells and the columnar subtype identity of motor neurons. These results suggest that the generation of motor neuron subtypes in the developing spinal cord involves the integration of distinct rostrocaudal and dorsoventral patterning signals that derive, respectively, from paraxial and axial mesodermal cell groups. PMID:9463344

  13. The use of magnetic motor evoked potentials in horses with cervical spinal cord disease.

    PubMed

    Nollet, H; Deprez, P; Van Ham, L; Verschooten, F; Vanderstraeten, G

    2002-03-01

    The aim of this study was to investigate the use of magnetic motor evoked potentials as an ancillary diagnostic test in horses with cervical cord lesions. Transcranial magnetic stimulation was performed in 12 ataxic horses and the results of the evoked responses were compared to those found in normal horses. The latency and peak-to-peak amplitude of the potentials in the 12 ataxic horses were significantly different from those measured in normal horses. The configuration of the abnormal potentials was also polyphasic. Normalisation of the evoked potentials occurred in none of the horses, presented after a period of clinical improvement. These findings demonstrate that the technique is also able to detect lesions in horses with subtle clinical signs of incoordination. Magnetic transcranial stimulation is a valuable ancillary test to assess the integrity of the motor tracts. The technique is painless and safe and shows good sensitivity to detect lesions along the descending motor pathways. PMID:11902758

  14. 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

  15. Stimulation of Glia Reveals Modulation of Mammalian Spinal Motor Networks by Adenosine.

    PubMed

    Acton, David; Miles, Gareth B

    2015-01-01

    Despite considerable evidence that glia can release modulators to influence the excitability of neighbouring neurons, the importance of gliotransmission for the operation of neural networks and in shaping behaviour remains controversial. Here we characterise the contribution of glia to the modulation of the mammalian spinal central pattern generator for locomotion, the output of which is directly relatable to a defined behaviour. Glia were stimulated by specific activation of protease-activated receptor-1 (PAR1), an endogenous G-protein coupled receptor preferentially expressed by spinal glia during ongoing activity of the spinal central pattern generator for locomotion. Selective activation of PAR1 by the agonist TFLLR resulted in a reversible reduction in the frequency of locomotor-related bursting recorded from ventral roots of spinal cord preparations isolated from neonatal mice. In the presence of the gliotoxins methionine sulfoximine or fluoroacetate, TFLLR had no effect, confirming the specificity of PAR1 activation to glia. The modulation of burst frequency upon PAR1 activation was blocked by the non-selective adenosine-receptor antagonist theophylline and by the A1-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, but not by the A2A-receptor antagonist SCH5826, indicating production of extracellular adenosine upon glial stimulation, followed by A1-receptor mediated inhibition of neuronal activity. Modulation of network output following glial stimulation was also blocked by the ectonucleotidase inhibitor ARL67156, indicating glial release of ATP and its subsequent degradation to adenosine rather than direct release of adenosine. Glial stimulation had no effect on rhythmic activity recorded following blockade of inhibitory transmission, suggesting that glial cell-derived adenosine acts via inhibitory circuit components to modulate locomotor-related output. Finally, the modulation of network output by endogenous adenosine was found to scale with the

  16. Stimulation of Glia Reveals Modulation of Mammalian Spinal Motor Networks by Adenosine

    PubMed Central

    Acton, David; Miles, Gareth B.

    2015-01-01

    Despite considerable evidence that glia can release modulators to influence the excitability of neighbouring neurons, the importance of gliotransmission for the operation of neural networks and in shaping behaviour remains controversial. Here we characterise the contribution of glia to the modulation of the mammalian spinal central pattern generator for locomotion, the output of which is directly relatable to a defined behaviour. Glia were stimulated by specific activation of protease-activated receptor-1 (PAR1), an endogenous G-protein coupled receptor preferentially expressed by spinal glia during ongoing activity of the spinal central pattern generator for locomotion. Selective activation of PAR1 by the agonist TFLLR resulted in a reversible reduction in the frequency of locomotor-related bursting recorded from ventral roots of spinal cord preparations isolated from neonatal mice. In the presence of the gliotoxins methionine sulfoximine or fluoroacetate, TFLLR had no effect, confirming the specificity of PAR1 activation to glia. The modulation of burst frequency upon PAR1 activation was blocked by the non-selective adenosine-receptor antagonist theophylline and by the A1-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, but not by the A2A-receptor antagonist SCH5826, indicating production of extracellular adenosine upon glial stimulation, followed by A1-receptor mediated inhibition of neuronal activity. Modulation of network output following glial stimulation was also blocked by the ectonucleotidase inhibitor ARL67156, indicating glial release of ATP and its subsequent degradation to adenosine rather than direct release of adenosine. Glial stimulation had no effect on rhythmic activity recorded following blockade of inhibitory transmission, suggesting that glial cell-derived adenosine acts via inhibitory circuit components to modulate locomotor-related output. Finally, the modulation of network output by endogenous adenosine was found to scale with the

  17. G-protein-coupled receptor 30-mediated antiapoptotic effect of estrogen on spinal motor neurons following injury and its underlying mechanisms

    PubMed Central

    CHEN, JINGYU; HU, RONG; GE, HONGFEI; DUANMU, WANGSHENG; LI, YUHONG; XUE, XINGSENG; HU, SHENGLI; FENG, HUA

    2015-01-01

    Spinal cord injury (SCI) may result in severe dysfunction of motor neurons. G-protein-coupled receptor 30 (GPR30) expression in the motor neurons of the ventral horn of the spinal cord mediates neuroprotection through estrogen signaling. The present study explored the antiapoptotic effect of estrogen, mediated by GPR30 following SCI, and the mechanisms underlying this effect. Spinal motor neurons from rats were cultured in vitro in order to establish cell models of oxygen and glucose deprivation (OGD). The effects of estrogen, the estrogen agonist, G1, and the estrogen inhibitor, G15, on motor neurons were observed using MTT assays. The effects of E2, G1 and G15 on spinal motor neuron apoptosis following OGD, were detected using flow cytometry. The role of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) inhibitor, LY294002, was also determined using flow cytometry. Rat SCI models were established. E2, G1 and E2+LY294002 were administered in vivo. Motor function was scored at 3, 7, 14, 21 and 28 d following injury, using Basso-Beattie-Bresnahan (BBB) standards. Cell activity in the estrogen and G1 groups was higher than that in the solvent group, whereas cell activity in the E2+G15 group was lower than that in the E2 group (P<0.05). Following OGD, the proportion of apoptotic cells significantly increased (P<0.05). The proportion in the estrogen group was significantly lower than that in the solvent group, whereas the proportion of apoptotic cells in the E2+G15 and E2+LY294002 groups was higher than that in the E2 group (P<0.05). Treatment with E2 and G1 led to upregulation of P-Akt expression in normal cells and post-OGD cells. The BBB scores of rats in the E2 and G1 groups were higher than those in the placebo group (P<0.05). The BBB scores of the E2+LY294002 group were lower than those of the E2 group (P<0.05). Estrogen thus appears to exert a protective effect on spinal motor neurons following OGD, via GPR30. The PI3K/Akt pathway may be one of those

  18. 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

  19. 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

  20. Novel Concept of Motor Functional Analysis for Spinal Cord Injury in Adult Mice

    PubMed Central

    Shinozaki, Munehisa; Takahashi, Yuichiro; Mukaino, Masahiko; Saito, Nobuhito; Toyama, Yoshiaki; Okano, Hideyuki; Nakamura, Masaya

    2011-01-01

    In basic research on spinal cord injury (SCI), behavioral evaluation of the SCI animal model is critical. However, it is difficult to accurately evaluate function in the mouse SCI model due to the small size of mice. Although the open-field scoring scale is an outstanding appraisal method, supplementary objective tests are required. Using a compact SCANET system, in which a mouse carries out free movement for 5 min, we developed a novel method to detect locomotor ability. A SCANET system samples the horizontal coordinates of a mouse every 0.1 s, and both the speed and acceleration of its motion are calculated at each moment. It was found that the maximum speed and acceleration of motion over 5 min varied by injury severity. Moreover, these values were significantly correlated with open-field scores. The maximum speed and acceleration of SCI model mice using a SCANET system are objective, easy to obtain, and reproducible for evaluating locomotive function. PMID:21253580

  1. 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

  2. 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

  3. Using Transcranial Magnetic Stimulation to Evaluate the Motor Pathways After an Intraoperative Spinal Cord Injury and to Predict the Recovery of Intraoperative Transcranial Electrical Motor Evoked Potentials: A Case Report.

    PubMed

    Grover, Helen J; Thornton, Rachel; Lutchman, Lennel N; Blake, Julian C

    2016-06-01

    The authors report a case of unilateral loss of intraoperative transcranial electrical motor evoked potentials (TES MEP) associated with a spinal cord injury during scoliosis correction and the subsequent use of extraoperative transcranial magnetic stimulation to monitor the recovery of spinal cord function. The authors demonstrate the absence of TES MEPs and absent transcranial magnetic stimulation responses in the immediate postoperative period, and document the partial recovery of transcranial magnetic stimulation responses, which corresponded to partial recovery of TES MEPs. Intraoperative TES MEPs were enhanced using spatial facilitation technique, which enabled the patient to undergo further surgery to stabilize the spine and correct her scoliosis. This case report supports evidence of the use of extraoperative transcranial magnetic stimulation to predict the presence of intraoperative TES responses and demonstrates the usefulness of spatial facilitation to monitor TES MEPs in a patient with a preexisting spinal cord injury. PMID:26061481

  4. 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

  5. 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

  6. 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

  7. Learning with the Spinal Cord.

    PubMed

    Robinson, Richard

    2015-06-01

    To what extent does the spinal cord play a role in the learning of motor tasks? A new study that simultaneously images the brain and spinal cord shows that the spinal cord is actively and independently involved in the earliest stages of motor learning. PMID:26125625

  8. The effect of Am-80, a synthetic retinoid, on spinal cord injury-induced motor dysfunction in rats.

    PubMed

    Takenaga, Mitsuko; Ohta, Yuki; Tokura, Yukie; Hamaguchi, Akemi; Shudo, Koichi; Okano, Hideyuki; Igarashi, Rie

    2009-02-01

    The present study investigated the effect of 4[(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-2-naphthalenyl)carbamoyl] benzoic acid (Am-80), a synthetic retinoid, on spinal cord injury (SCI) in rats. Treatment with Am-80 (orally and subcutaneously) significantly promoted recovery from SCI-induced motor dysfunction. On day 28 after injury, the lesion cavity was markedly reduced, while the expression of myelin basic protein (MBP; myelin), betaIIItubulin (neuron), and glial fibrillary acidic protein (GFAP; astrocyte) was increased, in comparison with SCI controls. Interestingly, expression of neurotrophin receptor, tyrosine kinase B (TrkB) was over 3-fold higher after Am-80 treatment than in SCI controls. A lot of TrkB-positive cells as well as brain-derived neurotrophic factor (BDNF)-positive ones were observed around the injured site. Am-80 (10 microM) combined with BDNF (100 ng/ml) promoted extensive neurite outgrowth and TrkB gene expression by cultured SH-SY5Y cells, as did all-trans retinoic acid (ATRA). Thymidine incorporation was dramatically suppressed, but there was little effect on cell viability. These findings suggest that Am-80 has the potential to be used for treating neurodegenerative disorders, including SCI. Its efficacy may be partly ascribed to promotion of cell viability and differentiation of neural stem cells through increased TrkB expression. PMID:19182380

  9. 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

  10. 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

  11. 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

  12. Effectiveness of intense, activity-based physical therapy for individuals with spinal cord injury in promoting motor and sensory recovery: Is olfactory mucosa autograft a factor?

    PubMed Central

    Larson, Cathy A.; Dension, Paula M.

    2013-01-01

    Background/objectives Rehabilitation for individuals with spinal cord injury (SCI) is expanding to include intense, activity-based, out-patient physical therapy (PT). The study's primary purposes were to (i) examine the effectiveness of intense PT in promoting motor and sensory recovery in individuals with SCI and (ii) compare recovery for individuals who had an olfactory mucosa autograft (OMA) with individuals who did not have the OMA while both groups participated in the intense PT program. Methods Prospective, non-randomized, non-blinded, intervention study. Using the American Spinal Injury Association examination, motor and sensory scores for 23 (7 OMA, 6 matched control and 10 other) participants were recorded. Results Mean therapy dosage was 137.3 total hours. The participants’ total, upper and lower extremity motor scores improved significantly while sensory scores did not improve during the first 60 days and from initial to discharge examination. Incomplete SCI or paraplegia was associated with greater motor recovery. Five of 14 participants converted from motor-complete to motor-incomplete SCI. Individuals who had the OMA and participated in intense PT did not have greater sensory or greater magnitude or rate of motor recovery as compared with participants who had intense PT alone. Conclusion This study provides encouraging evidence as to the effectiveness of intense PT for individuals with SCI. Future research is needed to identify the optimal therapy dosage and specific therapeutic activities required to generate clinically meaningful recovery for individuals with SCI including those who elect to undergo a neural recovery/regenerative surgical procedure and those that elect intense therapy alone. PMID:23433335

  13. Functional Preservation and Reorganization of Brain during Motor Imagery in Patients with Incomplete Spinal Cord Injury: A Pilot fMRI Study

    PubMed Central

    Chen, Xin; Wan, Lu; Qin, Wen; Zheng, Weimin; Qi, Zhigang; Chen, Nan; Li, Kuncheng

    2016-01-01

    Motor imagery (MI) is a cognitive process involved in mentally rehearsing movement representations, and it has great potential for the rehabilitation of motor function in patients with spinal cord injuries. The aim of this study was to explore changes in the brain activation patterns in incomplete spinal cord injury (ISCI) patients during motor execution (ME) and MI tasks, and to thereby explore whether MI shares similar motor-related networks with ME in ISCI patients. Seventeen right-handed ISCI patients with impaired motor function of their right ankles and 17 age- and gender-matched healthy controls were enrolled in this study. The activation patterns of the ISCI subjects and those of the healthy subjects were compared, both during mental dorsi-plantar flexion of the right ankle (the MI task) and the actual movement of the joint (the ME task). The patients and the healthy controls shared similar activation patterns during the MI or ME tasks. The activation patterns of the MI task between the patients and the healthy controls were more similar than those of the ME task. These findings indicate that the MI network is more functionally preserved than the ME network in ISCI patients. In addition, increased activation in the motor-related regions during ME task, and decreased activation in the parietal regions during both ME and MI tasks, were identified in the ISCI patients compared to the healthy controls, indicating a functional reorganization of these regions after ISCI. The functional preservation and reorganization of the MI network in the ISCI patients suggests a potential role for MI training in motor rehabilitation. PMID:26913000

  14. Trophic and proliferative effects of Shh on motor neurons in embryonic spinal cord culture from wildtype and G93A SOD1 mice

    PubMed Central

    2013-01-01

    Background The developmental morphogen sonic hedgehog (Shh) may continue to play a trophic role in the support of terminally-differentiated motor neurons, of potential relevance to motor neuron disease. In addition, it may support the proliferation and differentiation of endogenous stem cells along motor neuronal lineages. As such, we have examined the trophic and proliferative effects of Shh supplementation or Shh antagonism in embryonic spinal cord cell cultures derived from wildtype or G93A SOD1 mice, a mouse model of amyotrophic lateral sclerosis. Results Shh supported survival, and stimulated growth of motor neurons, neurite outgrowth, and neurosphere formation in primary culture derived from both G93A SOD1 and WT mice. Shh increased the percentage of ciliated motor neurons, especially in G93A SOD1 culture. Shh-treated cultures showed increased neuronal proliferation compared to controls and especially cyclopamine treated cultures, from G93A SOD1 and WT mice. Moreover, Shh enhanced cell survival and differentiation of motor neuron precursors in WT culture. Conclusions Shh is neurotrophic to motor neurons and has mitogenic effects in WT and mSOD1 G93A culture in vitro. PMID:24119209

  15. 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 ...

  16. 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

  17. Familial motor neuron disease with prominent onion-bulb-like structures and axonal swelling restricted to the spinal ventral root: autopsy findings in two siblings.

    PubMed

    Tokuyama, Wataru; Yagishita, Saburo; Ryo, Masafuchi; Kusunoki, Junichi; Hasegawa, Kazuko; Yoshida, Tsutomu; Mikami, Tetuo; Okayasu, Isao

    2010-02-01

    We report autopsy cases of two siblings who developed muscular atrophy and dementia, clinically considered to be familial motor neuron disease (MND). They presented with motor neuron signs predominantly in the distal limbs without sensory impairment. At autopsy, severe neuronal loss in the anterior horn consistent with MND was found, but histopathological hallmarks like Bunina bodies and skein-like inclusions were absent. Surprisingly, numerous huge axonal swellings (about 30 microm in diameter) and onion-bulb-like structures were found in the spinal ventral roots. These changes were not observed in spinal dorsal roots or peripheral nerves. However, obvious segmental demyelination of the ventral root was not found. In addition, neurofibrillary tangles (NFTs) and neuritic plaques were present in the frontal cortex, temporal cortex and hippocampus, and to a lesser degree, in the amygdala, substantia nigra and thalamus. Our two cases are a hitherto unreported type of MND, which shows focal giant axonopathy and prominent formation of onion-bulb-like structures due to Schwann cell proliferation restricted to the spinal ventral roots. PMID:19496941

  18. 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

  19. Characterization of thoracic motor and sensory neurons and spinal nerve roots in canine degenerative myelopathy, a potential disease model of amyotrophic lateral sclerosis.

    PubMed

    Morgan, Brandie R; Coates, Joan R; Johnson, Gayle C; Shelton, G Diane; Katz, Martin L

    2014-04-01

    Canine degenerative myelopathy (DM) is a progressive, adult-onset, multisystem degenerative disease with many features in common with amyotrophic lateral sclerosis (ALS). As with some forms of ALS, DM is associated with mutations in superoxide dismutase 1 (SOD1). Clinical signs include general proprioceptive ataxia and spastic upper motor neuron paresis in pelvic limbs, which progress to flaccid tetraplegia and dysphagia. The purpose of this study was to characterize DM as a potential disease model for ALS. We previously reported that intercostal muscle atrophy develops in dogs with advanced-stage DM. To determine whether other components of the thoracic motor unit (MU) also demonstrated morphological changes consistent with dysfunction, histopathologic and morphometric analyses were conducted on thoracic spinal motor neurons (MNs) and dorsal root ganglia (DRG) and in motor and sensory nerve root axons from DM-affected boxers and Pembroke Welsh corgis (PWCs). No alterations in MNs or motor root axons were observed in either breed. However, advanced-stage PWCs exhibited significant losses of sensory root axons, and numerous DRG sensory neurons displayed evidence of degeneration. These results indicate that intercostal muscle atrophy in DM is not preceded by physical loss of the motor neurons innervating these muscles, nor of their axons. Axonal loss in thoracic sensory roots and sensory neuron death suggest that sensory involvement may play an important role in DM disease progression. Further analysis of the mechanisms responsible for these morphological findings would aid in the development of therapeutic intervention for DM and some forms of ALS. PMID:24375814

  20. Characterization of Thoracic Motor and Sensory Neurons and Spinal Nerve Roots in Canine Degenerative Myelopathy, a Potential Disease Model of Amyotrophic Lateral Sclerosis

    PubMed Central

    Morgan, Brandie R.; Coates, Joan R.; Johnson, Gayle C.; Shelton, G. Diane; Katz, Martin L.

    2014-01-01

    Canine Degenerative Myelopathy (DM) is a progressive adult-onset multisystem degenerative disease with many features in common with amyotrophic lateral sclerosis (ALS). As with some forms of ALS, DM is associated with mutations in superoxide dismutase 1 (SOD1). Clinical signs include general proprioceptive ataxia and spastic upper motor neuron paresis in pelvic limbs, which progress to flaccid tetraplegia and dysphagia. The purpose of this study was to characterize DM as a potential disease model for ALS. We previously reported that intercostal muscle atrophy develops in dogs with advanced stage DM. To determine if other components of the thoracic motor unit (MU) also demonstrated morphological changes consistent with dysfunction, histopathologic and morphometric analyses were conducted on thoracic spinal motor neurons (MN) and dorsal root ganglia (DRG), and in motor and sensory nerve root axons from DM-affected Boxers and Pembroke Welsh Corgis (PWCs). No alterations in MNs, or motor root axons were observed in either breed. However, advanced stage PWCs exhibited significant losses of sensory root axons, and numerous DRG sensory neurons displayed evidence of degeneration. These results indicate that intercostal muscle atrophy in DM is not preceded by physical loss of the motor neurons innervating these muscles, or of their axons. Axonal loss in thoracic sensory roots and sensory nerve death suggest sensory involvement may play an important role in DM disease progression. Further analysis of the mechanisms responsible for these morphological findings would aid in the development of therapeutic intervention for DM and some forms of ALS. PMID:24375814

  1. The relationship of spinal muscular atrophy to motor neuron disease: investigation of SMN and NAIP gene deletions in sporadic and familial ALS.

    PubMed

    Orrell, R W; Habgood, J J; de Belleroche, J S; Lane, R J

    1997-01-01

    Amyotrophic lateral sclerosis (ALS) is found in a familial form in around 5-10% of cases. Of these familial cases around 20% are associated with mutations of SOD-1. The genetic basis of the disease in the remaining familial cases, and genetic risk factors in sporadic cases, are unknown. Recently, the common forms of spinal muscular atrophy (SMA) have been associated with mutations of the SMN and NAIP genes on chromosome 5, in the region q11.2-13.3. Some patients with both familial and sporadic motor neuron disease show only lower motor neuron signs, in common with SMA patients, and families containing individuals with phenotypes of both childhood SMA and adult motor neuron disease have been reported. We therefore examined the SMA locus as a candidate for ALS, in 54 patients with sporadic motor neuron disease, and 10 single-generation familial patients (with no evidence of SOD-1 mutations), and in a single patient with Brown-Vialetto-Van Laere syndrome. No mutations of the SMN or NAIP genes were detected. The difficulties of classification of lower motor neuron presentations of motor neuron diseases are discussed. The demonstration that mutations diagnostic of SMA are not found in ALS patients helps distinguish these conditions. PMID:9073029

  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. Intrathecal infusion of BMAA induces selective motor neuron damage and astrogliosis in the ventral horn of the spinal cord

    PubMed Central

    Yin, Hong Z.; Yu, Stephen; Hsu, Cheng-I; Liu, Joe; Acab, Allan; Wu, Richard; Tao, Anna; Chiang, Benjamin J.; Weiss, John H.

    2014-01-01

    The neurotoxin beta-N-methylamino-L-alanine (BMAA) was first identified as a “toxin of interest” in regard to the amyotrophic lateral sclerosis–Parkinsonism Dementia Complex of Guam (ALS/PDC); studies in recent years highlighting widespread environmental sources of BMAA exposure and providing new clues to toxic mechanisms have suggested possible relevance to sporadic ALS as well. However, despite clear evidence of uptake into tissues and a range of toxic effects in cells and animals, an animal model in which BMAA induces a neurodegenerative picture resembling ALS is lacking, possibly in part reflecting limited understanding of critical factors pertaining to its absorption, biodistribution and metabolism. To bypass some of these issues and ensure delivery to a key site of disease pathology, we examined effects of prolonged (30 day) intrathecal infusion in wild type (WT) rats, and rats harboring the familial ALS associated G93A SOD1 mutation, over an age range (80±2 to 110±2 days) during which the G93A rats are developing disease pathology yet remain asymptomatic. The BMAA exposures induced changes that in many ways resembles those seen in the G93A rats, with degenerative changes in ventral horn motor neurons (MNs) with relatively little dorsal horn pathology, marked ventral horn astrogliosis and increased 3-nitrotyrosine labeling in and surrounding MNs, a loss of labeling for the astrocytic glutamate transporter, GLT-1, surrounding MNs, and mild accumulation and aggregation of TDP-43 in the cytosol of some injured and degenerating MNs. Thus, prolonged intrathecal infusion of BMAA can reproduce a picture in spinal cord incorporating many of the pathological hallmarks of diverse forms of human ALS, including substantial restriction of overt pathological changes to the ventral horn, consistent with the possibility that environmental BMAA exposure could be a risk factor and/or contributor to some human disease. PMID:24918341

  4. Intrathecal infusion of BMAA induces selective motor neuron damage and astrogliosis in the ventral horn of the spinal cord.

    PubMed

    Yin, Hong Z; Yu, Stephen; Hsu, Cheng-I; Liu, Joe; Acab, Allan; Wu, Richard; Tao, Anna; Chiang, Benjamin J; Weiss, John H

    2014-11-01

    The neurotoxin beta-N-methylamino-l-alanine (BMAA) was first identified as a "toxin of interest" in regard to the amyotrophic lateral sclerosis-Parkinsonism Dementia Complex of Guam (ALS/PDC); studies in recent years highlighting widespread environmental sources of BMAA exposure and providing new clues to toxic mechanisms have suggested possible relevance to sporadic ALS as well. However, despite clear evidence of uptake into tissues and a range of toxic effects in cells and animals, an animal model in which BMAA induces a neurodegenerative picture resembling ALS is lacking, possibly in part reflecting limited understanding of critical factors pertaining to its absorption, biodistribution and metabolism. To bypass some of these issues and ensure delivery to a key site of disease pathology, we examined effects of prolonged (30day) intrathecal infusion in wild type (WT) rats, and rats harboring the familial ALS associated G93A SOD1 mutation, over an age range (80±2 to 110±2days) during which the G93A rats are developing disease pathology yet remain asymptomatic. The BMAA exposures induced changes that in many ways resemble those seen in the G93A rats, with degenerative changes in ventral horn motor neurons (MNs) with relatively little dorsal horn pathology, marked ventral horn astrogliosis and increased 3-nitrotyrosine labeling in and surrounding MNs, a loss of labeling for the astrocytic glutamate transporter, GLT-1, surrounding MNs, and mild accumulation and aggregation of TDP-43 in the cytosol of some injured and degenerating MNs. Thus, prolonged intrathecal infusion of BMAA can reproduce a picture in spinal cord incorporating many of the pathological hallmarks of diverse forms of human ALS, including substantial restriction of overt pathological changes to the ventral horn, consistent with the possibility that environmental BMAA exposure could be a risk factor and/or contributor to some human disease. PMID:24918341

  5. GAB(A) receptors present higher affinity and modified subunit composition in spinal motor neurons from a genetic model of amyotrophic lateral sclerosis.

    PubMed

    Carunchio, Irene; Mollinari, Cristiana; Pieri, Massimo; Merlo, Daniela; Zona, Cristina

    2008-10-01

    Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the selective degeneration of motor neurons in the spinal cord, brainstem and cerebral cortex. In this study we have analysed the electrophysiological properties of GABA(A) receptors and GABA(A) alpha1 and alpha2 subunits expression in spinal motor neurons in culture obtained from a genetic model of ALS (G93A) and compared with transgenic wild type SOD1 (SOD1) and their corresponding non transgenic litter mates (Control). Although excitotoxic motor neuron death has been extensively studied in relation to Ca(2+)-dependent processes, strong evidence indicates that excitotoxic cell death is also remarkably dependent on Cl(-) ions and on GABA(A) receptor activation. In this study we have analysed the electrophysiological properties of GABA(A) receptors and the expression of GABA(A)alpha(1) and alpha(2) subunits in cultured motor neurons obtained from a genetic model of amyotrophic lateral sclerosis (G93A) and compared them with transgenic wild-type Cu,Zn superoxide dismutase and their corresponding non-transgenic littermates (Control). In all tested motor neurons, the application of gamma-aminobutyric acid (GABA) (0.5-100 mum) evoked an inward current that was reversibly blocked by bicuculline (100 mum), thus indicating that it was mediated by the activation of GABA(A) receptors. Our results indicate that the current density at high GABA concentrations is similar in control, Cu,Zn superoxide dismutase and G93A motor neurons. However, the dose-response curve significantly shifted toward lower concentration values in G93A motor neurons and the extent of desensitization also increased in these neurons. Finally, multiplex single-cell real-time polymerase chain reaction and immunofluorescence revealed that the amount of GABA(A)alpha(1) subunit was significantly increased in G93A motor neurons, whereas the levels of alpha(2) subunit were unchanged. These data show that the functionality and

  6. Intermittent reductions in respiratory neural activity elicit spinal TNF-α-independent, atypical PKC-dependent inactivity-induced phrenic motor facilitation

    PubMed Central

    Baertsch, Nathan A.

    2015-01-01

    In many neural networks, mechanisms of compensatory plasticity respond to prolonged reductions in neural activity by increasing cellular excitability or synaptic strength. In the respiratory control system, a prolonged reduction in synaptic inputs to the phrenic motor pool elicits a TNF-α- and atypical PKC-dependent form of spinal plasticity known as inactivity-induced phrenic motor facilitation (iPMF). Although iPMF may be elicited by a prolonged reduction in respiratory neural activity, iPMF is more efficiently induced when reduced respiratory neural activity (neural apnea) occurs intermittently. Mechanisms giving rise to iPMF following intermittent neural apnea are unknown. The purpose of this study was to test the hypothesis that iPMF following intermittent reductions in respiratory neural activity requires spinal TNF-α and aPKC. Phrenic motor output was recorded in anesthetized and ventilated rats exposed to brief intermittent (5, ∼1.25 min), brief sustained (∼6.25 min), or prolonged sustained (30 min) neural apnea. iPMF was elicited following brief intermittent and prolonged sustained neural apnea, but not following brief sustained neural apnea. Unlike iPMF following prolonged neural apnea, spinal TNF-α was not required to initiate iPMF during intermittent neural apnea; however, aPKC was still required for its stabilization. These results suggest that different patterns of respiratory neural activity induce iPMF through distinct cellular mechanisms but ultimately converge on a similar downstream pathway. Understanding the diverse cellular mechanisms that give rise to inactivity-induced respiratory plasticity may lead to development of novel therapeutic strategies to treat devastating respiratory control disorders when endogenous compensatory mechanisms fail. PMID:25673781

  7. Intermittent reductions in respiratory neural activity elicit spinal TNF-α-independent, atypical PKC-dependent inactivity-induced phrenic motor facilitation.

    PubMed

    Baertsch, Nathan A; Baker-Herman, Tracy L

    2015-04-15

    In many neural networks, mechanisms of compensatory plasticity respond to prolonged reductions in neural activity by increasing cellular excitability or synaptic strength. In the respiratory control system, a prolonged reduction in synaptic inputs to the phrenic motor pool elicits a TNF-α- and atypical PKC-dependent form of spinal plasticity known as inactivity-induced phrenic motor facilitation (iPMF). Although iPMF may be elicited by a prolonged reduction in respiratory neural activity, iPMF is more efficiently induced when reduced respiratory neural activity (neural apnea) occurs intermittently. Mechanisms giving rise to iPMF following intermittent neural apnea are unknown. The purpose of this study was to test the hypothesis that iPMF following intermittent reductions in respiratory neural activity requires spinal TNF-α and aPKC. Phrenic motor output was recorded in anesthetized and ventilated rats exposed to brief intermittent (5, ∼1.25 min), brief sustained (∼6.25 min), or prolonged sustained (30 min) neural apnea. iPMF was elicited following brief intermittent and prolonged sustained neural apnea, but not following brief sustained neural apnea. Unlike iPMF following prolonged neural apnea, spinal TNF-α was not required to initiate iPMF during intermittent neural apnea; however, aPKC was still required for its stabilization. These results suggest that different patterns of respiratory neural activity induce iPMF through distinct cellular mechanisms but ultimately converge on a similar downstream pathway. Understanding the diverse cellular mechanisms that give rise to inactivity-induced respiratory plasticity may lead to development of novel therapeutic strategies to treat devastating respiratory control disorders when endogenous compensatory mechanisms fail. PMID:25673781

  8. 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

  9. 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. PMID

  10. 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

  11. 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

  12. Mitochondrial Division Inhibitor 1 Ameliorates Mitochondrial Injury, Apoptosis, and Motor Dysfunction After Acute Spinal Cord Injury in Rats.

    PubMed

    Li, Gang; Jia, Zhiqiang; Cao, Yang; Wang, Yansong; Li, Haotian; Zhang, Zhenyu; Bi, Jing; Lv, Gang; Fan, Zhongkai

    2015-07-01

    Mitochondrial division inhibitor 1 (Mdivi-1) is the most effective pharmacological inhibitor of mitochondrial fission. Spinal cord injury (SCI) is a common and serious trauma, which lacks efficient treatment. This study aimed to detect the role of Mdivi-1 in neuronal injury and its underlying mechanism after acute SCI (ASCI) in rats. Western blot analysis showed that Bax levels on the mitochondrial outer membrane, and release of cytochrome C (cytC) and apoptosis-inducing factor (AIF) from the mitochondria began to increase significantly at 4 h after ASCI, then peaked at 16 h, and declined significantly from 16 to 24 h. However, the mitochondrial levels of Bcl-2 increased significantly at 2 h, peaked at 4 h, and subsequently significantly decreased from 4 to 24 h after ASCI. In addition, Mdivi-1(1.2 mg/kg) significantly suppressed the translocation of dynamin-related protein 1 (Drp1) and Bax to the mitochondria, mitochondrial depolarization, decrease of ATP and reduced Glutathione, increase of the Malondialdehyde, cytC release, and AIF translocation at 16 h and 3 days after ASCI, and also inhibited the caspase-3 activation and decrease of the percentage of apoptotic cells at 16 h, 3 and 10 days, further, ameliorated the motor dysfunction greatly from 3 to 10 days after ASCI in rats. This neuroprotective effect was dose-dependent. However, Mdivi-1(1.2 mg/kg) had no effects on the translocation of Bcl-2 and fission protein 1 on the mitochondria, and did not affect the expression of total Drp1 at 16 h after ASCI. Our experimental findings indicated that Mdivi-1 can protect rats against ASCI, and that its underlying mechanism may be associated with inhibition of Drp1 translocation to the mitochondria, alleviation of mitochondrial dysfunction and oxidative stress, and suppression of caspase-dependent and -independent apoptosis. PMID:25968480

  13. 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 ...

  14. 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 ...

  15. 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. PMID:27370228

  16. 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. PMID:27260986

  17. Sodium vanadate combined with l-ascorbic acid delays disease progression, enhances motor performance, and ameliorates muscle atrophy and weakness in mice with spinal muscular atrophy

    PubMed Central

    2013-01-01

    Background Proximal spinal muscular atrophy (SMA), a neurodegenerative disorder that causes infant mortality, has no effective treatment. Sodium vanadate has shown potential for the treatment of SMA; however, vanadate-induced toxicity in vivo remains an obstacle for its clinical application. We evaluated the therapeutic potential of sodium vanadate combined with a vanadium detoxification agent, L-ascorbic acid, in a SMA mouse model. Methods Sodium vanadate (200 μM), L-ascorbic acid (400 μM), or sodium vanadate combined with L-ascorbic acid (combined treatment) were applied to motor neuron-like NSC34 cells and fibroblasts derived from a healthy donor and a type II SMA patient to evaluate the cellular viability and the efficacy of each treatment in vitro. For the in vivo studies, sodium vanadate (20 mg/kg once daily) and L-ascorbic acid (40 mg/kg once daily) alone or in combination were orally administered daily on postnatal days 1 to 30. Motor performance, pathological studies, and the effects of each treatment (vehicle, L-ascorbic acid, sodium vanadate, and combined treatment) were assessed and compared on postnatal days (PNDs) 30 and 90. The Kaplan-Meier method was used to evaluate the survival rate, with P < 0.05 indicating significance. For other studies, one-way analysis of variance (ANOVA) and Student's t test for paired variables were used to measure significant differences (P < 0.05) between values. Results Combined treatment protected cells against vanadate-induced cell death with decreasing B cell lymphoma 2-associated X protein (Bax) levels. A month of combined treatment in mice with late-onset SMA beginning on postnatal day 1 delayed disease progression, improved motor performance in adulthood, enhanced survival motor neuron (SMN) levels and motor neuron numbers, reduced muscle atrophy, and decreased Bax levels in the spinal cord. Most importantly, combined treatment preserved hepatic and renal function and substantially decreased vanadium accumulation

  18. 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. ...

  19. 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

  20. 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

  1. 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

  2. Subarachnoid Transplant of the Human Neuronal hNT2.19 Serotonergic Cell Line Attenuates Behavioral Hypersensitivity without Affecting Motor Dysfunction after Severe Contusive Spinal Cord Injury

    PubMed Central

    Eaton, Mary J.; Widerström-Noga, Eva; Wolfe, Stacey Quintero

    2011-01-01

    Transplant of cells which make biologic agents that can modulate the sensory and motor responses after spinal cord injury (SCI) would be useful to treat pain and paralysis. To address this need for clinically useful human cells, a unique neuronal cell line that synthesizes and secretes/releases the neurotransmitter serotonin (5HT) was isolated. Hind paw tactile allodynia and thermal hyperalgesia induced by severe contusive SCI were potently reversed after lumbar subarachnoid transplant of differentiated cells, but had no effect on open field motor scores, stride length, foot rotation, base of support, or gridwalk footfall errors associated with the SCI. The sensory effects appeared 1 week after transplant and did not diminish during the 8-week course of the experiment when grafts were placed 2 weeks after SCI. Many grafted cells were still present and synthesizing 5HT at the end of the study. These data suggest that the human neuronal serotonergic hNT2.19 cells can be used as a biologic minipump for receiving SCI-related neuropathic pain, but likely requires intraspinal grafts for motor recovery. PMID:21799949

  3. 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

  4. Mutant SOD1G93A Triggers Mitochondrial Fragmentation in Spinal Cord Motor Neurons: Neuroprotection by SIRT3 and PGC-1α

    PubMed Central

    Song, Wenjun; Song, Yuting; Kincaid, Brad; Bossy, Blaise; Bossy-Wetzel, Ella

    2014-01-01

    Mutations in the Cu/Zn Superoxide Dismutase (SOD1) gene cause an inherited form of ALS with upper and lower motor neuron loss. The mechanism underlying mutant SOD1-mediated motor neuron degeneration remains unclear. While defects in mitochondrial dynamics contribute to neurodegeneration, including ALS, previous reports remain conflicted. Here, we report an improved technique to isolate, transfect, and culture rat spinal cord motor neurons. Using this improved system, we demonstrate that mutant SOD1G93A triggers a significant decrease in mitochondrial length and an accumulation of round fragmented mitochondria. The increase of fragmented mitochondria coincides with an arrest in both anterograde and retrograde axonal transport and increased cell death. In addition, mutant SOD1G93A induces a reduction in neurite length and branching that is accompanied with an abnormal accumulation of round mitochondria in growth cones. Furthermore, restoration of the mitochondrial fission and fusion balance by dominant-negative dynamin-related protein 1 (DRP1) expression rescues the mutant SOD1G93A-induced defects in mitochondrial morphology, dynamics, and cell viability. Interestingly, both SIRT3 and PGC-1α protect against mitochondrial fragmentation and neuronal cell death by mutant SOD1G93A. This data suggests that impairment in mitochondrial dynamics participates in ALS and restoring this defect might provide protection against mutant SOD1G93A-induced neuronal injury. PMID:22819776

  5. 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

  6. Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

    PubMed Central

    Bogdanik, Laurent P.; Osborne, Melissa A.; Davis, Crystal; Martin, Whitney P.; Austin, Andrew; Rigo, Frank; Bennett, C. Frank; Lutz, Cathleen M.

    2015-01-01

    Clinical presentation of spinal muscular atrophy (SMA) ranges from a neonatal-onset, very severe disease to an adult-onset, milder form. SMA is caused by the mutation of the Survival Motor Neuron 1 (SMN1) gene, and prognosis inversely correlates with the number of copies of the SMN2 gene, a human-specific homolog of SMN1. Despite progress in identifying potential therapies for the treatment of SMA, many questions remain including how late after onset treatments can still be effective and what the target tissues should be. These questions can be addressed in part with preclinical animal models; however, modeling the array of SMA severities in the mouse, which lacks SMN2, has proven challenging. We created a new mouse model for the intermediate forms of SMA presenting with a delay in neuromuscular junction maturation and a decrease in the number of functional motor units, all relevant to the clinical presentation of the disease. Using this new model, in combination with clinical electrophysiology methods, we found that administering systemically SMN-restoring antisense oligonucleotides (ASOs) at the age of onset can extend survival and rescue the neurological phenotypes. Furthermore, these effects were also achieved by administration of the ASOs late after onset, independent of the restoration of SMN in the spinal cord. Thus, by adding to the limited repertoire of existing mouse models for type II/III SMA, we demonstrate that ASO therapy can be effective even when administered after onset of the neurological symptoms, in young adult mice, and without being delivered into the central nervous system. PMID:26460027

  7. 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.

  8. Weather, geography, and vehicle-related hyperthermia in children.

    PubMed

    Grundstein, Andrew; Null, Jan; Meentemeyer, Vernon

    2011-01-01

    Vehicle-related hyperthermia is an unfortunate tragedy that leads to the accidental deaths of children each year. This research utilizes the most extensive dataset of child vehicle-related hyperthermia deaths in the United States, including 414 deaths between 1998 and 2008. Deaths follow a seasonal pattern, with a peak in July and no deaths in December or January. Also, deaths occurred over a wide range of temperature and radiation levels and across virtually all regions, although most of them took place across the southern United States. In particular, the Phoenix, Houston, Dallas, and Las Vegas metropolitan areas had the greatest number of deaths. We utilize our vehicle hyperthermia index (vhi) to compare expected deaths versus actual deaths in a metropolitan area, based on the number of children in the area who are under the age of five and on the frequency of hot days in the area. The vhi indicates that the Memphis, West Palm Beach-Boca Raton, and Las Vegas metropolitan areas are the most dangerous places for vehicle-related hyperthermia. We conclude by discussing several recommendations with public health policy implications. PMID:22164877

  9. 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

  10. 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