Thread: ChinaSCINet Update

  1. #1321
    Quote Originally Posted by Moe View Post
    Dr. Wise, I liked and understood the comparison ‘chicken running with no head’ it was funny but clear and made sense, to whom that never experienced farm life, to kill a chicken or turkey the easy way was to chop off its head off with an axe… completely decapitated, in most cases the bird will still stand up and run all over the place in panic for a few minutes before dying, hitting anything on its way with full walking/running sequences… so that would be the CPG working since the brain was disconnected completely…
    I want to thank you deeply for all your dedication, hard work and patience.
    You are welcome. A headless chicken is a good example because it happens to be a bipedal animal that walks on two feet, like humans.

    I don't know if you have ever watched a flamenco sleeping with its head buried beneath one wing while standing on one leg. They are amazing because they are absolutely still when they do that. It must be entirely reflexive at the spinal cord level. Because the head is under the wing, it is not using its eyes or vestibular system to maintain its balance. The balance is being maintained through proprioceptive feedback, i.e. muscle tension and joint position. I have always wanted to reach out and pushed the flamenco to see how it would re-establish its balance. Will it hop without popping its head from under its wing?

    Wise.

  2. #1322
    Quote Originally Posted by khmorgan View Post
    Let's say voluntary movement was somehow restored, but CPG was not working. You can voluntarily move each muscle, but there is no coordination of the muscle groups. You are like a tiny baby who is trying to learn to move each leg in concert, except even babies have CPG.

    I think Dr. Young is saying that some patients have everything they need to stand and walk normally once voluntary control is restored. Now, he is hoping that will happen once the axons reach their targets. CPG is not all you need, but it is a significant milestone.
    khmorgan,

    What you suggest is an interesting scenario that I am afraid may happen with some people with lumbar spinal cord injury. The central pattern generator is located in the L2 spinal cord (which is usually under the T11 vertebral segment). So, people who have T11 bony injury may have damaged their central pattern generator but motoneuronal circuits for the legs below L2 are still intact. Such a person may not be able to walk well and walking has to be a very deliberate and conscious.

    In my opinion, unless you are a tap dancer or soccer player, for whom being able to tap your feet or to dribble a ball with your feet is important, voluntary control of the individual muscles of your legs is perhaps not as important as walking or running. If I had to choose one or the other, I would prefer to be able to walk without feeling or control of individual muscles, as opposed being able to feel and move individual muscles and being unable to walk without voluntarily thinking about it.

    Wise.

  3. #1323
    Quote Originally Posted by GRAMMY View Post
    The automaticity of movement is explained within Reggie Edgerton's presentation on this blog post: http://spinalcordresearchandadvocacy.wordpress.com/2012/12/03/dr-v-reggie-edgerton-strategies-for-recovery-of-neuromotor-function/
    Grammy,

    Thank you so much for posting this. I am a great fan of Reggie.

    Wise.

  4. #1324
    Quote Originally Posted by Ruben View Post
    Dr WIse,
    Do you think the procedure of Suzanne Harkema (electrodes in the spinal cord) could be added to what you are doing there would be any benifits?
    Yes, I believe that CPG stimulation should be helpful in locomotor training. This was first reported over 10 years ago by Dr. Herman in Phoenix, Arizona:

    Herman R, He J, D'Luzansky S, Willis W and Dilli S (2002). Spinal cord stimulation facilitates functional walking in a chronic, incomplete spinal cord injured. Spinal Cord 40:65-8. DESIGN: This paper describes a treatment paradigm to facilitate functional gait in a quadriplegic, ASIA C spinal cord injured (SCI), wheelchair-dependent subject who presented with some large fiber sensation, sub-functional motor strength in all lower limb muscles, and moderate spasticity. The study utilizes partial weight bearing therapy (PWBT) followed by epidural spinal cord stimulation (ESCS) with the assumption that both treatments would be necessary to elicit a well organized, near effortless functional gait with a walker. Function is defined in terms of accomplishing task-specific activities in the home and community. OBJECTIVES: To demonstrate the feasibility and benefits of combined PWBT and ESCS therapies aimed at promoting functional gait in a wheelchair-dependent ASIA C SCI subject. SETTING: The Clinical Neurobiology and Bioengineering Research Laboratories at Good Samaritan Regional Medical Center, Phoenix, Arizona, USA, and the Department of Bioengineering, Arizona State University, Tempe, Arizona, USA. METHODS: The study began with the application of PWBT. The subject walked on the treadmill until a plateau in gait rhythm generation was reached. Subsequently, ESCS, applied to the lumbar enlargement, was utilized to facilitate PWBT and, later, over-ground walking for a standard distance of 15 m. Gait performance was analyzed by measuring average speed, stepping symmetry, sense of effort, physical work capacity, and whole body metabolic activity. RESULTS: PWBT led to improved stereotypic stepping patterns associated with markedly reduced spasticity, but was insufficient for over-ground walking in terms of safety, energy cost, and fatigue. ESCS with PWBT generated immediate improvement in the subject's gait rhythm when appropriate stimulation parameters were used. When compared to the non-stimulated condition, over-ground walking with ESCS across a 15 m distance was featured by a reduction in time and energy cost of walking, sense of effort, and a feeling of 'lightness' in the legs. After a few months of training, performance in speed, endurance, and metabolic responses gradually converged with/without ESCS at this short distance, suggesting a learned response to these conditions. However, at longer distances (eg, 50-250 m), performance with ESCS was considerably superior. The subject was able to perform multiple functional tasks within the home and community with ESCS. CONCLUSION: We propose that ESCS augments the use-dependent plasticity created by PWBT and may be a valuable adjunct to post-SCI treadmill training in ASIA C subjects. We also conclude that ESCS elicits greater activation of an oxidative motor unit pool, thereby reducing the subject's sense of effort and energetic cost of walking.

  5. #1325
    Quote Originally Posted by lunasicc42 View Post
    wise, I am mostly worried about b/b/b, update your opinion on that.

    I may be wrong, but my understanding is that you can and have retrained general walking through strict physical training, but is b/b/b affected?
    lunasicc42,

    The centers that control the bowel and bladder are located at the very bottom of the spinal cord. They should take the longest to recover.

    Wise.

  6. #1326
    Quote Originally Posted by Skipow View Post
    My assumption of the CNS patteren generator working would be compared to the feeling like when one is running for a few miles, then immediately stops. One's legs want to keep moving. I have felt this, it is almost like your brain has to tell your legs to stop moving.

    I've been doing locomotive training for a year and some times my legs do kindof walk on the treadmill. I can also walk with help standing up. But I can't lift my legs up from a sitting position. All I can do voluntarily is slight muscle twitches in my legs when I'm seated or laying down. I'm a C4 ASIA C.

    Dr. Young, did the research subjects receive locomotive training before UCB & Lithium treatment? Also, from what your saying here, it seems like the new nerve "lines" need to go all the way to the brain stem? Is this correct, or can the connection be repaired & restored by just connecting the gap between the injured part of the spinal cord? (Just fixing 5 miles of the track instead of laying a whole new 300 miles of track)

    Also, what is your take on olfactory ensheathing cells (OEC) vs schwann cells vs umbillical cord blood? I would think there would be more research on OEC's since they don't scar.

    Thank you for the research and I hope it's going we'll over there!
    Skipow,

    Thank you for your observations. To my knowledge, most of the patients in the trial did not receive locomotor training before the treatment. We do require that the patients be able to stand and do weight support in a standing frame or similar equipment before they can enter the trial. However, I am not sure how rigorously this inclusion criterion was enforced.

    Yes, the sensory axons need to go all the way to the nucleus gracilis (for the legs) or nucleus cuneatus in the brain stem to restore proprioception (the feeling of touch and position). Sensory axons need to grow all the way to the thalamus to restore pinprick sensations. So, in cases of true regeneration, sensory axons must grow a long ways.

    We of course considered Schwann cells and olfactory ensheathing cells as candidate cells. Both are difficult to get for transplantation.

    In the case of Schwann cells, you have to ligate a peripheral nerve, cut the peripheral part of the nerve out, and then grow the Schwann cells from that nerve. You then have to grow the cells in culture and then transplant the cells into the spinal cord. This is an incredible amount of work and requires a very sophisticated laboratory at the hospital. This part of the reason why it has taken the Miami Project so long to get their cell processing facility going and to get the trial approved. I don't know how much this will cost but $100,000 would not be surprising.

    Olfactory ensheathing glial cells are even more difficult to get and grow. Most doctors in China used olfactory ensheathing glial cells from aborted fetuses. There are limited numbers of these cells and it is not easy to grow these cells for transplantation. More important, these cells are not immune-compatible with the patients. It is likely that these cells are rejected from the brain within several weeks. This is certainly true of OEG cells that we transplanted into animals. So, one has to either use the immunosuppressant cyclosporin or use OEG cells that comes from the patient. The latter is actually possible but even more difficult than Schwann cells. There are two sources for OEG cells: the olfactory bulb (OB) or the nasal mucosa. The OB is located at the base of the brain. Nasal mucosa are very hard to isolate and culture. Geoffrey Raisman and his group tried for many years to do this. Recently, it seems that his group has achieved some success in this and I know of one group in Taiwan that has been able to do this. But, both of these occurred only recently (i.e. last year). I know that Alan MacKay-Sim reported success in doing this nearly 10 years ago in Australia but nobody, including his group, was able to grow the cells consistently until recently.

    In any case, we decided not to transplant Schwann cells or OEG cells because of these difficulties of access and growing of the cells. We chose UCBMC because they were readily available, safe, and many groups had reported that they improve locomotor recovery in animals. We are considering OEG cells in future trials.

    Wise.

  7. #1327
    Dr. Young,
    This is a big hypothetical but: should the treatment prove effective but "incomplete" and there is reason to believe receiving multiple injections of umbilical cord blood would lead to further improvements, what's the protocol with respect to this? Once safety (and efficacy) is shown for a given amount, can that amount be used as a therapy repeatedly? Or would more, longer term, data be necessary for the FDA to approve? Feel free to answer in the most general way as, again, it's all hypothetical. Thanks!

  8. #1328
    Quote Originally Posted by ay2012 View Post
    Dr. Young,
    This is a big hypothetical but: should the treatment prove effective but "incomplete" and there is reason to believe receiving multiple injections of umbilical cord blood would lead to further improvements, what's the protocol with respect to this? Once safety (and efficacy) is shown for a given amount, can that amount be used as a therapy repeatedly? Or would more, longer term, data be necessary for the FDA to approve? Feel free to answer in the most general way as, again, it's all hypothetical. Thanks!
    Dr. Young addresses this question a few pages back. I'm not going to recheck but I believe he said they considered repeating treatments and are continuing to consider for phase III.

  9. #1329
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    Dr. Young,

    As I lay here in bed unable to move about 75% of my body (though strangely a few months ago I started to be able to move my right thumb) I'm wondering...what are the real prospects of research resulting in a reversal of paralysis? What might a "cure" look like? Will therapies for new and chronic injuries be completely different?

    I apologize if you've answered similar questions...the research is dense and a little hard to get an overview of. From my perspective it's easy to be impatient and want a "cure" to happen yesterday, get depressed about getting out of these chairs, dependence on others and to wonder if a cure will happen in our lifetime.

    Thanks for your time and effort,
    Kyle
    C4/5 incomplete, 17 years since injury

    "The trick is in what one emphasizes. We either make ourselves miserable, or we make ourselves happy. The amount of work is the same.” - Carlos Castaneda

    "We live not alone but chained to a creature of a different kingdom: our body." - Marcel Proust

  10. #1330
    Quote Originally Posted by Wise Young View Post
    Han Solo,

    I did not say that the person cannot control the walking. I said that the motor scores did not change, indicating that the person was not able to exert sufficient control of individual muscles to change motor scores. A motor score represents the strength of a muscle. A person may not be able to wiggle a toe or move the foot up and down better in response to command. However, that person may be able to start the walking, stop it, and even change the rate and direction of walking.

    Many people recover walking after spinal cord injury but cannot control individual muscles of their legs well and many have poor sensations in their feet and legs. For example, Patrick Rummersfield recovered walking and is running in marathons but has little feeling in his feet below the knees and has difficulty tapping his feet or wriggling his toes. Such situations happen if your brain can activate the central pattern generator (CPG) in your spinal cord that tells your legs to walk but your brain cannot activate individual muscles in your legs.

    The CPG can be activated by non-specific stimuli. For example, noxious stimuli can activate the CPG. Walking can also be activated by injecting serotonin (a neurotransmitter) into the cerebral spinal fluid around the spinal cord. If some descending nerve fibers from the brain has reached the central pattern generator and can spritz some serotonin onto the CPG, this will start walking even though the person cannot control the individual muscles of the leg.

    I understand that you may not have time to read all the posts in this topic but please do consider the following before you conclude that this clinical trial is a waste of time and money. These are very early results, between 6-12 weeks after transplantation of umbilical cord blood cells. It takes many months and possibly years for axons to grow long distances. Axons grow no faster (and probably slower) than hair grows. For axons to reach the motoneurons that control the individual muscles of the leg, they must grow from the injury site (which may be in the neck in the case of cervical spinal cord injury) to the lumbosacral spinal cord located in the spinal cord just below the ribs.

    In the Hong Kong study, where we imaged white matter (the spinal tracts), we did not see growth of the spinal tracts until at least 6 months or longer after transplantation. It is little unfair, don't you think, to expect people with "complete" spinal cord injury to walk only a few months after receiving a therapy to stimulate regeneration of the spinal cord. If the people had recovered function within weeks or a few months after transplantation, it is unlikely to be regeneration but may be from sprouting of surviving axons.

    In fact, I am not sure that one can or should declare the treatment does not work based on 6-month motor and walking scores. Even six months may too early to tell whether the treatment worked or not. Finally, even if the treatment does not work, I suggest that it was not a waste of time and money to have tried it in people. While I can understand your disappointment that people are not walking shortly after treatment, it is important to have tried it.

    Wise.
    http://www.youtube.com/watch?v=wERegS8PJ1g

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