ChinaSCINet Update

[Wise Young]

Im sorry, but I am majorly confused. The talk about this trial is in so many directions that I dont know whats what. Not to mention Wise Young saying they arent showing improved motor or sensory scores. But in one video says that a patient could feel that his leg was fractured and in another video says that a patient complained of increased neuropathic pain but the improved return was worth it.
Sorry but I think this is too unclear and confuse able. And that might not be good for raising money.

I am so sorry that you feel confused. Results from clinical trials are often confusing because they contain new information that change the way that we think about spinal cord injury. People are also forming expectations of these trials that are unfair to the therapy. These trials were intended to demonstrate safety and are not sufficiently powered to show efficacy but people are expecting miracles. Let me explain what I mean by this.

We believe that the best results will come from the highest safe dose of umbilical cord blood cells combined with a single bolus of methylprednisolone and a 6-week course of lithium. Methylprednisolone (MP) should allow more of the transplanted cells to survive. A 6-week course of lithium shouldcause the transplanted cells to proliferate and also to produce growth factors that stimulate regeneration. Lithium has also been reported to stimulate regeneration of the spinal cord.

However, we did not know the safe dose of umbilical cord blood mononuclear cell transplants. That was why we started with 4-µliter injections and then progressed to 8 µliters and then to 16 µliters. In Hong Kong, we only did the 4- and 8-µliter injections and never got to the groups where we would give methylprednisolone or lithium.

Despite this, we saw remarkable white matter growth in the patients that received transplants. We saw clear gaps in all other patients before treatment. Of course this finding needs to be confirmed in many more subjects and confirmed by other measures of regeneration but these findings are amazing. Many scientists are excited by these results.

The slow growth of white matter was also expected but the extent of the growth was surprising. Axons grow no faster than a mm a day, and probably slower and the fact that we did not see the growth until 6-12 months after transplantation is not surprising. We were shocked by the amount of white matter growth. The MRI/DTI probably cannot detect fiber tracts that are less than a millimeter in diameter and I think that many of the white matter growth that we saw were several mm thick.

At 6 months, one of the subjects showed growth across the injury site and, to our enormous surprise, the growth seemed to have retracted at 12 months and then grew back at 18 months. This was shocking although, in retrospect, perhaps we should not be surprised that white matter can both grow forward and retract. It suggests much greater plasticity of white matter than we could have imagined. Of course, these findings must be replicated on larger series and confirmed with other methods of assessing white matter growth. If confirmed and the regrowth leads to functional improvement, this would be the first demonstration of regeneration in human spinal cord injury.

Finally, I don't know why Paolo and others don't understand that people can walk without changes in motor and sensory scores. I have been posting about the central pattern generator for over 15 years here on CareCure. Many people who recover walking after spinal cord injury cannot voluntarily move their legs or feel their legs as well as you would expect from their walking. We should also remember that this is very early in the trial and we may well see improved motor and sensory scores at 2 or even 3 years. The axons have to grow a long distance before they can restore function. I have been posting about how slow regeneration is for many years here.

So, I am actually quite reassured and excited by these results. The DTI images indicate that umbilical cord blood mononuclear cell transplants are causing regrowth of long tracts in the spinal cord, both ascending and descending. The fact that we are seing some early walking improvement although no motor or sensory score change is reassuring as well. If the results had shown earlier sensory and motor score recovery with no DTI evidence of white matter regrowth, it would have suggested that the treatment caused sprouting of surviving tracts that the MRI/DTI could not detect. This is less exciting than the finding that UCBMC are stimulating regeneration.

I am very anxious to see the last group of four patients transplanted with 16 µliters coupled with a bolus dose of methylprednsiolone and a 6-week course of lithium. We won't have the 6-month results on these patients until December. My staff will be in Kunming next week to help them enter the data. Through the entire month of November, the nurses have been flying or travelling to the patients' homes to do the examinations.

Wise.

[kz]

Dr. Young ,

Hi, Thank you so much for your time and important and great work that you are doing ; as i said before , i believe this community may never find a better friend than you .The amount of time and energy that you have been spending on these projects are unbelieveable . I indeed appreciate everything that you do to help and find a solution and cure for spinal cord injury . take care.
All the best

[debbie1341]

Dr. Young ,

Hi, Thank you so much for your time and important and great work that you are doing ; as i said before , i believe this community may never find a better friend than you .The amount of time and energy that you have been spending on these projects are unbelieveable . I indeed appreciate everything that you do to help and find a solution and cure for spinal cord injury . take care.

Ditto, thank you, Dr. Wise!!!

[Chassmain]

Dr. Young, thank you for all the information you have just shared! I know it’s certainly gives me hope to read what you’ve written and know we have someone like you on our side.

I don’t blame you for reconsidering presenting any more data about the trials until they're complete. I think people have been completely unreasonable with their expectations, and need to take a step back and realize this treatment was never intended to be the miracle cure, but a way to test the safety and effiancy of a treatment that is indicating some real possibilities.

This isn’t the cure yet folks but one very important step along the journey of getting us there.

[paolocipolla]

..
Finally, I don't know why Paolo and others don't understand that people can walk without changes in motor and sensory scores. I have been posting about the central pattern generator for over 15 years here on CareCure. Many people who recover walking after spinal cord injury cannot voluntarily move their legs or feel their legs as well as you would expect from their walking.

...

Wise,

it's just that since I have no voluntary movement in my legs and supposing my CPG works, I can't understand how I can tell my legs to start moving when I want walk and how do I stop them when I want to stop. Or how can I go right and/or left if I let's say have to avoind an obstacle?

Can you show me a video of somemone walking who has no voluntary movements of the legs?

PatricK Rummerfield is not a good example as he has voluntary movements. I know him.

Paolo

[Buck503]

Wise,

it's just that since I have no voluntary movement in my legs and supposing my CPG works, I can't understand how I can tell my legs to start moving when I want walk and how do I stop them when I want to stop. Or how can I go right and/or left if I let's say have to avoind an obstacle?

Can you show me a video of somemone walking who has no voluntary movements of the legs?

PatricK Rummerfield is not a good example as he has voluntary movements. I know him.

Paolo

I had a hard time understanding how the CPG was activated
if there's no voluntary control. But then a member named Imight,
who can walk a little, explained how he can walk without any
real control. Imight doesn't function near as well as Rummerfield.

[CAS]

Hi Dr. Wise

question would the ability to inspect the white matter growth be restricted due to the fact that your unable open up and disect the cord to the extent of the rat experiments.

And do you think given time the persons walking will regain finer motor control of their like toes and fingers. Especially the fingers

I would like to thank you and your team for the great results as i would have been happy with 10% of respndance with improvement but two ot of five represents 40% great results at this early stage for HUMAN trails.

[Barrington314mx]

Thank you Dr. for trying to clear things up as best you can.
I was also unware that there was still another group of patients with follow up data still to come. I thought that last bit that was shared was that group. So that is very exciting, and I hope you can still share those findings with us. Thanks again.

[Chaz19]

This is a very interesting topic. Often – I think it is hard for many of us to understand and I know I have a hard time trying to comprehend walking without volitional/conscious thought.

To add another question to the list: from what I've noticed people sway their arms back and forth when they walk, could there be some sort of upper level generator that is responsible for this movement? I don't think people consciously think of swinging their arms as they walk – but I could be wrong.

[Geoman]

Wise,
Is there likely to be any further information reported on the effect of lithuim on neuropathic pain for this stage of the trial or is this something that will be further assessed separately?

Thanks,
Clayton

[Wise Young]

Wise,

it's just that since I have no voluntary movement in my legs and supposing my CPG works, I can't understand how I can tell my legs to start moving when I want walk and how do I stop them when I want to stop. Or how can I go right and/or left if I let's say have to avoind an obstacle?

Can you show me a video of somemone walking who has no voluntary movements of the legs?

PatricK Rummerfield is not a good example as he has voluntary movements. I know him.

Paolo

Paolo,

Your central pattern generator (CPG) has to receive some input from descending axons from your brain in order for your brain to activate walking movements. When you walk, you don't tell each of your individual muscles to move in sequence, e.g. left psoas, left quadriceps, left anterior tibialis, left gastrocnemius, right psoas, right quadriceps, right anterior tibialis, left gastrocnemius, etc. To walk, you activate your CPG to a given level of excitation and it generates walking patterns. If you activate more, you take longer steps. If you turn your body to one side, the CPG will lengthen its stride on that side to keep balance and your other side pivots. If you activate the CPG to even higher levels, you start trotting. And so on. The CPG contains the motor programs not only for walking, trotting, but galloping, skipping, cantering, hopping, and other movements that most children show when they play. You don't need the brain for such movements. In fact, if you cut the head off a chicken and put it on its feet, the chicken can run around and around until it falls or dies from blood loss. If some of the regrowing fibers have reached the CPG and can activate it somehow, it can result in stepping activity.

Do you remember the recent reports from Suzy Harkema at Louisville, Kentucky, where she reported being able to get one person with complete spinal cord injury to walk after putting electrodes into the spinal cord to stimulate the lower cord (presumably the CPG)? Apparently, she has gotten two people to walk like that now. Do you remember the posts that I did about Dr. Richard Herman of the Good Samaritan Hospital Hospital in Phoenix Arizona, where he showed that stimulation of the CPG will help a man who was just a "household" walker who took 150 seconds to walk 10 meters to a person who can walk a kilometer are near normal speeds?

Why do you say that Patrick is not a good example of somebody who walks. Have you seriously talked to him? He tells me that he has no feelings in his legs below the knees. He has a difficult time tap-dancing. By the way, a paper will be published later this year, reporting DTI findings on Pat Rummersfield. He has a thin strand of white matter growing down his spinal cord across the white matter gap, very similar to what we found in two patients from the five that we did DTI studies of in Hong Kong. By the way, white matter growth alone may not be sufficient to allow walking... Walking training may be necessary to get the CPG to operate. After years of not walking, the CPG itself may not function well unless it is repetitively activated. That is one of the reasons why we decided to do part of the study at Kunming where intensive locomotor training is available.

Wise.

[Wise Young]

Wise,
Is there likely to be any further information reported on the effect of lithuim on neuropathic pain for this stage of the trial or is this something that will be further assessed separately?

Thanks,
Clayton

We will be starting a two-center trial of lithium in China on 60 subjects with severe neuropathic pain. The trial will start in March, after the Chinese New Year (nothing happens in China for weeks before and a week or two after the Chinese New Year which happens to be on February 10, 2013). When that trial (which is double-blind, randomized, and placebo-controlled) is completed, we will of course publish the results and I will report it as soon as I can on these forums.

Wise.

[Wise Young]

This is a very interesting topic. Often – I think it is hard for many of us to understand and I know I have a hard time trying to comprehend walking without volitional/conscious thought.

To add another question to the list: from what I've noticed people sway their arms back and forth when they walk, could there be some sort of upper level generator that is responsible for this movement? I don't think people consciously think of swinging their arms as they walk – but I could be wrong.

Chaz,

I am not sure why indirect activation of locomotor activity is so difficult for people with spinal cord injury to understand. You can have involuntary movements of your legs without voluntary control of the legs. Every person that has ever had a spasm knows that this occurs. Many people can also inhibit spasms or spasticity. Some people can initiate spasms. For example, I have a friend with spinal cord injury whose legs would go into a spasm when he laughed or I would tell him a dirty joke.

Locomotor activity is another programmed activity of the spinal cord. Walking can be activated even when people don't have direct voluntary control of the individual muscles of the legs. There are many many walking quads and paras. Most of people with incomplete spinal cord injury do have or regain voluntary control of their legs but many with severe injuries don't have. They can walk but do not have good control of individual leg muscles. A lot of times, they blame this on "spasticity" and take anti-spasticity drugs such as baclofen to suppress the spasticity. But, the real reason is because they don't have sufficient motor axons reaching the motoneurons to control them and overcome local excitatory reflex activations.

Yes, there are links between the upper limbs and lower limbs when the CPG activates the legs to walk. Likewise, when you swim (which is close to quadripedal locomotion for human), there is facilitation of the arm movements with leg movements. For example, the crawl and breast stroke are likely to be variants of already present motor programs that can be modified through training to achieve more efficient swimming. In fact, there are people who believe that it may help walking in people with cervical spinal cord injury if people swing their arms when walking.

Recovering stepping function without any change in motor or sensory scores may be an initial stage of recovery from regeneration of the spinal cord. I would like to think that this is true. That is why these results are so exciting. We are still in the very early phases of this study and don't have all the results yet. That is why all these pessimistic statements being made about this study are premature.

Wise.

[swh2007]

Thank you for these explanations. Basically, our minds can tell our bodies to walk without actually having control of our individual leg muscles. Among other things, you are excited that it is possible that your research may be able to result in a treatment that allows enough improvement in the spinal cord mechanics and nervous system to get some SCI folks to walk, even if they can't control all or any of their leg muscles. You are not positive that this will happen, but the possibilities are high enough for you to devote a number of years of life to find out.

Thank you for your lifetime of work on behalf of the SCI community.

[Wise Young]

Thank you for these explanations. Basically, our minds can tell our bodies to walk without actually having control of our individual leg muscles. Among other things, you are excited that it is possible that your research may be able to result in a treatment that allows enough improvement in the spinal cord mechanics and nervous system to get some SCI folks to walk, even if they can't control all or any of their leg muscles. You are not positive that this will happen, but the possibilities are high enough for you to devote a number of years of life to find out.

Thank you for your lifetime of work on behalf of the SCI community.

You are very welcome. Wise.