ChinaSCINet Update

[Fly_Pelican_Fly]

It's clear that there is a variance of definitions for "Cure" and "walking". And this is part of the reason why this thread is so hot right now.

Activating the CPG with or without a pharmacological way of boosting plasticity may see some improvements in primitive functions for chronic SCI. Definitely a win for most of us but this is not walking as many of you will have known it before your injuries. Will we take it? Of course. But ask incomplete walkers as to how incredibly difficult this is and for many a return to the wheelchair becomes a must! We will want more than this (not in an ungrateful way - just a realist .

Whether activating the CPG will have any effect on functional recovery after regeneration of CST axons is yet to be known. The outcomes of this trial will go some way to confirming this. So let's see.

My hunch is (please note it's a hunch) that for regenerative strategies a different mode of training will be required here with less focus on autonomic functions and more focus on finer motor movement training. You would expect overground training with kinematic errors, proprioceptive prompts, functional training modalities and activity-based rehabilitation will be a better fit for regenerative strategies than just locomotor training alone. However, this variety of modalities will no doubt confuse researchers who are trying to simplify the parameters of the rehabilitation components of a potential therapy when clearly variety is important.

[Fly_Pelican_Fly]

I wish that someone really could explain to Paolo that these therapies are not for him. I wish that for example Wise Young and Jerry Silver could explain to Paolo that due to the complexity of injuries like the one Paolo has where big areas and networks of the spinal cord is damaged including lower motoneurons, systems connected to the CPG and other generators including large areas of segmental interneurons and ascending and descending axon pathways, - that it will be impossible to threat Paolo’s injury. As of today there are just some scattered proof in animal models that some axon sprouting can occur for any research in the SCI field, and to take it from there to humans is a huge step, let alone to cure injuries like the one Paolo has. It will be impossible in his lifetime. And like it is now I feel that scientists are fooling Paolo and giving him false hope. Someone should be realistic and explain all this in a good way to Paolo. It’s fine that Paolo is working for cures for others, but one should not fool Paolo letting him believing that there will be therapies for him in the near future.

Is that an informed opinion Leif or just that you are worried that you may have to abdicate your comfortable throne in Norway if someone comes up with a Cure in your lifetime?

[Wise Young]

I see a contradiction here, but maybe it's just me.

Perhaps it would be better to say "try to walk every day" rather than "are walking every day.

Just my personal opinion.

Paolo

Paolo,

Walking is a continuum. To me, a person who is taking weight-supporting steps, with or without help, is walking. It may not be normal walking but the people who are doing it call it walking and I agree with them.

Wise.

[Wise Young]

I wish that someone really could explain to Paolo that these therapies are not for him. I wish that for example Wise Young and Jerry Silver could explain to Paolo that due to the complexity of injuries like the one Paolo has where big areas and networks of the spinal cord is damaged including lower motoneurons, systems connected to the CPG and other generators including large areas of segmental interneurons and ascending and descending axon pathways, - that it will be impossible to threat Paolo’s injury. As of today there are just some scattered proof in animal models that some axon sprouting can occur for any research in the SCI field, and to take it from there to humans is a huge step, let alone to cure injuries like the one Paolo has. It will be impossible in his lifetime. And like it is now I feel that scientists are fooling Paolo and giving him false hope. Someone should be realistic and explain all this in a good way to Paolo. It’s fine that Paolo is working for cures for others, but one should not fool Paolo letting him believing that there will be therapies for him in the near future.

Leif,

We have now been spending the past year working on the problem to replacing motoneurons in contused rat lumbosacral spinal cord. Our first task has been to create a model of lumbosacral injury. It is actually quite a beautiful model. Contusions of different levels of the lumbosacral spinal cord produce very specific locomotor deficits associated with particular patterns of neuronal loss. The model includes upper lumbar, mid-lumbar, lumbosacral, and conus injuries.

So, we will be transplanting neural stem cells from various sources to replace neurons in the lumbosacral spinal cord in the coming months. One of the most interesting problems that we have had to solve is how to get the motoneurons to extend their axons out into the ventral roots and to reinnervate muscles. I think that we may have developed a way to do so.

I use to be quite discouraging to people who have lumbosacral spinal cord injuries or ischemic spinal cord injuries that frequently damage gray matter, saying that I don't know how to fix the problem and that regeneration of spinal tracts alone will not restore function. To me the solution to the problem require four fairly difficult steps but we have accomplished at least two of these and have been working on the second two.
• development of a reliable lumbosacral spinal cord injury model with specific behavioral deficits with which to judge efficacy of therapies.
• identification of a source of immunocompatible neural stem cells that can be transplanted to replace neurons that have been lost.
• find a way to attract axons of the new motoneurons to send their axons into the ventral roots and grow all the way to muscles.
• getting interneurons from the central pattern generator and descending spinal tracts to make synapses with the motoneurons.

If we work hard and are lucky, we might have the therapies ready for trial by 2015.

Wise.

[Chaz19]

I just wanted to comment, that I really appreciate this dialogue. It is very helpful, informative and does provide context to our problem. As a passive viewer, I value this discussion and wish many therapies could be discussed in this manner (without any personal attacks). Thanks to all for their contributions.

[Jawaid]

Wise it means no trials for lumbosacral even in 2014?

Long wait bit discouraging

[Cspine]

Wise,
The important thing is that you and your team know the results, not us. I personally would love to hear any news you have and I won't be too terribly upset no matter how vague and reserved that news may be. We are all so desperate for even a sliver of hope that we at times act like a pack of hungry dogs.

[Sue Pendleton]

Whoa, Wise, first I have to agree with Paolo because I did take a few steps on my own in the parallel bars and many more with help. That was exercising and trying to get to independent, no help needed 'walking'. As in ASIA normals.

As far as comparing complicated and large lumbrosacral complete injuries and incomplete ischemia injuries as saying they are equally difficult to fix, um, I'm confused. I know I'm rusty on my science after a few years of other things to brush up on but won't getting the cortico-spinal tract regenerated lead to 'walking' in the future? Yes, I do remember the 1mm a day pace but with PT and a CST fix I assumed we were looking at the fix that someone who didn't know us wouldn't see a person who had had a SCI. I do not extend that to my contracted hand because of fusion of joints, etc.
Oh, and Merry Christmas!

[Wise Young]

It's clear that there is a variance of definitions for "Cure" and "walking". And this is part of the reason why this thread is so hot right now.

Activating the CPG with or without a pharmacological way of boosting plasticity may see some improvements in primitive functions for chronic SCI. Definitely a win for most of us but this is not walking as many of you will have known it before your injuries. Will we take it? Of course. But ask incomplete walkers as to how incredibly difficult this is and for many a return to the wheelchair becomes a must! We will want more than this (not in an ungrateful way - just a realist .

Whether activating the CPG will have any effect on functional recovery after regeneration of CST axons is yet to be known. The outcomes of this trial will go some way to confirming this. So let's see.

My hunch is (please note it's a hunch) that for regenerative strategies a different mode of training will be required here with less focus on autonomic functions and more focus on finer motor movement training. You would expect overground training with kinematic errors, proprioceptive prompts, functional training modalities and activity-based rehabilitation will be a better fit for regenerative strategies than just locomotor training alone. However, this variety of modalities will no doubt confuse researchers who are trying to simplify the parameters of the rehabilitation components of a potential therapy when clearly variety is important.

Pelican,

I am not sure what you mean by "locomotor training" but I use the term locomotor training to refer to overground walking. Perhaps you are thinking of locomotor training as weight-supported treadmill training. If so, let me emphasize none of the subjects in our studies have had any treadmill training. They start with overground walking.

There are two serious limitations to weight-supported treadmill training. First, weight support harnesses place significant pressure on certain body parts, such as the straps that go between the legs) and carry a significant risk of pressure sores and walking time must be limited to an hour or less at a time. Second, due of the weight support, the walking is abnormal and the sensory cues for the legs are incorrect. It is like teaching the person to walk on the moon and then having to reteach the person how to walk on the earth when transferring to overground walking. The group in Kunming believes that walking should be done with full-weight bearing from the beginning.

When I first visited Kunming in 2004, I am surprised by how fast the people start to step and walk without assistance when they get the training starting 2 weeks after their spinal cord injury. Many (particularly incomplete or complete patients who received the intradural decompression) recovered walking within 3 months. However, people with chronic spinal cord injury do not recover as fast and almsot all reach a plateau within 3 months.

To the best of my knowledge, our current trial is the first time that the Kunming group has been systematically training a significant cohort of patients with chronic spinal cord injury with their 6:6:6 overground walking program after cell transplants. Incidentally, several of the patients currently in Kunming are training but without having received any transplants, so they constitute a form of control.

While some of the subjects (about 25%) in our study showed improvements during the first 3 months, we are now seeing subjects that showed little improvement during the first 3-6 months but are getting locomotor function late at 6-12 months. Please withhold judgment on the walking until you have actually seen the data and the walking. I cannot present the detailed data or videos here without attracting criticism from people like Jerry Silver but I think that you will be surprised. We will get the work published as soon as we can.

I have been observing spinal-injured people doing locomotor training for several decades. In the 1980's, for example, Barbara Devine headed a group that trained people with spinal cord injury to walk 7 or more hours every day. She had dozens of people walking in her facility in Cottonwood, Alabama and then later in Galveston, Texas. In my opinion, very few got functional walking back.

Wise.

[Skipow]

Dr. Wise,

According to the model of nerve regeneration you provided, wouldn't the clinical trials show improved arm and hand function in cervical level injury subjects (C5 and below) at this point? What motor scores are being used to test upper level extremities? Is there arm therapy being used in this trial as well, or is this a consideration for phase 3 studies?

Is this model for nerve regrowth a disagreed topic for SCI researchers as well, where the nerves just need to jump across the injury site or to the location of the nerve root?

Everyone,

I am really appreciative of top researchers discussing results on this web site and allowing open questions and discussion, but we should try to be more polite to one another. Critical questions are important and are great for understanding what is going on, but when people get negative towards one another and then talk about it more. It removes focus of why we even come to this forum. Both sides of the fence are not innocent here either. Lets stick to the point.

It would be really interesting to go to a thread that is limited to researchers to discuss their opinions, ideas, and findings among one another, without the clutter of the general public, so it is condensed and easier to page through. Does this exist? Some of the best ideas are formed during the after hours of conventions where a bunch of researchers collaborate and debate their ideas, why not do this every day?! I'm sure it would speed up the rate of progress for SCI research. This would be really interesting to observe as well.

Thanks! Merry Christmas!

[Fly_Pelican_Fly]

Pelican,

I am not sure what you mean by "locomotor training" but I use the term locomotor training to refer to overground walking. Perhaps you are thinking of locomotor training as weight-supported treadmill training. If so, let me emphasize none of the subjects in our studies have had any treadmill training. They start with overground walking.

There are two serious limitations to weight-supported treadmill training. First, weight support harnesses place significant pressure on certain body parts, such as the straps that go between the legs) and carry a significant risk of pressure sores and walking time must be limited to an hour or less at a time. Second, due of the weight support, the walking is abnormal and the sensory cues for the legs are incorrect. It is like teaching the person to walk on the moon and then having to reteach the person how to walk on the earth when transferring to overground walking. The group in Kunming believes that walking should be done with full-weight bearing from the beginning.

When I first visited Kunming in 2004, I am surprised by how fast the people start to step and walk without assistance when they get the training starting 2 weeks after their spinal cord injury. Many (particularly incomplete or complete patients who received the intradural decompression) recovered walking within 3 months. However, people with chronic spinal cord injury do not recover as fast and almsot all reach a plateau within 3 months.

To the best of my knowledge, our current trial is the first time that the Kunming group has been systematically training a significant cohort of patients with chronic spinal cord injury with their 6:6:6 overground walking program after cell transplants. Incidentally, several of the patients currently in Kunming are training but without having received any transplants, so they constitute a form of control.

While some of the subjects (about 25%) in our study showed improvements during the first 3 months, we are now seeing subjects that showed little improvement during the first 3-6 months but are getting locomotor function late at 6-12 months. Please withhold judgment on the walking until you have actually seen the data and the walking. I cannot present the detailed data or videos here without attracting criticism from people like Jerry Silver but I think that you will be surprised.

I have been observing spinal-injured people doing locomotor training for several decades. In the 1980's, for example, Barbara Devine headed a group that trained people with spinal cord injury to walk 7 or more hours every day. She had dozens of people walking in her facility in Cottonwood, Alabama and then later in Galveston, Texas. In my opinion, very few got functional walking back. I am seeing locomotor recovery that I have not seen before. Be patient. We will get the work published.

Wise.

Wise, I agree that overground walking training will be much more effective than weight assisted treadmill training.

But, from what I have seen so far a walking programme alone will not really be enough for unassisted walking - no matter how how intensive. Surely there is more than just walking in the programme in Kunming? For example how are the trunk muscles, glutes and hamstrings being stimulated and conditioned appropriately? Maybe there is more to the programme that you havent described because unassisted walking needs a hell of lot of conditioning - something that you dont get by simply walking.

Let me give you an example. I know a number of incomplete walkers who walk with crutches and canes very well. They walk all day long. Not just at home but everywhere. However, without stimulating, strengthening and some serious conditioning of the trunk, hamstrings and glutes they can never progress to unassisted walking.

Is there perhaps more to the programme in Kunming than 6 hours of walking?

Cheers

[Wise Young]

Wise, I agree that overground walking training will be much more effective than weight assisted treadmill training.

But, from what I have seen so far a walking programme alone will not really be enough for unassisted walking - no matter how how intensive. Surely there is more than just walking in the programme in Kunming? For example how are the trunk muscles, glutes and hamstrings being stimulated and conditioned appropriately? Maybe there is more to the programme that you havent described because unassisted walking needs a hell of lot of conditioning - something that you dont get by simply walking.

Let me give you an example. I know a number of incomplete walkers who walk with crutches and canes very well. They walk all day long. Not just at home but everywhere. However, without stimulating, strengthening and some serious conditioning of the trunk, hamstrings and glutes they can never progress to unassisted walking.

Is there perhaps more to the programme in Kunming than 6 hours of walking?

Cheers

Pelican,

I share your view. Most people with ASIA A spinal cord injuries reach a low plateau in their walking and more walking, no matter how intensive, will not get them beyond that plateau. Of course, you get an occasional person who never seriously tried walking and may even be incomplete that will show dramatic improvement with training. But, in general, intensive locomotor training does not restore unassisted walking to people with chronic ASIA A spinal cord injury.

We don't have a non-transplanted group of chronic spinal cord injury patients in this study. However, there are some patients at Kunming now who are not part of the study but are training without having received any cell transplnats. Also, this is an escalating dosing study where dose of cells injected increased. When we complete analysis of the data, we will correlate recovery with the dose and HLA-matching of cells.

In our study, the subjects averaged 12 years after injury and none were able to walk without assistance before the treatment. All were ASIA A. Although some (25%) showed improved locomotor scores without motor score changes within 6 months, most (75%) of them showed only slight or no improvements in locomotor scores after 3 months of training. Now, some subjects are showing delayed locomotor recovery at 6-12 months.

I want to emphasize that this is a phase II study. It was designed to ascertain whether the treatment is safe, feasible, and improves recovery of some patients. So far, the study results indicate that the therapy is safe. It certainly appears to be feasible. Finally, it improves recovery in some of the subjects, even though it was only 3 months after treatment.

The study showed several unexpected findings. First, MR/DTI showed fiber bundles growing across the injury site at 6-18 month after cell transplants. Second, even by 3 months some subjects (25%) showed improved locomotor scores. Third, at 6-12 months, we are seeing delayed locomotor recovery in some subjects.

The data suggest that the bundles of fibers and the improvements in locomotor scores result from the transplants. None of the subjects has had bundles of fibers crossing the injury site before transplantation. None showed such bundles <6 months after the treatment. At least in two subjects, the fiber bundles were growing longer between 6-18 months.

Only a Phase III trial, a true double-blind randomized controlled trial will prove this. That is why we are pushing forward to do that trial in 2013.

Wise.

[cripwalk]

Paolo,
I know you have good intentions, but getting bogged down with this is just semantics and not helpful in any way, and in fact may be detrimental due to the fact that Wise is now considering whether or not he will be providing us with any of the preliminary findings of the trial/s. It really just comes across that you're just feeding your own ego rather than genuinely trying to help the cause. If it's your "personal opinion" and it doesn't help our understanding, in future it's probably best to keep it that way..."personal" that is.

Clayton

While I agree with your general point, I think you're doing the same thing on another level. Who cares if Wise gives us preliminary results? The important thing is that the data gets published in a peer reviewed journal. Giving us prelim results is pointless and gets us no where. You are missing the forest for the trees.

[Wise Young]

Great question about the arms. The picture that I showed in /forum/showpost.php?p=1627571&postcount=1403 applies to the arms as well as the legs. We are collecting ASIA motor and sensory scores from the arms and the legs. In the arms, the ASIA standard examination includes five muscles: deltoids, biceps, wrist extensors, triceps, and wrist flexors. We did not include other hand function measures but plan to include them in the Phase III trial. We are hoping that we will see some improvements in those scores but I want to emphasize that less than half of the subjects in the Hong Kong and Kunming trial have cervical spinal cord injuries.

Wise.

Dr. Wise,

According to the model of nerve regeneration you provided, wouldn't the clinical trials show improved arm and hand function in cervical level injury subjects (C5 and below) at this point? What motor scores are being used to test upper level extremities? Is there arm therapy being used in this trial as well, or is this a consideration for phase 3 studies?

Is this model for nerve regrowth a disagreed topic for SCI researchers as well, where the nerves just need to jump across the injury site or to the location of the nerve root?

Everyone,

I am really appreciative of top researchers discussing results on this web site and allowing open questions and discussion, but we should try to be more polite to one another. Critical questions are important and are great for understanding what is going on, but when people get negative towards one another and then talk about it more. It removes focus of why we even come to this forum. Both sides of the fence are not innocent here either. Lets stick to the point.

It would be really interesting to go to a thread that is limited to researchers to discuss their opinions, ideas, and findings among one another, without the clutter of the general public, so it is condensed and easier to page through. Does this exist? Some of the best ideas are formed during the after hours of conventions where a bunch of researchers collaborate and debate their ideas, why not do this every day?! I'm sure it would speed up the rate of progress for SCI research. This would be really interesting to observe as well.

Thanks! Merry Christmas!

[Skipow]

Great question about the arms. The picture that I showed in /forum/showpost.php?p=1627571&postcount=1403 applies to the arms as well as the legs. We are collecting ASIA motor and sensory scores from the arms and the legs. In the arms, the ASIA standard examination includes five muscles: deltoids, biceps, wrist extensors, triceps, and wrist flexors. We did not include other hand function measures but plan to include them in the Phase III trial. We are hoping that we will see some improvements in those scores but I want to emphasize that less than half of the subjects in the Hong Kong and Kunming trial have cervical spinal cord injuries.

Wise.

Can you discuss preliminary outcomes in arm motor/ sensory improvement from this trial from the cervical subjects?

Since the study seems to be safe in C5 subjects and below, will C4 or higher be considered for phase 3? Or does another phase 1 and 2 study need to be done to assess the safety of this procedure with C4 and higher?

Thanks!