Page 1 of 2 12 LastLast
Results 1 to 10 of 19

Thread: Peripheral Nerve Growth

  1. #1
    Senior Member BigK's Avatar
    Join Date
    Oct 2008
    Location
    Pittsburgh, PA
    Posts
    551

    Peripheral Nerve Growth

    I was wondering if Dr. Wise or anyone else could help me understand peripheral nerve growth. When I had my accident they had to put a rod in my left humerus. They hit my radial nerve and my hand was limp and useless. They told me peripheral nerves like the one they damaged in my arm do grow back and function again. Well, they were right. I worked with a therapist to get my hand working again and I got back about 95% function and the spot on my thumb that went numb has almost all of the feeling back. My question is why are peripheral nerves capable of repairing themselves and functioning again but nerves of the spinal cord cannot. Also, is there anyone studying why this is possible and is anyone also trying to gather information from this to see if they can learn anything from this and use the information to find out ways to help with SCI research? Or, do they know enough about it to realize nothing can be done with it? Thanks.
    Ken

    Guns don't kill people. Daddys with cute daughters do!

  2. #2
    Senior Member
    Join Date
    May 2004
    Location
    Houston, texas
    Posts
    392
    I heard because if the spinal cord had a lot of regenerating functions that it would get too crowded and chaotic. Plus scar tissue grows around the area so the little regenerating affects teh spinal cord does has is cock blocked.

  3. #3
    Quote Originally Posted by BigK View Post
    I was wondering if Dr. Wise or anyone else could help me understand peripheral nerve growth. When I had my accident they had to put a rod in my left humerus. They hit my radial nerve and my hand was limp and useless. They told me peripheral nerves like the one they damaged in my arm do grow back and function again. Well, they were right. I worked with a therapist to get my hand working again and I got back about 95% function and the spot on my thumb that went numb has almost all of the feeling back. My question is why are peripheral nerves capable of repairing themselves and functioning again but nerves of the spinal cord cannot. Also, is there anyone studying why this is possible and is anyone also trying to gather information from this to see if they can learn anything from this and use the information to find out ways to help with SCI research? Or, do they know enough about it to realize nothing can be done with it? Thanks.
    BigK, very good question. Let me take three types of nervous tissue and describe the spontaneous axonal regeneration in these tissues. Let me first describe three anatomical aspects of the motor and sensory system. First, when I use the word regeneration, I am referring to regrowth of axons (or nerve fibers) which are extensions of neurons (or nerve cells). If a neuron is killed, regeneration cannot occur from that neuron. Second, the neurons for sensory axons reside in little groups called dorsal root ganglia (DRG) that are situated just outside of the spinal cord. The DRG neurons send one branch of their axon out the peripheral nerve to the skin, muscle, bone, etc. and the other branch into the spinal cord where they contact spinal neurons and also travel up the spinal cord to the brain. Third, the neurons for muscles reside in the spinal cord where they receive signals from the brain and they send their axons through the ventral or anterior roots into peripheral nerve to muscle.

    Peripheral nerves do regenerate, particularly after compression or crush accidents like what you describe. In general, they do not regenerate as well if the nerves have been cut and a gap is allowed to be present between the two cut ends of the nerve. When the two cut ends of the nerves were re-opposed together, regeneration of about 10% of the axons take place and some limited functional recovery may occur. Both motor and sensory axons will regenerate and thus one gets back both motor and sensory function.

    Spinal roots do not regenerate as well as peripheral nerves. For example, injury to the spinal roots can occur with herniated discs pressing on them or compression or crushing of the cauda equina (below L1 of the spine) where most of the lumbosacral spinal roots are located. Such injuries generally result in limited sensory recovery and partial motor recovery. The reason why little sensory improvement occurs is because the injury is occurring to the spinal root between the dorsal root ganglia. The sensory axon from the dorsal root ganglion has to grow into the spinal cord before it can make any connections and axons will stop at the edge of the peripheral and central nervous system, called the CNS/PNS interface. Motor axons will regenerate to some extent unless the injury is close enough to the spinal cord to damage the motoneurons in the spinal cord.

    Spinal cord does not regenerate well. This does not mean that the spinal cord does not regenerate at all. I suspect that the spinal cord (particularly incomplete injuries) may regenerate. Surviving axons certainly can sprout additional branches. Regeneration takes a long time (years) and the spinal cord (particularly the injury site) is not particularly hospitable to growing axons and have proteins like Nogo and chondroitin-6-sulfate proteoglycans that stop axonal growth. Therapy is necessary to provide long-term sustained growth factor support, cells are needed to bridge the injury site, and growth inhibitor blockers are necessary to allow axons to grow long-distances.

    For many years, the reason why peripheral nerve was believed to be able to regenerate was because of the Schwann cells that myelinate axons in the peripheral nerve. In the central nervous system, the cells that myelinate axons are oligodendroglia. Each Schwann cell wraps around one segment of one axon. Each oligodendroglia may provide myelin segments to as many as 20 axons. Oligodendroglia myelin express a protein called Nogo, which stop axonal growth. For many years, scientists through that Nogo expression is the difference between peripheral and central nervous nerve growth. However, as it turns out Schwann cell myelin also expresses Nogo.

    The important difference between Schwann cell and oligodendroglial myelin is that Schwann cells in injured peripheral nerves transform into cells that look by macrophages and that scavenge myelin fragments. Oligodendroglia do not. Because they myelinate multiple axons, as long as some of the axons are still alive, the oligodendroglia myelin is still present. At the injury site, there are macrophages (mostly from blood or microglia in the spinal cord) that eat myelin fragments, although some recent studies by a colleague in my laboratory showed that microglial macrophages stop taking up myelin debris after a while because they cannot process them. In any case, in the central nervous system, the cleanup of the myelin debris is slow and inefficient. In the peripheral nerve, the myelin is cleared out and the axons are able to regenerate in the nerve.

    Finally, there is now growing evidence that certain spinal tracts do not grow as well as others. In particular, the corticospinal tract is the main spinal tract that goes from the brain to the spinal cord. A former student of mine has found out the reason why corticospinal neurons do not regenerate well and has discovered a treatment that can make them do so. This is quite exciting and I am very hopeful that this will be part of the therapies that we will be able to take to clinical trials in the coming years.

    Wise.

  4. #4
    Quote Originally Posted by Wise Young View Post
    BigK, very good question. Let me take three types of nervous tissue and describe the spontaneous axonal regeneration in these tissues. Let me first describe three anatomical aspects of the motor and sensory system. First, when I use the word regeneration, I am referring to regrowth of axons (or nerve fibers) which are extensions of neurons (or nerve cells). If a neuron is killed, regeneration cannot occur from that neuron. Second, the neurons for sensory axons reside in little groups called dorsal root ganglia (DRG) that are situated just outside of the spinal cord. The DRG neurons send one branch of their axon out the peripheral nerve to the skin, muscle, bone, etc. and the other branch into the spinal cord where they contact spinal neurons and also travel up the spinal cord to the brain. Third, the neurons for muscles reside in the spinal cord where they receive signals from the brain and they send their axons through the ventral or anterior roots into peripheral nerve to muscle.

    Peripheral nerves do regenerate, particularly after compression or crush accidents like what you describe. In general, they do not regenerate as well if the nerves have been cut and a gap is allowed to be present between the two cut ends of the nerve. When the two cut ends of the nerves were re-opposed together, regeneration of about 10% of the axons take place and some limited functional recovery may occur. Both motor and sensory axons will regenerate and thus one gets back both motor and sensory function.

    Spinal roots do not regenerate as well as peripheral nerves. For example, injury to the spinal roots can occur with herniated discs pressing on them or compression or crushing of the cauda equina (below L1 of the spine) where most of the lumbosacral spinal roots are located. Such injuries generally result in limited sensory recovery and partial motor recovery. The reason why little sensory improvement occurs is because the injury is occurring to the spinal root between the dorsal root ganglia. The sensory axon from the dorsal root ganglion has to grow into the spinal cord before it can make any connections and axons will stop at the edge of the peripheral and central nervous system, called the CNS/PNS interface. Motor axons will regenerate to some extent unless the injury is close enough to the spinal cord to damage the motoneurons in the spinal cord.

    Spinal cord does not regenerate well. This does not mean that the spinal cord does not regenerate at all. I suspect that the spinal cord (particularly incomplete injuries) may regenerate. Surviving axons certainly can sprout additional branches. Regeneration takes a long time (years) and the spinal cord (particularly the injury site) is not particularly hospitable to growing axons and have proteins like Nogo and chondroitin-6-sulfate proteoglycans that stop axonal growth. Therapy is necessary to provide long-term sustained growth factor support, cells are needed to bridge the injury site, and growth inhibitor blockers are necessary to allow axons to grow long-distances.

    For many years, the reason why peripheral nerve was believed to be able to regenerate was because of the Schwann cells that myelinate axons in the peripheral nerve. In the central nervous system, the cells that myelinate axons are oligodendroglia. Each Schwann cell wraps around one segment of one axon. Each oligodendroglia may provide myelin segments to as many as 20 axons. Oligodendroglia myelin express a protein called Nogo, which stop axonal growth. For many years, scientists through that Nogo expression is the difference between peripheral and central nervous nerve growth. However, as it turns out Schwann cell myelin also expresses Nogo.

    The important difference between Schwann cell and oligodendroglial myelin is that Schwann cells in injured peripheral nerves transform into cells that look by macrophages and that scavenge myelin fragments. Oligodendroglia do not. Because they myelinate multiple axons, as long as some of the axons are still alive, the oligodendroglia myelin is still present. At the injury site, there are macrophages (mostly from blood or microglia in the spinal cord) that eat myelin fragments, although some recent studies by a colleague in my laboratory showed that microglial macrophages stop taking up myelin debris after a while because they cannot process them. In any case, in the central nervous system, the cleanup of the myelin debris is slow and inefficient. In the peripheral nerve, the myelin is cleared out and the axons are able to regenerate in the nerve.

    Finally, there is now growing evidence that certain spinal tracts do not grow as well as others. In particular, the corticospinal tract is the main spinal tract that goes from the brain to the spinal cord. A former student of mine has found out the reason why corticospinal neurons do not regenerate well and has discovered a treatment that can make them do so. This is quite exciting and I am very hopeful that this will be part of the therapies that we will be able to take to clinical trials in the coming years.

    Wise.
    So all the theories that so far are used to explain why CNS does not rigenerate are becoming obsolete or even completly wrong.

    I have been thinking for a while that researcher probably have been shooting just at the shadow of the real target so far.
    I guess the CNS is full of shadows that make it difficult to understand what the target should be.


    Paolo

  5. #5
    Quote Originally Posted by paolocipolla View Post
    So all the theories that so far are used to explain why CNS does not rigenerate are becoming obsolete or even completly wrong.

    I have been thinking for a while that researcher probably have been shooting just at the shadow of the real target so far.
    I guess the CNS is full of shadows that make it difficult to understand what the target should be.


    Paolo
    Paolo,

    It is very important to separate out what various scientists believe and what the evidence shows. Some scientists who proposed and advocate certain theories, such as Martin Schwab and Nogo, will do experiments to prove their theories and argue against the other theories. Other scientists, such as Jerry Silver, advocate a central role for chondroitin-6-sulfate-proteoglycans and will point out data against the Nogo theory. Some believe that certain types of astrocytes are bad, i.e. Stephen Davies.

    In many cases, the evidence is incomplete and the story turns out to be more complex than the simplistic pictures depicted by early papers. Early papers by Martin Schwab in 1991 suggested that myelin is the main and perhaps only inhibitor of axonal growth in the spinal cord. In 1994, Saburo Kawaguchi showed that sharply transected neonatal rats spinal cords can regenerate. Kawaguchi believed that immature astrocytes are critical for regeneration (similar to what Stephen Davies is proposing) but he was never able to show regeneration in sharply transected adult rat cords.

    Others tried to show that animals that don't express Nogo, i.e. Nogo-knockout mice, can regenerate but these mice don't regenerate well either, suggesting that other factors besides Nogo may prevent regeneration. So, at the present, most scientists in the field believe that at least two factors inhibit axonal regeneration in the adult spinal cord: Nogo and chondroitin-6-sulfate-proteoglycans (CSPG). There is evidence that blockade of Nogo will stimulate regeneration. Likewise, there is evidence that chondroitinase, which breaks down CSPG, will stimulate regeneration.

    it is not true that the theories (such as the Nogo and CSPG theories) are wrong. They just don't account for all the factors in the central nervous system that regulate axonal growth. This is not surprising. Early scientists had the hubris to assume that they had the one and only factor that regulates regeneration. They should know better. Nothing in our bodies or central nervous system is controlled by only one factor. Multiple factors play a role, especially when it is a phenomenon as important as regeneration of the spinal cord.

    The science is much stronger and better than the impression that you are giving, i.e. that we are shooting at shadows. It is also not surprising that multiple mechanisms affect regeneration and growth of axons. There are other factors. Marie Filbin and Mary Bunge have shown that axons that are expressing high levels of cAMP ignore whatever inhibitors might be present. Likewise, a former student of mine will be coming out with a beautiful story suggest that certain spinal tracts express factors that make them less likely to regenerate than others. These aren't shadows but real evidence-based mechanisms that will lead to definitive regenerative therapies.

    Wise.

  6. #6
    Quote Originally Posted by Wise Young View Post
    Paolo,

    It is very important to separate out what various scientists believe and what the evidence shows. Some scientists who proposed and advocate certain theories, such as Martin Schwab and Nogo, will do experiments to prove their theories and argue against the other theories. Other scientists, such as Jerry Silver, advocate a central role for chondroitin-6-sulfate-proteoglycans and will point out data against the Nogo theory. Some believe that certain types of astrocytes are bad, i.e. Stephen Davies.

    In many cases, the evidence is incomplete and the story turns out to be more complex than the simplistic pictures depicted by early papers. Early papers by Martin Schwab in 1991 suggested that myelin is the main and perhaps only inhibitor of axonal growth in the spinal cord. In 1994, Saburo Kawaguchi showed that sharply transected neonatal rats spinal cords can regenerate. Kawaguchi believed that immature astrocytes are critical for regeneration (similar to what Stephen Davies is proposing) but he was never able to show regeneration in sharply transected adult rat cords.

    Others tried to show that animals that don't express Nogo, i.e. Nogo-knockout mice, can regenerate but these mice don't regenerate well either, suggesting that other factors besides Nogo may prevent regeneration. So, at the present, most scientists in the field believe that at least two factors inhibit axonal regeneration in the adult spinal cord: Nogo and chondroitin-6-sulfate-proteoglycans (CSPG). There is evidence that blockade of Nogo will stimulate regeneration. Likewise, there is evidence that chondroitinase, which breaks down CSPG, will stimulate regeneration.

    it is not true that the theories (such as the Nogo and CSPG theories) are wrong. They just don't account for all the factors in the central nervous system that regulate axonal growth. This is not surprising. Early scientists had the hubris to assume that they had the one and only factor that regulates regeneration. They should know better. Nothing in our bodies or central nervous system is controlled by only one factor. Multiple factors play a role, especially when it is a phenomenon as important as regeneration of the spinal cord.

    The science is much stronger and better than the impression that you are giving, i.e. that we are shooting at shadows. It is also not surprising that multiple mechanisms affect regeneration and growth of axons. There are other factors. Marie Filbin and Mary Bunge have shown that axons that are expressing high levels of cAMP ignore whatever inhibitors might be present. Likewise, a former student of mine will be coming out with a beautiful story suggest that certain spinal tracts express factors that make them less likely to regenerate than others. These aren't shadows but real evidence-based mechanisms that will lead to definitive regenerative therapies.

    Wise.
    Thanks for this clarification, that gives me a much better picture of the present situation.

    I think it is ok that a researcher goes on with his line of research until the bottom, but sometimes it just look like once they get to the bottom a few wants to go deeper and deeper to get nowhere.

  7. #7
    Senior Member BigK's Avatar
    Join Date
    Oct 2008
    Location
    Pittsburgh, PA
    Posts
    551
    When God or whoever you believe in made our extraordinary bodies, he did a great job with everything except our central nervous sytem. Why would the body fight itself like that when it has so many life saving mechanisms? Thanks for your response doc.
    Ken

    Guns don't kill people. Daddys with cute daughters do!

  8. #8
    Quote Originally Posted by BigK View Post
    When God or whoever you believe in made our extraordinary bodies, he did a great job with everything except our central nervous sytem. Why would the body fight itself like that when it has so many life saving mechanisms? Thanks for your response doc.
    BigK,

    Regeneration of the spinal cord is one of those goals that is similar to getting to the moon. For almost all of human history, doctors have believed that the spinal cord cannot regenerate. Some 3000 thousand years ago, an anonymous Egyptian physician (in the Edwin-Smith papyrus) described spinal cord injury in warriors (including the priapism) and recommended that water should be withheld and not to treat the condition. In the early 1900's, the father of neuroanatomy, Santiago Ramon y Cajal proposed the neuron theory and described the frustrated efforts of axons to grow across a cut in the spinal cord.

    Cutting the spinal cord is perhaps the most difficult challenge that one can present to growing axons. When the spinal cord is cut and no repair of the dura or pia is done, fibroblasts from surrounding tissues invade into the injury site and astrocytes from the spinal cord proliferate in response to form a "glial scar". Axons will not grow across such scars. I have pointed on this forum and elsewhere that such cuts of the spinal cord are abnormal and unusual spinal cord injury. A vast majority of spinal cord injuries involve contusion and compression of the spinal cord, without a penetrating wound.

    In contused and compressed cords, there is astrocytosis (proliferation of astrocytes or glial cells) but no invasion of fibroblasts. Unlike cut spinal cords, most contused spinal cords have a loose matrix of tissue at the injury site and not always a cyst. In a 1997 paper by the Multicenter Animal Spinal Cord Injury Study, we reported histological studies of several rat spinal cords injured with a standardized contusion. We found many axons growing into the loose tissue matrix at the injury site. So, while the injury site is a barrier to axonal growth in cut spinal cords, it is not an absolute barrier in contused cords.

    Having watched many people with spinal cord injury recover over the years, I believe that the human spinal cord does regenerate spontaneously to some extent. For example, many people with incomplete spinal cord injuries do continue to recover over many years. The timing of such recovery is consistent with regrowth of axons at 1 mm a day. Some of the recovery is a result of surviving axons sprouting but there is also a descent of the sensory level by 4-5 segments.

    Our goal is to help the contused and compressed spinal cord regenerate better. Much of the pessimism surrounding the inability of the spinal cord to regenerate comes from the transection model of spinal cord injury that many researchers have been using. A transection the spinal cord without dural repair is very rarely seen clinically. It is not representative of spinal cord injury in humans. It is one of the reasons why I have spent the past two decades developing and training now over 600 laboratories around the world to do the contusion model of rat spinal cord injury. In my opinion, we should be studying regeneration in the contused or compressed spinal cord, rather than the sharply transected spinal cord.

    Wise.

  9. #9
    Senior Member KIM's Avatar
    Join Date
    Jul 2001
    Location
    Piedralaves (Avila) SPAIN
    Posts
    1,015
    Wise. Could we cheat the CNS and make it believe it is peripheral?

  10. #10
    Senior Member Foolish Old's Avatar
    Join Date
    Jun 2006
    Location
    Florida Keys
    Posts
    16,412
    Wise, understanding that "atraumatic" (sez who?) injuries to the cns are markedly different than the average SCI resulting from trauma, many of us with congenital causes of paralysis still see SCI research as the most accessible way to gain insight into our paralysis.

    You have differentiated between cut and crush injuries. How would you describe the CNS damage created by a tethered cord?
    Foolish

    "We have met the enemy and he is us."-POGO.

    "I have great faith in fools; self-confidence my friends call it."~Edgar Allan Poe

    "Dream big, you might never wake up!"- Snoop Dogg

Similar Threads

Posting Permissions

  • You may not post new threads
  • You may not post replies
  • You may not post attachments
  • You may not edit your posts
  •