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Thread: Intermittent Hypoxia Elicits Prolonged Restoration of Motor Function in Human SCI

  1. #11
    [double-post]
    Last edited by Lacrossa; 01-30-2016 at 09:00 PM.

  2. #12
    Quote Originally Posted by mocha-rain View Post
    Do any of you understand the mechanism underlying the benefit of intermittent hypoxia? I always thought that hypoxia was damaging to the nervous system. For example, sleep apnea results in chronic intermittent hypoxia during sleep which is not good for the nervous system.
    Intermittent hypoxia is a hormesis phenomenon, a kind of conditioning response. Basically, mild stressors induce inflammation sufficient to elicit an endogenous neuroprotective response producing numerous plasticity-promoting proteins -- but not sufficient to actually cause significant harm. After acute and repeated bouts of hypoxia, animal models have shown increases in the expression of Brain Derived Neurotrophic Factor (BDNF) and its receptor Tropomyosin receptor kinase B (TrkB), Vascular Endothelial Growth Factor (VEGF) and its receptor, serotonergic receptors and several other supportive molecules within the cervical and lumbar spinal cord. All of these molecules are intimately connected to neuroplasticity broadly, and return of function more specifically, in both SCI and TBI.

    Critically, this hypoxia signaling cascade has been shown to induce downstream reductions in PTEN expression, and concomitant up-regulation of mTOR (which is negatively regulated by PTEN). This is a big deal, as mTOR has been lately recognized to be one of several "growth switches" underlying the internal growth potential of neurons, and shows up everywhere in all the recent breakthroughs in axonal regeneration. But, significant PTEN reduction/deletion has only been achieved to date in the lab with invasive gene therapy approaches. So having a noninvasive, minimally-disrupting intervention that effectively augments mTOR would be a very powerful therapy.

    (Much of the work on intermittent hypoxia was done in the 2000s in Gordon Mitchell's lab at the University of Wisconsin-Madison, now at the University of Florida. This work actually had little to do with SCI motor function, and was oriented towards exploration of a related respiratory phenomenon termed "phrenic long-term facilitation" (pLTF). In 2009, the researchers observed a spillover of neuroprotective response outside of the respiratory nervous system, in somatic motoneurons -- and this led to the idea it could be more widely utilized for locomotive recovery in human SCI, and the trials by Randy Trumbower at Emory. If you want to get into the nuts and bolts of everything, this 2014 paper from Mitchell's group is a good review.)

    How can something as bizarre as oxygen deprivation lead to all this? Next to energy/metabolism, oxygen is essential for survival for all living cells, and oxygen deprivation is a very deep and universal environmental trigger for a robust survival response. Cells have evolved to utilize much of the same internal machinery to mediate survival/repair ? and growth, and adaptation. In effect, intermittent hypoxia is a kind of clever hijacking of this survival response, with the intent of creating an environment conducive to growth and adaptation. Notably, cancer tumors actually also do this, as uncontrolled tumor growth inevitably becomes locally hypoxic.

    ---

    @mocha-rain: you wouldn't happen to be the /u/mocha-rain on Reddit, would you?
    Last edited by Lacrossa; 01-30-2016 at 09:04 PM. Reason: formatting

  3. #13
    Thanks for sharing the additional information about IH. The link to the PTEN reduction by the Warren Alilain group was interesting at the time due to the discovery and publicity via the HE group but is indeed an invasive gene manipulation. The MTOR piece is also very interesting. I think for clinical relevance, I'm watching for progression in the field toward minimum and simple options. The Alilain group showed such techniques about a year ago where a single injection of Chondroitinase into the phrenic nerve would restore activity and additionally new data on chronic and super chronic animals. Their acute and sub-acute animals were able to recover also with several injections to strengthen the bulbospinal pathways. On recent experiments, the results with IH didn't bump up the recovery very much. Hopefully in the future successful treatment would entail an injection rather than the purchase of expensive machines and breathing treatments. The relevant discussion is at 45:00 minutes...


  4. #14
    I agree that minimal and simple options have by far the most translational potential -- we will not be seeing gene-knockout humans in this half of the 21st century. I like IH for this reason: this could be implemented off-label tomorrow with minimal investment necessary on the part of clinics. It is not precluded from sale due to FDA marketing restrictions, the device that Trumbower & Co. is using is marketed as a high-altitude athletic trainer. The protocol employed is markedly milder than that utilized in athletic conditioning (albeit in an injured population).

    Warren has some work in prepublication now that is more supportive of IH in combination with chondroitin manipulations, particularly for phrenic function restoration. Based on the results reported so far at Emory, it is likely that IH is effective for walking and not too difficult to administer in highly incomplete populations; of great interest will be the results of the reach-and-grasp trials. Gillian Muir's group just published in September indicating some efficacy in rats, but some nuance as well. I would not hold out hope that something as mild as this would have great impact for complete injuries. Nevertheless, it's a rather elegant demonstration of the potential of endogenous growth factors.

    Thanks for the video!

  5. #15
    Quote Originally Posted by Lacrossa View Post
    I agree that minimal and simple options have by far the most translational potential -- we will not be seeing gene-knockout humans in this half of the 21st century. I like IH for this reason: this could be implemented off-label tomorrow with minimal investment necessary on the part of clinics. It is not precluded from sale due to FDA marketing restrictions, the device that Trumbower & Co. is using is marketed as a high-altitude athletic trainer. The protocol employed is markedly milder than that utilized in athletic conditioning (albeit in an injured population).

    Warren has some work in prepublication now that is more supportive of IH in combination with chondroitin manipulations, particularly for phrenic function restoration. Based on the results reported so far at Emory, it is likely that IH is effective for walking and not too difficult to administer in highly incomplete populations; of great interest will be the results of the reach-and-grasp trials. Gillian Muir's group just published in September indicating some efficacy in rats, but some nuance as well. I would not hold out hope that something as mild as this would have great impact for complete injuries. Nevertheless, it's a rather elegant demonstration of the potential of endogenous growth factors.

    Thanks for the video!
    Lacrossa,

    do you think gene-knockout will be really needed to reverse paralysis?

    I would say this is questionable if, for example, you consider a DRG neuron that will regenerate the axon that goes in the PNS after injury, while it does not regenerated the axon that goes in the CNS after SCI.

    If gene silencing will be needed there seem to be an exponential progress in the field:

    https://gladstone.org/about-us/news/...ion-stem-cells
    In God we trust; all others bring data. - Edwards Deming

  6. #16

    used iht

    Quite uncomfortable and I couldn't get down to 80 percent saturation level in 90 secs but it took 4 mins when I rented equipment for month. Made me vulnerable to bad coldbug too and I never get sick. Had to refill my 4ap prescription just to walk again with walker when IHT suddenly stopped helping my spasticity. Bad experience. -Jan

  7. #17
    Quote Originally Posted by FellowHawkeye View Post
    Quite uncomfortable and I couldn't get down to 80 percent saturation level in 90 secs but it took 4 mins when I rented equipment for month. Made me vulnerable to bad coldbug too and I never get sick. Had to refill my 4ap prescription just to walk again with walker when IHT suddenly stopped helping my spasticity. Bad experience. -Jan
    What device were you using? What kind of protocol (length of intervals, % oxygen, etc)?

  8. #18
    I remember back in 1981 when I was injured a lot of people where being put in Hyperbaric chambers as it was thought to help get function back, now it's the opposite, they don't have a clue.
    "Life is about how you
    respond to not only the
    challenges you're dealt but
    the challenges you seek...If
    you have no goals, no
    mountains to climb, your
    soul dies".~Liz Fordred

  9. #19
    Sadlyyou are right researchers are taking their best educated shot in the dark to treat SCI, Let's just hope they hit a bull's-eye. For god sake's we don't even fully understand the anatomy and the mechanisms of the spinal cord.truly baffling little string of energy... If their is a God I don't know what he was doingwith that idea. We need to be like the hero shrew

  10. #20

    my experience using iht

    Quote Originally Posted by tomsonite View Post
    What device were you using? What kind of protocol (length of intervals, % oxygen, etc)?
    I rented hypoxico's iht equipment (had to buy mask) which Trumbower uses and I followed the Trumbower Protocol, but I couldn't get down to 80 percent saturation level for at least 4 minutes instead of advised 90 seconds, which is the hypoxic air phase, followed by 90 seconds of regular air breathing. I did this for a week trying to get down to 80 percent quicker and even did it morning and night, but not usually for the full 45 minutes. I experimented and overdid the therapy. Woke up one morning and couldn't walk with my walker or get up from my elevating scooter, which I fairly easily did before. I had stopped using 4-AP cuz the therapy energized me until it didn't. Suddenly my legs felt like lead and I could only walk/rise again when I started taking 4-AP or 4-AP-3-MeOh. Also got a terrible cold and I never ever get colds. Last time I got such a cold was nearly 23 yrs ago right before injury. IHT was a horrible experience maybe cuz I tried too hard to get down to 80 percent and stay there for 90 seconds, which required holding my breath mostly. I think my lungs were too strong for IHT and a sci researcher should've been helping me with it. -Jan

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