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Intermittent Hypoxia Elicits Prolonged Restoration of Motor Function in Human SCI

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    Intermittent Hypoxia Elicits Prolonged Restoration of Motor Function in Human SCI

    http://cdmrp.army.mil/scirp/highlights.shtml#2_13

    Intermittent Hypoxia Elicits Prolonged Restoration of Motor Function in Human SCI
    Posted April 4, 2013
    Gordon Mitchell, Ph.D., University of Wisconsin, Madison;
    Gillian Muir, D.V.M., Ph.D., University of Saskatchewan;
    Randy Trumbower, Ph.D., Emory University

    Spinal cord injury (SCI) disrupts the connections between the brain and spinal cord, leading to lifelong paralysis in soldiers. However, many spinal cord injuries are incomplete, leaving at least some spared neural pathways to the motor neurons that initiate and coordinate movement. Consequently, spinal plasticity can contribute to spontaneous recovery of limb and respiratory function following SCI. Unfortunately, spontaneous recovery is slow, variable, and of limited extent. Dr. Gordon Mitchell, Dr. Gillian Muir, and Dr. Randy Trumbower received a Translational Research Partnership Award from the Fiscal Year 2010 Spinal Cord Injury Research Program to study the potential value of repeated acute intermittent hypoxia (AIH), alone or in combination with locomotor training, for improving limb function in animals with chronic SCI. They are applying AIH to elicit cellular and synaptic mechanisms of spinal plasticity in non-respiratory motor neurons, and hope to determine whether it can improve leg function in patients with chronic, incomplete SCI. Preliminary animal experiments have shown that AIH combined with daily training elicits sustained improvement in limb motor function of treated animals with chronic cervical SCI. In addition, preliminary clinical studies reveal a sustained increase in walking speed and distance following a 10-meter walk test and a 6-minute walk test, respectively. If successful, AIH could represent a novel method for stimulating spinal plasticity in individuals with SCI, providing an avenue for controlled restoration of motor neuron excitability, and eventual restoration of volitional movement after incomplete SCI.
    Links:
    Public and Technical Abstracts: Intermittent Hypoxia Elicits Prolonged Restoration of Motor Function in Human SCI
    T5/6, ASIA A, injured 30 Nov 08
    Future SCI Alumnus.
    I don't want to dance in the rain, I want to soar above the storm.

    #2
    This needs a big update! SCI patients at Emory Univ in NY are indeed reaping physical benefits from intermittent hypoxic training and I include a link with video of this. I heard back from Aussie company who recently sold a specially made IHT equipment to US. I'm wondering if they sent it to Valeria Cavalli at Washington University. Kate here wrote about Cavalli at her blog curescience.wordpress.com. I'm waiting to hear back from Cavalli.

    http://www.hypoxico.com/about-altitude/

    Comment


      #3
      I believe the Emory University you're referring to is in Georgia rather than New York (Atlanta to be exact). There is a clinical trial currently underway at Emory utilizing hypoxia for SCI. Here is the LINK about that human clinical study.

      Valeria's lab work is in a petri dish rather than human studies and is working between peripheral nerve and central system to identify genes involved in hypoxia responses. Here's her most recent paper abstract. She has an axon regeneration lab that is at Washington University in St. Louis.

      "The primary goal of the Cavalli lab is to unravel the molecular events that dictate the regenerative response of neurons in the peripheral nervous system and to relate this information to the lack of regenerative capacity in the central nervous system. Our proposed research has a broad clinical impact, since axonal damage can occur in traumatic SCI, stroke and many other neurodegenerative diseases".

      This is her publication listing.

      This is the study taking place at Emory University in the video...




      Open Access: Daily intermittent hypoxia enhances walking after chronic spinal cord injury A randomized trial
      Last edited by GRAMMY; 11 Jan 2016, 10:25 PM.
      http://spinalcordresearchandadvocacy.wordpress.com/

      Comment


        #4
        Thanks, Grammy! Yes, it's the Emory School of Medicine doing the trial and it's very likely a therapy that'll help me move better. I wonder if other rehab places can do the trial. It doesn't make sense it's taken so many years to get to "experimental" study. -Jan

        Comment


          #5
          Originally posted by FellowHawkeye View Post
          Thanks, Grammy! Yes, it's the Emory School of Medicine doing the trial and it's very likely a therapy that'll help me move better. I wonder if other rehab places can do the trial. It doesn't make sense it's taken so many years to get to "experimental" study. -Jan
          They are also in the middle of an intermitten hypoxia trial where they are adding caffeine to the test subjects which are chronic incompletes. LINK
          There's also IH trials going on over in Chile. I did visit with two researchers just last month that had actually tried this IH themselves. They said it was not an easy session to get through at all. It doesn't look too bad, but they described it as quite uncomfortable.
          http://spinalcordresearchandadvocacy.wordpress.com/

          Comment


            #6
            Could This be evidence that hyperbaric oxygen therapy could actually help? Specially if combined with gait training

            Comment


              #7
              Originally posted by JamesMcM View Post
              Could This be evidence that hyperbaric oxygen therapy could actually help? Specially if combined with gait training
              I don't think so. The intermitten hypoxia treatment is entirely different than the hyperbaric oxygen therapy. Hypoxia is taking away the oxygen whereas the hyperbaric is adding it.. The way hypoxia was described, I wouldn't even take a chance on standing and doing some kind of gait training in conjunction.
              http://spinalcordresearchandadvocacy.wordpress.com/

              Comment


                #8
                hold your breath.

                Comment


                  #9
                  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.

                  Comment


                    #10
                    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.
                    It's the prolonged hypoxia that is damaging. The work being done in both animal and human trial are short bursts (intermittent). I'll be posting a video tonight on the SCI research blog with Dr. Jerry Silver where he goes into a lot of detail about this. Listen closely around 45:00 in the presentation to hear more about IH in both animal and human research results.
                    http://spinalcordresearchandadvocacy.wordpress.com/

                    Comment


                      #11
                      [double-post]
                      Last edited by Lacrossa; 30 Jan 2016, 9:00 PM.

                      Comment


                        #12
                        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; 30 Jan 2016, 9:04 PM. Reason: formatting

                        Comment


                          #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...

                          http://spinalcordresearchandadvocacy.wordpress.com/

                          Comment


                            #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!

                            Comment


                              #15
                              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

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