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The latest news and information about what's going on with SCI science and research. Brought to you by Sam Maddox, author of the Christopher & Dana Reeve Foundation Paralysis Resource Guide.

Low Oxygen Treatment Boosts Walking In Incomplete SCI

It was hard to miss this recent research report: the news media were all over it. A short and simple low oxygen environment appeared to help people with spinal cord injury regain mobility.

Note: I reported on therapeutic hypoxia in early 2012, looking at the animal research that makes human trials possible.

It may not make sense that lack of life-giving oxygen would produce a beneficial neurological result. But a paper from a group at Emory University in Atlanta, “Daily intermittent hypoxia enhances walking after chronic spinal cord injury: A randomized trial,” published a few days ago in the journal Neurology, a shows that there may be promise in this concept.

It’s important to note that the all but two people in this trial of 19 patients were ASIA Ds – that means they had very incomplete injuries and could already initiate walking on their own. But the paper shows that the intermittent O2 treatment quite effectively boosted their speed and endurance.

Lead researcher Randy Trumbower worked with incomplete injuries because he figured there were lingering spinal cord connections that might be strengthened beyond what physical therapy is able to do. He found evidence from the Gordon Mitchell lab at the University of Wisconsin that interrupted breathing during episodes of sleep apnea triggered the release of the neuerotransmitter serotonin, which then turned on production of BDNF (brain-derived neurotrophin factor). BDNF is important for forming nerve connections.

Note: Trumbower worked with a team including Zev Rymer from the Rehab Institute of Chicago and Gordon Mitchell at the University of Wisconsin. The Mitchell lab's hypoxia work was supported by way of a Reeve research grant to post-doc Frances Golder in 2003.

So, Trumbower set out to see if controlled hypoxia might allow controlled release of BDNF -- perhaps to reboot an injured spine. He told a reporter the idea was to alternate breathing air at its full 21 percent oxygen and then at 9 percent. That’s like going from sea level to the top of 20,000-foot Mt. McKinley. "You're continuously alternating between the summit and base camp," he said.

Photo: Mt. McKinley

Trumbower and his group split 19 people with injuries between levels C2 and T12 into two groups; nine were exposed to hypoxia -- short periods of breathing low oxygen through a mask for 90 seconds, followed by 60 seconds of normal oxygen. They did this 40 minutes a day for five days. The other group got a sham treatment (control) in which they received only normal oxygen levels. After 2 weeks, the two groups crossed over; the treatment group got the sham oxygen and the sham group got the hypoxia.

Neither group was aware of the oxygen content; hypoxia did not cause discomfort because exposure was short.

At the end of the five days, the participants who received low-oxygen treatment walked a 10-metre course an average of 3.8 seconds faster than those who breathed normal oxygen levels. They not only walked faster but also farther – averaging an extra 100 meters during a 6 minute walk – that’s a 250 percent increase, compared with those who received sham treatment plus walking.

From the paper:
Daily acute intermittent hypoxia (dAIH) plus walking improved walking speed and distance in persons with chronic incomplete SCI [iSCI]. The impact of dAIH is enhanced by combination with walking, demonstrating that combinatorial therapies may promote greater functional benefits in persons with iSCI.

The scientists were surprised how robust the recovery was, considering how small the intervention was, and considering how modest recovery usually is in walking therapies.
Contemporary walking therapies for persons with iSCI are typically 4 to 12 weeks in duration, but effect sizes and clinically meaningful improvements are limited. A recent study examined the effects of 4 types of walking therapy applied for 60 sessions (12 weeks), all showing small to moderate effect sizes. The most effective, overground walking training, improved walking speed by 0.09 m/s and endurance by 14.2 m.

In comparison, dAIH achieved nearly double the effect size for speed and equivalent for endurance, while the combination of dAIH walking achieved more than double the effect size for speed and endurance. dAIH walking resulted in increased walking speed of 0.09 m/s and endurance of 100 m, which are comparable to or greater than those seen with much longer training studies.
....More than 30 percent of all subjects achieved a clinically meaningful change in walking speed (0.13 m/s) and more than 70 percent achieved a clinically meaningful change in walking endurance (50 m).

So how does oxygen deprivation over short bursts of time affect mobility? The Trumbower team says intermittent hypoxia may be a “plasticity-promoting primer, when coupled with task-specific training to bolster training outcomes.”
....dAIH may elicit improved walking ability in humans with iSCI via a serotonin- and BDNF-dependent mechanism similar to that shown in rats. .... Available evidence suggests that AIH-induced recovery of breathing and walking function after spinal injury is a result of increased synaptic strength and/or motor excitability.
So, is it respiratory recovery or more than that? Trumbower says more: while respiratory plasticity may partially contribute to improved walking endurance by increasing cardiorespiratory reserve, “it is likely accompanied by changes in somatic motor areas more closely related to locomotor control.”
Serotonin and BDNF have been linked to spinal locomotor recovery after SCI, consistent with the hypothesis that dAIH elicits walking improvements in persons with iSCI through similar mechanisms. In animal models, BDNF is more effective when combined with locomotor training and its benefits are primarily seen on the trained task.

Scientist-neurosurgeon Michael G. Fehlings, of the University of Toronto (whose neuroscience research is partly funded by the Reeve Foundation), wrote an editorial to accompany the Trumbower manuscript. His title tells you that he thinks Trumbower may be on to something: “Hypoxic locomotor rehabilitation for incomplete spinal cord injury: Not an oxymoron.”

"It may seem a little counterintuitive, but these findings make very good sense," said Fehlings. "Because hypoxia acts as a stress to the nervous system, it can elicit a beneficial response if controlled correctly."

He has a few questions, including, will the treatment benefit people with more severe spinal cord trauma, those who walk unassisted?

From Fehlings’ editorial”
The unique nature of the protocol raises several questions. How does a treatment that requires individuals to inhale low concentrations of oxygen really help locomotor function, let alone in those with compromised respiratory and motor capacity? Plausible mechanisms were addressed previously in translational work.

In rat models, acute hypoxic episodes enhance respiratory and forelimb motor capacities in association with spinal plasticity below the level of lesion. The signatures of plasticity include greater expression of trophic proteins in the phrenic motor neurons (C4, diaphragmatic muscles) and in those supplying forelimb muscles (C7). The trigger may be hypoxia-induced release of spinal serotonin, which sets off a cellular cascade enhancing changes in proteins subserving respiratory and motor plasticity. Other unexplored mechanisms could include induction of the hypoxia-inducible factor - vascular endothelial growth factor (HIF-VEGF) signaling cascade, known to be triggered by hypoxia, which influences posttraumatic neural repair and plasticity.

Another obvious question is whether the technique is safe and clinically feasible. Trumbower and his team emphasize that acute rather than chronic hypoxia "was associated with no clinical signs of respiratory or cardiac distress or emergent paroxysmal autonomic response (dysreflexia) that can occur in individuals with lesions above T6."

The effects from of intermittent hypoxia did not last for more than two weeks. Still, Trumbower hopes longer treatment regimens will produce lasting effects. "Our hope is that this therapy can be used for months, not just days, and enhance the improvements of physical therapy."
Posted by Sam Maddox on Nov 29, 2013 9:52 PM America/New_York