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At the Bench-Stroke Recovery
Inducing Spinal Plasticity Amplifies Benefits of Rehabilitative Training and Improves Stroke Recovery

ARTICLE IN BRIEF

In an animal model of stroke, researchers removed plasticity-inhibiting signals in the spinal cord (via intraspinal injections of the enzyme chondroitinase ABC), which augmented rewiring of circuits connecting the brain to the spinal cord, even weeks after stroke. The researchers proposed that this plasticity can be harnessed by rehabilitative training to significantly promote sensorimotor recovery.

A combination of spinal therapy and rehabilitative training resulted in improved recovery in rats, even 28 days after experimental stroke conditions were induced, according to a study published October 12 in The Journal of Neuroscience.

The investigators amplified spinal plasticity during chronic stroke in male rats via intraspinal injections of chondroitinase ABC (ChABC), an enzyme that has been found to remove plasticity-inhibiting signals in the brain. Injections into the contralesional grey matter of the cervical spinal cord administered 28 days after stroke resulted in significant sprouting of corticospinal axons originating in the peri-infarct cortex.

Without rehabilitative training, ChABC injection during chronic stroke led to moderate improvements of sensorimotor deficits, said Ian R. Winship, PhD, a study author and associate professor and director of the neurochemical research unit at the University of Alberta's department of psychiatry in Edmonton, Alberta in Canada. But combined with the spinal therapy, rehabilitative training during chronic stroke was much more effective.

“These data suggest that the permanent disability affecting millions of individuals living with the chronic effects of stroke may be treatable with spinal therapy and rehabilitation initiated even months or years after the stroke,” the study authors wrote. “Our data also emphasize that inducing a state of plasticity is not sufficient to induce recovery, and that combining such therapies with rehabilitative therapy is required for optimal recovery.”

After inducing initial ischemic injury in the rats via photothrombosis, investigators tested their hypothesis that promoting plasticity in the spinal cord during chronic stroke could spur advances in recovery from persistent sensorimotor impairment. Sprouting of spared corticospinal tract axons in the contralesional spinal cord has a major impact on sensorimotor recovery, they noted, but this structural plasticity is limited to the first few weeks after stroke.

“The major drawback of the current approach is that injection of the enzyme only extends a certain distance and acts for a finite period of time,” Dr. Winship said. “In a human, we need the enzyme to be active over a much larger region,” he said, because “the spinal cord is so much bigger in human than in a rat.”

“Our findings strongly suggest that such a treatment could reduce disability due to stroke. The next question is, what would actually be required to undertake this approach in humans?” Dr. Winship told Neurology Today.

He acknowledged that “probably a different delivery system would be required for humans. One solution may be to employ viral vectors, which present a way to genetically express the same enzyme in tissue rather than injecting it directly,” Dr. Winship said. “A viral delivery system would allow for longer expression and greater spread within the spinal cord, and therefore, could be safer and possibly effective in larger animals such as dogs as well as humans.”

“We can do very similar injection procedures without damaging the spinal cord, without inducing any kind of injury, but we would need a system like one of these vectors, if the drug is going to trying to strengthen the wiring between the brain and the spinal cord,” he said.

STUDY METHODOLOGY

To induce photothrombosis — an experimental stroke model in rats — the researchers located stereotaxic coordinates of the forelimb sensorimotor cortex corresponding to the preferred limb in skilled reaching tasks. They thinned the skull over the cortex and injected a sterile phosphate buffered saline in the tail veins of the rats. They then illuminated the cortex using a beam of green laser light. Sham-stroke controls underwent similar procedures without the photo illumination.

The researchers divided the rats into different experimental groups. The photothrombotic stroke group received a delayed spinal cord injection of ChABC enzyme or the control enzyme penicillinase (Pen), as did the sham-stroke group.

Twenty-four of the photothrombotic rats were injected with ChABC or Pen on post-stroke day 28 followed by either delayed high-intensity rehabilitative training in a forelimb-reaching task or delayed moderate intensity training. Finally, 16 photothrombotic rats received moderate reaching training that was initiated three days after stroke and continued until spinal injections of ChABC or Pen on day 28. Training restarted for an additional 28 days after injection.

At the conclusion, extracted brains were assigned a letter code to ensure that the investigator was blind to surgical and rehabilitative training groups.

Despite notable increases in the number, length, and distribution of corticospinal axons originating in the peri-infarct cortex and projecting to the cervical grey matter, there was only limited functional benefit of ChABC alone (without rehabilitative training).

Delayed rehabilitative training of moderate intensity was ineffective when paired with the control injection, but ChABC combined with training induced significant improvement.

Rats that underwent intense reaching training initiated after ChABC injection on day 28 showed major improvement, with the ChABC-treated animals again performing significantly better than controls.

To simulate what happens to stroke patients who plateau early after rehabilitation after the initial injury, the prothrombtic rats received moderate rehabilitative training starting three days after stroke and proceeding for eight weeks. Rehabilitative training efficacy plateaued by 28 days after stroke and was not significantly improved by the control injection, but rats exhibited amplified training-induced recovery after intraspinal ChABC at 28 days.

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DR. IAIN R. WINSHIP: “Our findings strongly suggest that such a treatment could reduce disability due to stroke. The next question is, what would actually be required to undertake this approach in humans?”

“Consistent with previous preclinical and clinical studies, our paradigm of extremely intense rehabilitative training (2,000 reaches per day) was associated with the best sensorimotor improvement,” the authors wrote.

“More moderate rehabilitative training (200 reaches per day) was effective when initiated early after stroke (with a plateau in recovery after two to three weeks), but provided less benefit when initiated 28 days after stroke. In all groups, rehabilitative training was improved by intraspinal ChABC at 28 days after stroke, suggesting that optimal rehabilitation can be attained by combining pro-plasticity therapy with training.”

EXPERT COMMENTARY

Several experts in neural plasticity commended the investigators for amplifying the functional benefit of delayed rehabilitative training after stroke, potentially prompting research that could improve recovery in stroke survivors with permanent disability.

“This study was well-performed and provides evidence that a sensitive period for neural plasticity can be reopened even in the early chronic phase using chondroitinase ABC injection to the contralesional spinal cord,” said Matthew A. Edwardson, MD, assistant professor in the departments of neurology and rehabilitation medicine at Georgetown University.

“The novelty of this study lies in that the chondroitinase ABC injections were beneficial even 28 days after stroke, which may correlate with the subacute-chronic phase after stroke in humans when treatment gains have plateaued,” Dr. Edwardson told Neurology Today. “It is also novel that additional reach training added to the beneficial effects of chondroitinase ABC injections.”

Challenging the animals to execute tasks that simulate humans' reaching and grasping functions as well as using the forepaws spontaneously for contact and support (in the cylinder test) contributed to the study's sound methodology and potential applications to humans, said Beth Fisher, PhD, PT, FAPTA, a professor in the division of biokinesiology and physical therapy and the department of neurology in the Keck School of Medicine at the University of Southern California.

The investigators evaluated multiple experimental groups of animals, which enabled them to examine the effects of using the drug alone, the drug along with rehabilitation delivered at different time points and various intensities, as well as the effectiveness of rehabilitation at different time points of drug administration, said Dr. Fisher, who is also director of the university's neuroplasticity and imaging laboratory.

“They did a very good job designing the experiment to address these questions as well as control for any possible confounding factors.” However, she added, “how quickly these results can be translated to humans with stroke is always a question.”

In humans, “the idea of injecting into the spinal cord following a stroke seems concerning given the risks of such a procedure,” which could lead to paralysis, said Steven C. Cramer, MD, FAAN, FAHA, professor in the departments of neurology, anatomy & neurobiology, and physical medicine and rehabilitation at the University of California, Irvine.

The study's findings could still be valuable if they trigger further research into stroke recovery interventions that either involve the spinal cord or have a broader aim, he added. Focusing on the spinal cord as a possible target to aid stroke recovery is novel and potentially useful, especially because so much research centers on the brain. The study highlights that “following a stroke in the brain — indeed in the cortex at the vertex of the brain — one can intervene at level of the spinal cord and achieve behavioral gains,” Dr. Cramer said.

In translating animal studies to humans, Dr. Edwardson suggested starting with severely affected patients to avoid the risk of losing function in those with some preserved use of the impaired limb. “A spinal injection is fairly invasive, but on the other hand, there are many patients actively enrolling in studies that inject stem cells into the central nervous system in the hopes of restoring function,” he said. Dissolved by chondroitinase ABC, chondroitin sulfate proteoglycans are believed to help solidify existing neural connections. In that sense, Dr. Edwardson added that injections into the spinal cord instead of the cortex seem less likely to harm existing desirable neural connections.

Weaknesses of the study stem from using a cortical stroke model in animals, whereas most human motor disability results from direct injury to the corticospinal tract from middle cerebral artery occlusion or subcortical strokes, Dr. Edwardson said. Testing the same paradigm in those areas, and at least 90 days after stroke in rodents, would be very helpful in evaluating whether a sensitive period can be reopened to simulate a post-stroke phase of greater than six months in humans. Because many chronic stroke survivors have been living with neurological damage for a while, he added that it remains unclear whether this large population would derive benefit.

Testing the efficacy of these treatments in larger animals is a possibility. “The [study's] effects are robust and should encourage these or other leading investigators to consider primate trials,” said Larry Benowitz, PhD, professor of neurosurgery and ophthalmology at Harvard Medical School and neurosurgical innovation and research endowed professor at Boston Children's Hospital. “Monkeys can be taught to use their fingers in very precise tasks, and there are several labs around the world that would be in a position to study the recovery of these skills after stroke or spinal cord injury.”

Dr. Fisher, also director of the Neurologic Physical Therapy Professional Education Consortium, viewed the new study in rats as a boon for rehabilitation experts who have been discouraged by the number of randomized controlled trials in arm recovery post-stroke bearing negative results.

“Recently, the question from therapists has become, ‘Can we really intervene in a way to help people recover?’ This study describes results that create excitement again about potentially achieving the kinds of outcomes we had hoped for.”

EXPERTS: ON PLASTICITY AFTER CHRONIC STROKE

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DR. MATTHEW A. EDWARDSON: “This study was well-performed and provides evidence that a sensitive period for neural plasticity can be reopened even in the early chronic phase using chondroitinase ABC injection to the contralesional spinal cord.”

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DR. STEVEN C. CRAMER said that in humans, the idea of injecting into the spinal cord following a stroke seems concerning given the risks of such a procedure, which could lead to paralysis. He added that the studys findings could still be valuable if they trigger further research into stroke recovery interventions that either involve the spinal cord or have a broader aim.

Figure

DR. BETH FISHER: “Recently, the question from therapists has become, ‘Can we really intervene in a way to help people recover?’ This study describes results that create excitement again about potentially achieving the kinds of outcomes we had hoped for.”

Figure

DR. LARRY BENOWITZ: “The [studys] effects are robust and should encourage these or other leading investigators to consider primate trials. Monkeys can be taught to use their fingers in very precise tasks, and there are several labs around the world that would be in a position to study the recovery of these skills after stroke or spinal cord injury.”

LINK UP FOR MORE INFORMATION:

• Wiersma AM, Fouad K, Winship IR. Enhancing spinal plasticity amplifies the benefits of rehabilitative training and improves recovery from stroke http://www.jneurosci.org/content/early/2017/10/12/JNEUROSCI.0770-17.2017. J Neurosci 2017: pii: 0770–17.