by 
When investigators in the Stanford University School of Medicine applied light-driven stimulation to nerve cells within the brains of mice which had suffered strokes a few days earlier, the mice showed significantly greater recovery in motor ability than mice which had experienced strokes but whose brains weren’t stimulated.
These findings, which will be published online Aug. 18 in Proceedings of the National Academy of Sciences, may help identify important brain circuits involved with stroke recovery and usher in new clinical therapies for stroke, including the keeping electrical brain-stimulating devices similar to those employed for treating Parkinson’s disease, chronic pain and epilepsy. The findings also highlight the neuroscientific strides made possible by a powerful research technique known as optogenetics.
Stroke, with 15 million new victims per year worldwide, is the planet’s second-largest cause of death, based on Gary Steinberg, MD, PhD, professor and chair of neurosurgery and the study’s senior author. In the usa, stroke is the largest single cause of neurologic disability, comprising about 800,000 new cases every year – several each minute – and exacting an annual tab of approximately $75 billion in medical costs and lost productivity.
The only approved drug for stroke in the usa is an injectable medication called tissue plasminogen activator, or tPA. If infused within a few hours from the stroke, tPA can limit the extent of stroke damage. But a maximum of 5 percent of patients actually benefit from it, largely because when they arrive at a medical center the harm is already done. No pharmacological therapy has been shown to enhance recovery from stroke in the future.
But within this study – the first one to make use of a light-driven stimulation technology called optogenetics to enhance stroke recovery in mice – the stimulations promoted recovery even when initiated five days after stroke occurred.
“Within this study, we discovered that direct stimulation of the particular group of nerve cells within the brain – nerve cells in the motor cortex – was able to substantially enhance recovery,” said Steinberg, the Bernard and Ronni Lacroute-William Randolph Hearst Professor in Neurosurgery and Neurosciences.
About seven of every eight strokes are ischemic: They occur when a blood clot reduces oxygen flow to 1 or any other part of the brain, destroying tissue and leaving weakness, paralysis and sensory, cognitive and speech deficits in its wake. While some amount of recovery can be done – this varies greatly among patients based on many factors, notably age – it’s seldom complete, and typically grinds to a halt by three months following the stroke has occurred.
Animal research has indicated that electrical stimulation of the brain can improve recovery from stroke. However, “existing brain-stimulation techniques activate all cell types in the stimulation area, which not just causes it to be difficult to study but could cause unwanted side effects,” said the study’s lead author, Michelle Cheng, PhD, a study associate in Steinberg’s lab.
For the new study, the Stanford investigators deployed optogenetics, a technology pioneered by co-author Karl Deisseroth, MD, PhD, professor of psychiatry and behavioral sciences and of bioengineering. Optogenetics involves expressing a light-sensitive protein in specially targeted cognitive abilities. Upon exposure to light of the right wavelength, this light-sensitive protein is activated and results in the cell to fire.
Steinberg’s team selectively expressed this protein within the brain’s primary motor cortex, that is involved with regulating motor functions. Nerve cells within this cortical layer send outputs with other brain regions, including its counterpart within the brain’s opposite hemisphere. Using an optical fiber implanted for the reason that region, they could stimulate the main motor cortex near where the stroke had occurred, and then monitor biochemical changes and blood flow there plus other brain areas with which this region was at communication. “We wanted to find out whether activating these nerve cells alone can contribute to recovery,” Steinberg said.
By several behavioral, blood flow and biochemical measures, the answer fourteen days later was a strong yes. On one test of motor coordination, balance and muscular strength, the mice had to walk the length of a horizontal beam rotating on its axis, just like a rotisserie spit. Stroke-impaired mice whose primary motor cortex was optogenetically stimulated did significantly better in what lengths they might walk along the beam without falling off as well as in the rate of their transit, in contrast to their unstimulated counterparts.
The same treatment, applied to mice which had not a break down stroke but whose brains had been similarly genetically altered after which stimulated just as stroke-affected mice’s brains were, didn’t have effect on either the length they traveled across the rotating beam before falling off or how quickly they walked. This means it was stimulation-induced repair of stroke damage, not the stimulation itself, yielding the improved motor ability.
Stroke-affected mice whose brains were optogenetically stimulated also regained substantially more of their lost weight than unstimulated, stroke-affected mice. Furthermore, stimulated post-stroke mice showed enhanced blood circulation in their brain in contrast to unstimulated post-stroke mice.
In addition, substances called growth factors, produced naturally in the brain, were more abundant in key regions on sides of the brain in optogenetically stimulated, stroke-affected mice compared to their unstimulated counterparts. Likewise, certain brain parts of these optogenetically stimulated, post-stroke mice showed increased levels of proteins related to heightened ability of nerve cells to change their structural features in reaction to experience – for example, practice and learning. (Optogenetic stimulation from the brains of non-stroke mice produced no such effects.)
Steinberg said his lab is following up to see whether the improvement is sustained in the long run. “We’re also seeking to see if optogenetically stimulating other brain regions after a stroke might be equally or more effective,” he explained. “The aim would be to find out the precise circuits that would be most amenable to interventions within the mind, post-stroke, to ensure that we can take this approach into clinical trials.”
