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Investigators reported that stimulating a rat's whiskers after inducing stroke completely prevented brain damage.
DR. JAMES GROTTA: “The recruitment of collateral flow is certainly logical, the question is how do you do it. I don't believe the paramedic just rubbing someone's hand is going to do it. You'd have to design a study to test it. Acute stimulation has never been tried clinically. It's not outside the realm of possibility, but it's not something you are going to just run out and do.”
Imagine this: Two rats lie anesthetized on a lab bench. A researcher completely occludes the middle cerebral artery (MCA) in each. An hour later, he touches a single whisker on one of the rats, and continues to do so on an off for the next two hours. He lets the other lie undisturbed. The next day, the rat that was left alone shows all the signs of having suffered a massive stroke. The rat that got touched, on the other hand, is completely normal — its movements are unimpaired, and, when sacrificed, its brain is indistinguishable from a healthy brain; indeed, it is a healthy brain. Despite permanent blockage of one its major blood vessels, there was no stroke.
This complete and unexpected protection appears to be the effect of recruiting collateral vessels to supply blood to the occluded area. There are several strong caveats to extrapolating the results to human stroke victims, but both the study authors and independent researchers suggest that little stands in the way of exploring the effect in humans.
The discovery “is a story of failure,” said senior researcher Ron Frostig, PhD, professor of neurobiology and behavior at the University of California-Irvine, with a laugh. Dr. Frostig, whose lab is devoted to basic research on cortical plasticity, added: “We decided to do something more relevant clinically, so we wanted to study plasticity after stroke.”
The plasticity work involved observing cortical changes following whisker stimulation, so they continued with that protocol, stimulating the whisker at baseline and immediately following occlusion. “But we never got the stroke to begin with, and we didn't understand why. It drove us crazy!” he said. “We slowly realized it is the stimulation itself” that was protecting the rats.
To formally explore the phenomenon, Dr. Frostig compared rats receiving stimulation at zero, one, two, or three hours after occlusion to unstimulated rats. With no stimulation, infarct volume was 20 cubic millimeters. Stimulation at either zero or one hour offered complete protection, with no detectable infarct.
“If you stimulate at the right time, you get full protection, absolutely full structural and functional protection. I've been looking at these images for 20 years, and I cannot tell you an MCA occlusion has happened,” Dr. Frostig said.
Protection from stimulation at 2 hours was incomplete, and if it was delayed until 3 hours, the damage was worse than no stimulation at all.
INVESTIGATORS COMPARED rats receiving stimulation at zero, one, two, or three hours after occlusion to unstimulated rats. With no stimulation, infarct volume was 20 cubic millimeters. Stimulation at either zero or one hour offered complete protection, with no detectable infarct.
Whiskers are vital sensory organs for the tunnel-dwelling rat, and the rat cortex devotes as much neural real estate to their input as to that from the forepaw. Within milliseconds of their arrival at the cortex, stimulatory signals from a single whisker spread out across the cortical surface, causing a subthreshold activation in a large portion of the cortex.
It is thought that subthreshold activation stimulates increased blood flow to the activated area. “We believe the region protected is this late stimulated area,” he said, though further experiments will be needed to confirm that. The reason the cortex suffers more damage from stimulation three hours post-occlusion than from no stimulation at all is unknown, but may be connected to this same activation phenomenon.
The source of the blood is almost certainly collateral circulation, Dr. Frostig said. The distal branches of the MCA sometimes connect to other arteries, forming collateral vessels, a phenomenon seen in both rats and humans. When he blocked the distal branches of the MCA as well, the protective effect of stimulation was lost. Although proof that collateral circulation is the only explanation will require further experiments, “unless there are hidden reserves of oxygen somewhere no one has imagined, this is the simplest explanation.”
More work remains to test the potential of the technique. Dr. Frostig has already shown it works just as well in aged rats as in young ones, data he presented at the Society for Neuroscience annual meeting in San Diego in November. He is now studying whether the same effect occurs without anesthesia.
DR. DAVID KLEINFELD said the difference between the anesthetized and awake states is potentially important, noting that anesthesia causes both vessel dilation and a profound silencing of background activity in the cortex.
The difference between the anesthetized and awake states is potentially important, according David Kleinfeld, PhD, professor of physics and neurobiology at the University of California-San Diego. He noted that anesthesia causes both vessel dilation and a profound silencing of background activity in the cortex. “The system may have been much more poised to jump,” he said, versus the awake state.
Nonetheless, the effect Dr. Frostig has shown is “kind of amazing.” Dr. Frostig, he said, “is an interesting guy, who has a history of a couple of papers that really went against the status quo. He just finds things that other people don't find, and maybe in the stroke world, he found something really very special.”
“I think it's certainly a provocative finding,” said Tim Murphy, PhD, professor of psychiatry and cellular and physiological sciences at the University of British Columbia in Vancouver. “I don't know of anything like this that involves just a rehab-type intervention. This is completely out of the blue.”
Redistributing flow has been considered before, but the attempts have involved more dramatic interventions, such as stopping flow to the limbs. In contrast, he said, “Dr. Frostig's method is kind of mild. No one would have ever thought that would be enough to block the effects of a permanent occlusion.”
One factor that may be involved in its success is that the relationship between stroke damage and blood flow is not a linear one. “There could be thresholds,” Dr. Murphy said. “They many not need to restore all the flow; they may only need to restore 10 percent to get this chunk of cortex out of the woods. Even small changes in perfusion, on the cusp, could be critical.”
DR. TIM MURPHY: “I think it's certainly a provocative finding. I don't know of anything like this that involves just a rehab-type intervention. This is completely out of the blue.”
As for whether a trial in humans would be feasible, Dr. Murphy was optimistic. “It is something that really could be done.” But, he added, it would be important to determine where the stroke was through neurological signs or diagnostic imaging, in order to determine the best type of stimulation.
“The recruitment of collateral flow is certainly logical, the question is how do you do it,” said James Grotta, MD, chair of neurology at the University of Texas Medical School in Houston, and director of the Stroke Program at Memorial Hermann-Texas Medical Center. “I don't believe the paramedic just rubbing someone's hand is going to do it. You'd have to design a study to test it. Acute stimulation has never been tried clinically. It's not outside the realm of possibility, but it's not something you are going to just run out and do.”
“It's also not a given that this would be a clinical success, he said. “Many things work in rodents and not in humans.” To proceed, he said, the result would needs to be duplicated in other laboratories, and in other animal species, in order to demonstrate consistency and robustness in the results. “That would be the first step.”
Dr. Frostig commented, “One has to be very cautious, but if it is applicable to humans, the beauty of it in my mind is that long before an ambulance arrives, you may be able to help people. There is no drug, no special equipment. It's so darn simple!”