Wednesday, June 26, 2013

Rescuing the brain after a stroke

Neurons in the brain, like any other cell in our body, require oxygen to live.  They get this oxygen from the blood vessels that run nearby.  When there is a stroke, the cause is often a particle that has gotten stuck in a branch of an artery, blocking the flow of blood, producing ischemia. This loss of oxygen starts a cascade of events that culminate in the death of the neurons that live nearby.   In the last 3 years, there have been a couple of remarkable papers from a small laboratory in University of California Irvine that suggest a new and non-invasive way to fight this plumbing problem.

The connection between neurons and blood vessels

When someone touches your arm, the neurons in the arm area of your somatosensory cortex become highly active, producing what are called action potentials.  Action potentials are the only mechanism that neurons have to communicate with each other.  Generating an action potential requires energy, and this energy is supplied via the nutrients and oxygen that are carried by nearby blood vessels.  When neurons generate action potentials, support cells that monitor the neurons send signals to the cells that line the blood vessels, causing the vessels to locally enlarge.  This enlargement produces an increase in the blood volume and arrival of a greater amount of food and oxygen.   Indeed, this fact is the basis of a form of functional magnetic resonance imaging (fMRI) in which blood oxygenation levels are imaged and act as a proxy for activity in the nearby neurons.  So the neurons are in close contact with the vessels, and the vessels are the gardeners that provide the neurons with nutrients precisely when they need it.

Activating neurons in the hour after a stroke

When a blood vessel is blocked, the cells in the vicinity are deprived of their oxygen.  But blood vessels are not like branches on a tree where there is only one way to get to a spot.  Rather, they are a little like the highway system: there are multiple ways to get to a spot.  This is important because blocking a branch of an artery need not be catastrophic if a healthy branch could enlarge and supply some of the nutrients that are needed by the cells near the blocked branch of the artery.  But how can this be done?

In 2010, Christopher Lay and colleagues at University of California Irvine reported the results of an experiment that did just that, find a simple way to alert the healthy blood vessels to compensate for the blocked one.  In Lay et al. (2010), the authors first took a group of rats, anesthetized them, and then gave them a stroke in the base of the proximal middle cerebral artery (MCA).  They did this by tying a suture around a branch of MCA that supplies blood to the area of the rat’s somatosensory cortex which encodes sensory information from its whiskers.  This stopped the blood flow to that region, causing ischemia, and produced brain damage (called an infarct).  The next day, the rats were impaired in their ability to use their whiskers, and the somatosensory cortex showed clear signs of neural damage. 

They next took another group of rats and also gave them an MCA stroke, but rather than just letting them lie there, during the hour after the stroke they kept touching and moving their whisker (1sec of 5Hz deflections of a single whisker, once every 20 seconds).  Twenty four hours after the stroke, they tested the stimulated rats and found that the damage to the neural tissue was much less than in the non-stimulated rats.  Behavior, imaging, and neurophysiological investigation of the stimulated rats showed that by all measures touching the whisker seemed to have made a very significant difference.  

This positive effect happened only if the whisker was touched in the one hour or so after the stroke.  If the same touching was done at 3 hours, the effect was to worsen the stroke.  So there was a critical one hour time window after a stroke in which touching the body part (and presumably activating the neurons that reside in the affected cortex) seemed to dramatically reduce the damage normally caused by the stroke.  Stimulating the neurons in the stroke affected region seemed to provide them with a pathway to survival.

How could this have happened?  Further testing showed that blood reperfusion to the affected tissue was established via collateral flow from distal branches of the MCA (Lay et al. 2010). This reperfusion started at stimulation onset, and then grew gradually, reaching near normal levels at around 1.5 hours (Lay et al. 2011).  The reperfusion was absent in the non-stimulated animals.  It is possible that stimulating the whiskers immediately after the stroke had signaled a much larger blood vessel network than the nearby, blocked vessel.  In a control experiment, if a larger network of vessels was also blocked, then the stimulation made no difference.

One problem with these studies is that the rats were fairly young (in human terms, in their 20s).  People at that age do not usually have a stroke, and the brain is generally more plastic and forgiving at an early age.  So Lay and colleagues repeated their experiment in elderly rats, equivalent to around 60 year old humans (Lay et al. 2012).  They found that the stimulated elderly rats suffered an infarct that was much smaller than their control rats.  Stimulation was effective in the elderly as well as young.

Another problem with these studies is that the rats were anesthetized during the stroke and during the stimulation.  Of course, people are usually awake when they have a stroke.  Did the anesthesia play a critical role in the unusual success of the stimulation?  In a further study, the authors tried a new anesthetic that allowed them to occlude the MCA under anesthesia, but once that surgical procedure was completed and anesthesia removed, the animal could return to an awake state within minutes (Lay et al. 2013).  During this awake state they stimulated the whiskers and found recovery data similar to their previous results on deeply anesthetized animals.  The stimulation, and not the anesthesia, seemed to be the key factor.

These results are all from one laboratory, and need to be confirmed by other labs.  However, the results are tantalizing, as they suggest a stimulation based, non-invasive strategy during a critical period after stroke that may rescue the brain.

Lay, C. C., Davis, M. F., Chen-Bee, C. H., & Frostig, R. D. (2010). Mild sensory stimulation completely protects the adult rodent cortex from ischemic stroke. PloS one, 5(6), e11270.
Lay, C. C., Davis, M. F., Chen-Bee, C. H., & Frostig, R. D. (2011). Mild sensory stimulation reestablishes cortical function during the acute phase of ischemia. The Journal of Neuroscience, 31(32), 11495-11504.
Lay, C. C., Jacobs, N., Hancock, A. M., Zhou, Y., & Frostig, R. D. (2013). Early stimulation treatment provides complete sensoryinduced protection from ischemic stroke under isoflurane anesthesia. European Journal of Neuroscience, in press.

Tuesday, June 4, 2013


In the movie "Promised Land", there is a scene in which the main character, a corporate type, has been sent from New York to a small farming town to lease the land for gas drilling (played by Matt Damon).  After he arrives in town, he puts on his boots to go visit a farmer and make his proposition.  The boots are old, and not much to look at, but they are something that he has owned since his early days in a small town in Iowa.  In more ways than one, the boots are the only authentic thing about him.
It made me think of my old boots.  When I was 14, my first winter in America was approaching, and my American mom took me to the store to get some winter boots.  She, being a gentle soul, let me choose the one that I liked.  When my American dad saw them, he said that they were fine work boots, but they had no insulation and would not really do for the winter.  They were about ready to take them back, but I hemmed and hawed and said that I liked them and would be fine with them in the snow.  And so they let me keep them.

And indeed we were fine together.  With some bees wax, I made them waterproof and then took them on my little adventures: a week long hiking trip through the North Cascade Wilderness (where a bear tried to tear down the bag of food that we had hung from a tree), bucking bales on a hay farm (where I lasted only a single day, as the bales were 60+ pounds and I weighed barely twice as much), and oh so many fishing trips (where despite the loads of fish, we fried hot dogs for dinner).

This afternoon, after coming home from lab, I went down to the basement, pulled the boots out of the shoe rack, and put them on to do some lawn edging.  They are as comfortable as a pair of slippers, though aged a bit.  They are the oldest thing that I own, and still use.