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.
References
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 sensory‐induced protection from ischemic stroke under isoflurane anesthesia. European
Journal of Neuroscience, in
press.
