A theory that Christopher Moore, PhD ‘98, kept under his hat for more than a decade could change the way neuroscientists understand the dynamics of perception.
Christopher Moore was teaching a group of doctors about
functional magnetic resonance imaging (fMRI) 13 years ago when it dawned on him
that he didn’t really believe what he was saying. A common brain-scanning
technique, fMRI allows doctors and researchers to see local changes in blood
flow, indicating where information processing is most active. Moore, who was at
MIT working on his PhD in neuroscience at the time, told the doctors that blood
was rushing to those areas to resupply hungry neurons with the oxygen and sugar
their work was consuming. But it seemed to Moore that metabolism alone couldn’t account
for the volume of blood showing up in the scans. “This makes no sense,” he
thought. “There must be something else going on beyond just metabolism.”
The more he pondered the fMRI signal, the more it seemed to
him that blood was not merely feeding neurons but directly helping neurons
process information. He wasn’t yet in a position to test his hypothesis, but he
knew that if he could prove it, it could change neuroscience. Now, new research
suggests that he may have been right.
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Because different regions of the brain are responsible for
different kinds of information processing, the sensitivity of their
circuitry–even the sensitivity of individual neurons–changes in response to new
stimuli. That’s what makes it possible for us to react to the world around
us–to come up with a witty riposte or hit a fastball, as the occasion demands. Moore thinks that
increases and decreases in blood flow contribute to these shifts in
sensitivity; that blood and neurons work hand in hand to produce perception and
cognition. Given that neuroscientists have always attributed information
processing to neurons alone, the notion that blood helps us think is radical.
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It also has practical implications. If Moore is right, many brain disorders might be
treatable in new ways. Drugs or devices that control blood flow, for instance,
could be used to control problems, such as epileptic seizures, that can result
when neurons become oversensitive.
To test whether blood modulates the sensitivity of neurons, Moore had to find a way
to experimentally alter blood flow within single small vessels of the brain in
living animals, and then to watch what happens in individual cells. Such fine
control over blood flow in the brain had never previously been achieved. But
this spring, Moore, an assistant professor in the Department of Brain and
Cognitive Sciences and a principal investigator at the McGovern Institute for
Brain Research, teamed up with assistant professor Edward Boyden, a neurotechnology
whiz in the Media Lab, to tackle the challenge. They’ve embarked on a series of
technically sophisticated experiments that are letting Moore test his 13-year-old hypothesis at
last.
More Than a Delivery Service
“The old-school view is, blood is the pizza delivery man,”
says Moore.
“It’s delivering food to the hardworking neurons, and then it leaves. It
doesn’t even say hello.” But the volume of blood flowing to active areas of the
brain far outstrips neurons’ metabolic needs: it’s bringing a large meat-lover’s
pizza when a slice of cheese would do. Blood flow in other parts of the body is
much less profligate; active muscles, for example, get only the blood they
need, and sometimes less (which explains that burning sensation in your quads
when you take a longer-than-usual run). “The rest of the body doesn’t have a
hyperflow of blood to an area,” says Moore.
“Only the brain does that.”
That’s why Kenneth Kwong, the father of fMRI, thinks Moore’s radical
hypothesis is plausible. Kwong, who is now a physicist at Harvard Medical
School, demonstrated in
1990 that fluctuations in blood flow as measured by fMRI are correlated with
the brain’s response to stimuli such as viewing a checkerboard pattern. Since
blood does feed neurons, neuroscientists assumed that the fluctuations occurred
in response to the neuronal activity. “A neuron fires first, then blood flow
changes,” Kwong says, summarizing that view. “Chris says, That’s true, but
maybe blood flow has a bigger role to play. Maybe it’s more than a passive reflector.”
After all, biological systems are often characterized by two-way feedback: if
one cell talks to another, the second cell typically talks back. Initially the
blood responds to the call of the neurons, feeding them the glucose and oxygen
they need. But Moore
believes that the neurons respond to the blood in turn.
In Moore’s
theory, called the hemo-neural hypothesis, “blood doesn’t direct the neuronal
circuitry,” Kwong says: it isn’t what kicks a neuron into gear in the first
place. But once the blood arrives, it might fine-tune the circuitry by changing
a neuron’s sensitivity from one second to the next, which in turn determines
its activity level. A relatively sensitive neuron will fire off a relatively
large number of electrical signals called action potentials–the basic unit of
communication in the brain–in response to stimulation by another neuron. This
cell-level activity is what makes a thought. If changes in blood flow cause a
neuron to fire more or fewer action potentials, then changes in blood flow
influence thought.
This fine-tuning might take place by chemical or mechanical
means. Brain tissue is interlaced with blood vessels that expand and shrink in
response to the contractions of the smooth muscle surrounding them, causing
blood volume to increase or decrease. This exerts physical pressure on neurons
and the cells, called glia, that support them. And of course, the blood itself
carries any number of chemical compounds beyond oxygen and glucose that might
affect neuronal sensitivity.
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Moore
believes that the hemo-neural hypothesis provides a more biologically
satisfying explanation for how the brain works, and one that fits better with
fMRI data. But the idea is new, so “people are having a hard time grokking
this,” he says. To him, it’s intuitive. It just seems right when he looks at a
microscope image of a neuron, its armlike extensions wrapped around a blood
vessel in a cellular embrace. It seems right when he watches fMRI scans
produced in his studies of sensory perception. But now he’s got to prove it in
the lab, to himself and to the neuroscience community.
Turning Up the Volume
The ebb and flow of neuronal activity and sensitivity in
different areas of the brain is called neural dynamics. The basic idea is simple:
different parts of the brain specialize in processing different types of
information. Depending on what you’re concentrating on at a given moment, some
neurons are very sensitive and others are merely on call.
“You might imagine there are conditions under which you want
[certain nerves] to be very sensitive–you’re just trying to detect a dot of
light or something barely touching your finger,” says Moore. In those situations, regions of the
brain responsible for vision or touch become more sensitive. In other
situations, heightened sensitivity is a disadvantage. “You’re at a cocktail
party and there’s lots of noise all around. The last thing you want to do is
amplify all that noise,” says Moore.
“What you really want to do is focus just on one person’s voice.” But when a
friend across the room starts calling out your name, you need to regroup and
amplify the noise again.
“Neural dynamics are what allow you to be inventive on a
moment-to-moment timescale, to see information and act on it,” explains Moore. You’d never be
able to stay asleep if you were as attuned to noises as you are when you ride a
bike or wait for an important phone call. But it’s crucial to be able to shift
back into a waking state in the morning–or when the fire alarm goes off in the
middle of the night. These shifts are accomplished as neurons in different
areas of the brain become more or less sensitive.
Moore
studies the neural dynamics of sensory perception, and one of his favored
subjects is the ebb and flow of electrical activity among a group of 60,000
neurons in the human cortex. This group processes touch sensations from the tip
of the left middle finger. Moore
put subjects inside a brain scanner called an MEG, which records electrical
activity, and tapped that finger with a mechanical actuator. Subjects were then
asked whether they felt anything.
Strangely, sometimes you will be conscious of having been
tapped on the finger, and sometimes you won’t–even though the force and timing
of the tap are identical. Moore
has shown that the difference depends on the electrical activity of the 60,000
fingertip neurons a fraction of a second before the tap occurs. Certain
patterns predict sensitivity to the tap, while others are associated with
failure to notice it.
What is the source of these differences in sensitivity? That
isn’t completely understood, but they’re known not to be random. Moore believes that an
increase or decrease in blood flow to the dedicated fingertip neurons might
function as a sensitivity dimmer switch that determines whether you feel a tap.
That situation is a very simple one–a model system that’s easy to study in the
lab–but similar dynamics govern all our thinking and perception.
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Testing the hypothesis
Moore
has been thinking about the role of blood in the brain for a long time. But, he
says, “I didn’t even want to talk about it until I could test it.” As a grad
student working in others’ labs, he was committed to research already under
way. And even once he got his own lab, launching the project was no simple
matter. “Frankly,” he says, “the main thing that held me back was, I couldn’t
come up with an answer to the question ‘How do you independently manipulate the
blood flow?’” Working with a dish of cells wasn’t an option; he had to do his
experiments in living, thinking animals.
The neural dynamics of complex human behaviors such as
conducting a conversation or hitting a fastball are governed by cell-level
processes like those revealed by the finger tap experiment. But complex
behaviors emerge from activity in many different parts of the brain, which
makes them more difficult to study in the lab. And even during a simple
experiment like the finger tap, you can’t open up a healthy person’s brain and
probe individual neurons. So Moore
does most of his studies in rats–“model systems where we can actually do the
down-and-dirty details,” he says.
Moore
has done some preliminary tests of the hemo-neural hypothesis by applying a
drug called pinacidil, which increases blood flow, to rats’ brains; he
presented the results at a conference a few years ago. But this approach is
sloppy. It’s very difficult to limit the application of pinacidil, a chemical
like the one found in Rogaine, to a small group of blood vessels and cells. Moore knew that the
behavior of single cells determines neural dynamics, and he needed a way to
control blood flow at a much finer level.
This spring, Moore and the Media Lab’s Boyden began working
out a way to regulate blood flow in very small regions of the brain. Through a
feat of genetic engineering, Boyden had already developed a method for altering
neurons in living animals so that they can be electrically activated and
deactivated by blue and yellow laser light. He uses a virus to insert into
neurons a gene that codes for an altered version of a protein from
light-activated cells in the retina (see “The TR35,” September/October 2006).
In collaboration with Moore,
Boyden has developed a way to apply the technique he used in neurons to the
smooth-muscle cells that surround blood vessels in rats’ brains. Once the
muscle cells are modified, the vessels should dilate and contract in response
to light, letting more or less blood through. “For the experimental question,
it’s a fantastic invention,” Moore
says of Boyden’s work. “Now instead of the brain controlling it, I hope to
control local blood flow with a laser.”
Through a glass window implanted in an opening in the rats’
skulls, Moore and Boyden can shine laser light onto a few tiny blood vessels at
a time. And by inserting an electrode into the brain, Moore can monitor the electrical activity of
individual neurons as he turns blood flow up and down in the vessels they
border. “Now I can test what happens if I turn up this faucet and turn down
that one,” he says. “What happens to the neurons right next to it?”
He’s looking for evidence that blood flow is fine-tuning
neuronal activity: “Are they firing ten spikes now when they used to fire five?
Or are they firing two spikes where they used to fire five?” Either case would
suggest that blood flow could play a role in neural dynamics. The work is
unpublished and is in its early stages, so Moore won’t disclose what he has seen. But he
will say that he thinks the preliminary results provide evidence of a
regulatory role for blood.
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Figuring out what happens to individual neurons when blood
flow is altered involves considerable technical finesse. Moore and Boyden are
now building a fiber-optic system that will enable them to shine laser light
into the brains of rats inside an fMRI machine, so they can observe what
happens to the entire brain when they manipulate blood flow. They’re also
imaging individual neurons.
“Every step has been solved, but putting them
together”–fiber optics, fMRI, microscopy, electrode readings–“is going to be a
technical challenge,” says Moore.
If Moore and Boyden’s work on optically controlled
smooth-muscle cells succeeds, it could have much broader implications than just
illuminating the role of blood in the brain. If blood flow does contribute to
epileptic seizures, it might be possible to develop an implant that uses laser
light to control them.
“You never know the reality of these things when they get
beyond the bench, but this is about the most promising research I’ve been
associated with,” says Moore.
“This is really cool stuff. It’s a fun time to be in the lab, because any day
you could learn something entirely new.”