Rethinking Thought

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.

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.

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.

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.

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.

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.”

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