Neuroscience—The imaging edge

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A variety of visualization techniques give neuroscientists new views of cells, synapses, and even broad networks in the brain. Even more exciting, noninvasive approaches help biologists view the human brain at work. As described here, these advances create opportunities for neurobiologists as well as physicists and chemists.

The concept of imaging covers more ground than many students of neuroscience might think. P. Read Montague, professor of neuroscience at Baylor College of Medicine, says, “In a sense, every measurement that you make in neuroscience—electrophysiological, optical, gene expression, and so on—is imaging. It’s just making some image of a physical problem at work.” And the work of imaging keeps taking big, new steps in studying how the nervous systems work in animals and humans.

That wide definition of imaging covers many techniques. Michael F. Huerta, associate director of the division of neuroscience and basic behavioral science at the National Institute of Mental Health, points out a broad spectrum of the advancing areas of imaging in neuroscience. “At the very microscopic level,” he says, “we have developed techniques like two-photon microscopy, which allows extremely detailed examinations of structures and processes within cells.” Huerta also calls attention to fluorescent resonance energy transfer, which he says, “really allowed us to start imaging processes in cells as they occur.” At the broader end of imaging, Huerta sees increasing value in positron emission tomography (PET) and functional magnetic resonance imaging (MRI), or fMRI. He says, “These techniques give us the ability to look in on the intact, functioning human brain—in some cases in very noninvasive ways.” Consequently, modern imaging views neuroscience from cells to systems.

Zooming in

More than simply seeing structures, neuroscientists want to watch the action. At the synapse, where two neurons meet, Montague says, “It takes very sophisticated fluorophores to mark pathways inside and outside of the cells.” By creating such markers, though, neuroscientists can actually make movies of synapses at work. In addition, Montague points out that such marking can be done in vivo, so that a synapse can be labeled and then observed over weeks in an animal. These advances and many more change the questions that neuroscientists can ask, and make room for new investigators.

For example, getting a better view of the mechanics of the human nervous system plays a fundamental role in pharmaceuticals. More than ever, a neuroscientist can see—in a way—how and where a drug might work. For one thing, if an investigator has a hypothesis that a specific CNS system may be involved in a neurobiological disease and designs a drug to target those pathways, then it is essential to ensure that sufficient drug reaches its intended sites of action to adequately test the treatment concept . So-called receptor occupancy studies measure just that. Richard Hargreaves, executive director of imaging at Merck Research Laboratories, says, “Nuclear imaging using radiotracers gives the opportunity to put your arms around proof-of-concept very early in a drug discovery and development program by focusing the selection of doses to study on those proven to deliver enough drug to the target therapeutic sites.”

If a drug doesn’t get to its target in adequate amounts, the drug won’t work, but then you can’t tell if it’s the molecule or the concept that’s flawed. With neuroimaging, a neuroscientist can watch a drug’s interaction with its receptor and judge its probability of success long before embarking on expensive late phase clinical trials. “In any CNS drug discovery program,” Hargreaves says, “occupancy studies form a very early part of research. You develop a radio tracer alongside the drug. That takes an investment, but—to me—it provides a great benefit because it helps you say ‘no’ to a drug before investing even more.”

Skills to build

With imaging carving out such a central role in neuroscience, budding investigators might wonder just how much imaging they need to know. For example, does a future neuroscientist need only the knowledge to use imaging techniques or the ability to create them? Montague says, “Those are really separate career paths. Some people want to gear up the technology itself. Others just want to use it, and the equipment is easy enough to use that any scientist can think up things to do with it.”

On the development side of imaging, opportunities open up for nonbiologists. “The appreciation of chemistry often gets overlooked in imaging research,” says Hargreaves. “You always need to design new tracers that can be imaged to reveal drug targets .” Beyond chemistry, Hargreaves also indicates the value of mathematics. “The images are just numbers,” he says, “and the numbers come from math. You need the very best mathematicians to analyze and reconstruct the data.” He adds, “There’s an enormous demand in neuroscience imaging, all over the world, for mathematical modelers.”

Paul Matthews, director of the Centre for Functional Magnetic Resonance Imaging of the Brain at University of Oxford, also sees lots of opportunities for skills beyond biology when it comes to imaging. “For example,” he says, “there is a worldwide shortage of magnetic resonance physics graduates who are interested in a career in neuroscience imaging.” Matthews adds that the increase in centers for imaging over the past five years fuels the need for physicists. “In the United Kingdom, alone,” Matthews says, “there were bids for 10 new image centers just last year, and each one will need physicists to implement novel imaging methods and engineers or mathematicians to focus on the problems of image analysis.”

The call for other areas of expertise clearly goes beyond hardware needs. “Increasingly, the focus is moving toward extracting information from data,” Matthews says. “So a large group of people who would have been in robot vision work or remote sensors, like satellites, are finding a very happy home in neuroscience imaging.”

For neuroscientists, though, Huerta says, “Keep your eye on the prize.” That is, follow the questions that you want to answer, not just the hot technology of the day. He says, “Neuroscientists need to be familiar with the language of imaging and in contact with people who understand the fundamentals of imaging, but the people who make the breakthroughs in neuroscience will be the ones who bring the intriguing questions to the new techniques.”

Higher level thinking

For centuries, great thinkers have wondered how we think. The field of cognitive neuroscience tackles that question, and Matthews says, “Imaging has given a particular shot in the arm to the study of cognition.” He adds, “Imaging provides an accessible way of looking for a brain correlate of some mental activity.”

Matthews sees several new cognitive avenues opened by imaging. First, he says, “It democratizes cognitive neuroscience, because MRI is so widely accessible that many groups can now carry on investigations without the support of a major research center.” Second, Matthews indicates that new problems can be addressed. “In the past few years,” he says, “people have tackled quite remarkable challenges—even trying to understand the emotion of love.” In addition, he believes that modern imaging provides a bridge between human cognitive neuroscience and animal studies, allowing more inferences from one to the other.

The comparison of animal studies with humans catches the attention of many neuroscientists. Montague says, “Neuroscience imaging has given people the will to connect lots of basic neuroscience and taking it to the human, really applying to the human, those things that we’ve been finding in fruit flies and monkeys.” As a result, molecular biology and cognitive psychology could eventually connect.

Indeed, the idea of watching drugs at work and linking molecular biology to thinking leaves observers nearly breathless. But future neuroscientists should look beyond the technology. “People tend to get mesmerized by what is hot at the moment, which is based on tools,” Matthews says. “Once you get tooled up, the hot thing has passed.” So use the technology, perhaps even create it, but look even further beyond the technology. There Matthews sees an exciting future. He says, “Most people going into neuroscience should be able to find an exciting niche that they can make their own.” Much more excitement inside the brain remains to be exposed.

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