The biology of behavior

CAMBRIDGE, Mass. — The human body is assaulted by hundreds of thousands of stimuli every day. Sights: A car is coming down the street, so you step out of the way. Sounds: Someone calls your name and you answer. Touch: A glossy magazine arrives in your mailbox and you thumb through its pages.

We take in these and other sensations and use them in ways that help us adapt and survive in our physical world. But human life is much more than such simple response mechanisms might suggest. We feel emotions, have memories, and process myriad thoughts about who we are and what we’re experiencing. Responding physically to our senses is an action controlled by the brain. The voice of reason that tells us why we react in a particular way and allows us to interpret the larger significance of that response is the mind at work.

For centuries, scientists have sought to understand how the brain—a physical entity that can be touched and observed—gives rise to the mind, that intangible amalgamation of thoughts and perceptions that makes us who we are. That the two are linked is without question: Kill a portion of the brain and some part of the mind goes with it. But the biological basis of this connection and the way it changes when someone is sick or injured is a mystery.

Today, scientists are using a new form of an old technology to study the intricacies of human consciousness and brain functioning. This tool, known as functional magnetic resonance imaging, or fMRI, is providing insights into the biology of behavior, perception, and emotion. Most people think of MRI as a means to visualize brain tumors and other medical anomalies. But in behavioral studies, scientists use the tools of fMRI to generate rapid, time-sequenced snapshots of the brain in action, watching the flow of blood as it meanders throughout the brain, delivering oxygen where it is needed. By tracking blood flows, it’s possible to identify which areas of the brain are activated by certain activities and feelings, such as learning or fear. This information is critical to understanding how the brain processes stimuli and stores information, says Alan Jasanoff, a Whitehead Institute Fellow who is among a handful of scientists pushing new uses of fMRI to analyze the basic elements of brain function.

“In terms of brain physiology, even these basic behaviors are complex and difficult to study,” Jasanoff says. “So today, we focus our efforts on simple processes, which are building blocks to more ‘cognitive’ phenomena, like how the mind experiences hope or helps you play chess.”

A New Twist on an Old Technique

MRI’s origins date to the 1940s. At first, the technique was used mainly for experiments in chemistry and physics. But in the 1970s, MRI was adapted for medical uses, an advance speared by Paul Lauterbur, an American chemist, and Peter Mansfield, a British physicist. The pair shared the 2003 Nobel Prize in Medicine or Physiology for their efforts.

Functional uses of MRI first emerged in the early 1990s, when Seiji Ogawa, then a physicist at Bell Laboratories, modified the technique to monitor blood flows in the brains of rodents. Later research at Massachusetts General Hospital performed by Kenneth Kwong, who now teaches radiology at Harvard Medical School, led to fMRI’s use in humans. Kwong pioneered the use of injected “contrasting agents”—liquids that enter the brain through the bloodstream and make blood flows easier to detect. Since then, fMRI has become an indispensable tool for research in neuroscience and cognitive psychology. fMRI methods also are improving treatments for a broad range of neurological ailments.

Nancy Kanwisher, a psychologist and professor at Massachusetts Institute of Technology, says her fMRI studies of the brain’s organizational structure help her understand the mind itself. Much of her current research focuses on how the brain processes visual images. Kanwisher’s studies have shown that image recognition is highly localized to specific areas of the brain. Faces, for instance, are processed in a tiny region of the cortex measuring barely 1 square centimeter. Kanwisher has dubbed this region the “fusiform face area.” All other human body parts are processed in a different part of the brain, she says.

Recently, Kanwisher’s lab began an exploration of how the brain coordinates its perceptions of other people. In a remarkable finding, her graduate student, Rebecca Saxe, demonstrated that our understanding of other people’s beliefs is processed in one region of the brain while our understanding of their goals is processed in another. “Both these regions help us to understand people,” Kanwisher says. “But each is involved in a different aspect of that activity.”

While some mental functions are therefore highly localized, others—for instance, number processing—may engage what Kanwisher calls “general purpose brain machinery,” which does many different things. But getting to the core of this functionality—and the organic foundations that make us cry, or laugh, or cheer at a football game—require increasingly more detailed investigations into how different regions of the brain are coordinated.

Describing this coordination is pushing the current resolution of fMRI technology. Larry Wald, a radiologist at MGH’s Athinoula A. Martinos Center for Biological Imaging, one of the top imaging research facilities in the world, says current fMRI techniques are limited in part because they don’t measure the brain’s primary response to stimulus. Blood flow actually is a secondary response, triggered by electrical impulses in neurons. The time-lag between these electrical triggers and a blood surge can be several seconds—a significant lapse, notes Wald, because it hides the interplay between activated regions.

“We might be able to say that two regions are involved in memory, for example, but we can’t see how they interact,” Wald explains. “We need to figure out how these activated regions form a network.”

Identifying such networks is a goal that drives Jasanoff, who is pioneering new fMRI techniques that go beyond blood flow to expose the brain’s electrical activity—a series of impulses that transmits messages between neurons. The techniques are still experimental, so Jasanoff works with laboratory animals to isolate neural circuits involved in simple behaviors. “What we learn about simple behaviors in animals guides us toward an understanding of more complex behaviors in humans,” Jasanoff says. “Our findings can influence the direction of human research.”

Researchers trying to “get inside the brain” during experimental research traditionally have relied on electrodes wired directly into neural tissue. This process is not only invasive and cumbersome, it’s also limited in terms of its spatial coverage—electrodes gather data only from the area to which they are attached. Jasanoff’s research is offering another option, namely, a set of MRI contrasting, or imaging, agents that can selectively be activated by the brain’s electrical currents. “My approach will provide a direct assay for neural activity deep within the brain,” Jasanoff says. “This is unlike anything that is currently available.”

To date, Jasanoff’s focus has been on establishing a way to test imaging agents for fMRI in single brain cells of an oversized housefly called a “blowfly.” He presented the blowfly brain imaging approach in a 2002 article in the Journal of Magnetic Resonance, and demonstrated an oxygen imaging application using the setup in a 2003 article in the journal Magnetic Resonance in Medicine. Now Jasanoff is completing work on two new brain imaging agents, and intends to adapt the agents so they can be used safely in higher organisms, for instance, rodents. Studies in animals are necessary before the agents can be used in experiments with human subjects, a step in the research that Jasanoff notes is many years away.

Beyond the Brain-Mind Connection

With the aid of fMRI technology, scientists are expanding their understanding of not only the brain-mind connection, but also chemical and structural changes in a diseased or injured brain. fMRI techniques now are being developed to quickly identify salvageable brain tissue in stroke patients. Targeting these tissues quickly with drugs greatly increases the likelihood they can be saved, Wald says. “This is a lot better than giving a drug and then waiting and watching to see how the patient responds, for instance, by how well they speak,” he adds. “You want a good functional assessment that can tell you quickly how well a drug is working.”

Scientists also are using the technique to study how the brain “rewires” itself after a stroke or physical injury. Evidence suggests that some brain regions actually may take over for other areas that die after these events, says Christopher Moore, assistant professor of neuroscience at MIT. Researchers use fMRI to define these regions with the aim of harnessing recovery mechanisms using rehabilitative physiotherapy.

Moore’s own studies with fMRI have shown that brainrewiring might inflict deleterious effects, including “phantom limb” pain among amputees or patients suffering from paralysis, for example. In these patients, Moore explains, brain activity is reorganized by a dramatic loss of sensory input from the affected parts of the body. Brain regions that used to respond to being touched on the arm, for instance, could be activated by the sensation of being touched on the chest. This aberrant activation may induce misperceptions of painful input. Clinicians can use the information gleaned from fMRI to develop therapies for pain management. “Sometimes you can train these patients to shift their perceptions away from pain,” Moore says.

Today, many different specialists are using fMRI—each with a distinct focus, but all with a common goal of understanding brain function and the mysteries of human perception.

In the future, Wald says, scientists increasingly will seek higher resolution fMRI tools to study the neural circuits that drive mental processes. Jasanoff’s imaging agents, Wald suggests, represent an important advance that will uncover the molecular events that drive these systems. Meanwhile, scientists such as Jasanoff, Wald, and Kanwisher say fMRI will produce ever more valuable research contributions that someday may bring that elusive mind-body connection into greater focus.

“It’s a lucky fact that the mind lives in the brain,” Kanwisher quips. “So, if we want to really understand how the mind works, then studying the basic organization of the brain is a pretty good place to start.”

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