Mapping Fear Itself
New MRI technology could help diagnose mental illness
John Sullivan, left, and Reinhold Ludwig with two of the devices that make it possible for the Center for Comparative NeuroImaging to use MRI to create extraordinarily detailed images of the brains of alert animals. Sullivan peers through a special tunable RF (radio-frequency) coil designed to respond to the ultra-high-strength magnetic fields in state-of-the-art MRI instruments. Ludwig holds an RF surface coil designed to receive signals from an animal's brain. The coils work in concert with a restraint that keeps the animal's head motionless while it is being imaged.
The detailed brain images produced by the novel RF coils shown on page 10 are processed with sophisticated software that converts the data into a complex mesh consisting of hundreds of thousands of data triangles. These detailed surface topology maps make it possible to correlate the effects of stimuli on precise areas within the brain. In time, it is hoped, this technology will make it possible to better diagnose and treat with pharmacological agents specific mental disorders in humans, including addiction and chronic depression.
In the summer of 2001, Jean King used a small bottle to test a big idea. The associate professor of psychiatry at the University of Massachusetts Medical School wanted to know if she could capture pictures of the brain activity associated with inborn fear. But first she had to run a preliminary experiment to find out if she could elicit such fear in lab animals. So she walked into a laboratory at the Center for Comparative NeuroImaging (CCNI), which is run jointly by UMass and WPI, and uncorked a bottle, releasing the sharp odor of fox urine. Immediately, the dozens of white rats caged there scrambled, then froze, their eyes bulging in panic.
"This was definitely an expression of the animals' innate fear," says King. "They're all lab animals. None of them had ever seen or smelled a fox before." Satisfied, she closed the bottle, and the rats calmed down.
King knew that as long as the rats feared the fox, she had the ingredient she needed to test the brain imaging capacity of a new MRI technology developed by a WPI team led by professors John Sullivan and Reinhold Ludwig. Ludwig, who teaches electrical and computer engineering, created the hardware, while Sullivan, who teaches mechanical engineering, directed software development.
The WPI researchers' challenge had been to find ways to use new, ultra-high-field magnets to capture pictures sharp and detailed enough that King and her colleagues could pinpoint which of the brain's many regions were activated by the animal's fear. Because resolution improves as a magnet's Tesla, or field strength, increases, the researchers knew that the most powerful MRIs had the potential to produce the desired images.
Most important for the applied research being conducted at CCNI, the scientists devised a way to gather images from the brains of alert animals. To do this, they had to solve the problem of movement because motion interferes with MRI scans. The new hardware keeps the animal's head immobilized while the rest of the body can squirm without compromising the image. Prior to this invention, laboratory animals had to be anesthetized during imaging. The unconscious animals didn't move, but they also didn't respond to stimuli the way conscious animals would.
A dual radio-frequency (RF) coil system is another critical innovation of the WPI team. It was developed to take advantage of the ultrastrong magnets. Traditional MRI technology uses superconducting magnets to generate a magnetic field roughly 20,000 times stronger than the earth's. Today's state-of-the-art magnets are at least three times stronger than that. In all MRI technology, the body's atomic nuclei react to the magnet's powerful force, spinning around the imposed field. A separate RF field causes a reorientation of the nuclei, which begin to relax when the RF field is turned off. The reversion of each nucleus to its original state gives off a signal that is captured through the process of magnetic resonance imaging.
As magnets grow stronger, the nuclei spin at much higher frequencies, affecting signal reception and transmission. "The rapidly increasing field strengths of magnetic resonance instruments pose major RF coil design challenges," Ludwig notes.
Ludwig's brainchild is RF transmitter and receiver coils that can be activated and deactivated while the magnets work their magic on the body's nuclei. The frequencies at which the coils operate coincide with the new magnets' strength, so that the transmitter coil is capable of initiating the wildly spinning nuclei's reorientation. When the transmitter coil is switched off, the nuclei relax and give off their telltale signals, which are recorded by the receiver coil.
And there is more to the coils than their tune-ability. Ludwig holds up one of his inventions, a dome-shaped device equipped with the coils that fits over an animal's head and nestles close to the tissue being studied. "A coil that receives only information from the brain is going to produce much more accurate images of the brain," he explains, "because there's far less interference from other biological regions or atmospheric 'noise' sources."
All this new hardware needs software to analyze and manipulate the images. That's where Sullivan comes in. "We take the MR image and create a surface topology, a mesh comprising hundreds of thousands of data triangles," Sullivan says of the programs he and his team worked on for three years. "You can slice through this geometry, getting tremendous resolution."
"This was definitely an expression of the animals' innate fear. They're all lab animals. None of them had ever seen or smelled a fox before."
Sullivan points to a computer screen showing a colorful 3-D image of a rat brain. "The entire brain--over 1,300 regions--is itemized," he explains, "so you can pinpoint which area is affected by, say, a certain medication."
Just as the MRI's pinpoint precision is helping researchers understand rats' brains, so too is it bringing scientists closer to solving the mysteries of mental disorders in humans. "We hope by better understanding the innate responses to fear, we'll have some clues about what sites or processes to target with pharmacological agents," King says.
She expects that within the decade scientists will be able to select medicine specifically geared to an individual's brain biology, thus providing targeted treatment of everything from psychological disorders induced by addiction to chronic illnesses like depression.
"This collaboration between our two schools," King says, "is bringing a different paradigm to the field of neuroimaging."