Computers work wonders. Computers break. Computers can be fixed.
Not so easily, the human brain. The most sophisticated of computers comes with no instructions, spare parts or warranty. Yet it is the hardest working organ in the body.
The brain and its 13 billion nerve cells are firing at a frenetic pace, making so many connections that it would take millions of years just to count them.
To a world fascinated but baffled by workings of the mind, Peter T. Fox, MD, says: "How would you like a map?"
A noted neurologist, Dr. Fox is a professor of medicine, psychiatry and radiology. He directs the Health Science Center's Research Imaging Center (RIC), a $38 million site devoted to the technologies of biomedical imaging.
In the world of neuroscience, the RIC is as emblematic of Texas as oil, cowboys, computers and the 10-gallon hat. It was built in 1991 with the bold idea of putting the most advanced imaging devices under one roof and in the hands of the brightest scientists. The RIC has become one of the world's biggest, busiest and most productive sites for brain research.
After a tour last year, a visiting Canadian scientist was so impressed by the scope of the RIC's work that he called it the "Manhattan Project of the mind." The Manhattan Project, a U.S. government research initiative in 1942, produced the first atomic bomb.
"We are asking a very basic question," Dr. Fox said. "What is it to be human?"
Researchers are learning how people see, speak, act, hear, think and behave the way they do. Exciting answers are emerging.
Neurologists regard the medical advances from current brain mapping as incidental rewards on what promises to be a lengthy expedition. Brain mappers are sure the unknown territories they are charting will hold new cures and therapies and even secrets about the mind and consciousness if not the soul itself.
Experiment by experiment, brain researchers are becoming more certain of how the mind works. Issues that once were grist for debate among theologians and philosophers now are being explained in scientific terms. Yet RIC scientists see nothing mystical in their work. Rather they have seized the opportunities afforded by modern technology to explore issues previously subject to speculation and faith.
"Human neuroscience is inherently awe inspiring. We are exploring the bases of thought and emotion, the very things that make us human. It's as if a light has been brought into mankind's darkest cellar," Dr. Helen S. Mayberg, an associate professor of neurology and psychiatry, said. Dr. Mayberg, who was recruited from Johns Hopkins University, said few institutions offer the same capabilities as the RIC. "We have the best available technology and access to every type of imaging device all in one place. This is an unusual opportunity for me or any neuroscientist because you cannot find this anywhere else in the world."
The work blends research and clinical applications and involves Health Science Center faculty members and researchers from the Defense and Veterans Affairs departments.
James J. Young, PhD, dean of the Medical School, said the RIC's work is important "because there are a host of issues from brain mapping that are in the translational stage from basic research to clinical application." He cited the center's role in helping Health Science Center faculty members and military scientists use imaging technology to accelerate research in dozens of fields.
Imaging experts routinely make presentations to help public and private health-care professionals stay up to date on the technology. In addition, the RIC provides a working environment for many students in the Health Science Center's advanced programs in medical physics. Started in 1988, the master's and doctoral degree programs are beginning to fill a shortage of qualified people who understand the computational medicine that modern imaging demands. For example, nine of the current 27 doctoral students are working on thesis projects that involve immediate needs of the RIC. "Their efforts are supporting, often in pivotal ways, our scientific progress here," Dr. Fox said.
Another important role for the RIC involves developing tools and techniques for tomorrow's brain imaging.
Perfecting functional MRI is a priority. RIC scientists are working to make fMRI's neuroscience applications more reliable. Already fMRI holds great promise. In certain areas it has more potential than PET. For example, fMRI uses no radiation and researchers could use children in their studies. In PET, they cannot. Scientists still know almost nothing about how humans develop their language skills.
"PET is like a Clydesdale horse, plodding but reliable. Functional MRI is more like a thoroughbred horse, fast, elegant but fragile," said Charles C. Martin, PhD, a medical physicist and assistant professor who heads the pilot project, which was requested by the Energy Department.
Many laboratories report that fMRI fails to detect brain activity about a third of the time. PET usually identifies brain activation at least 90 percent of the time.
Working with private industry, the RIC is developing an fMRI unit specifically designed for functional brain mapping. It is less expensive than others because it scans the head instead of the full body and its functions are integrated into one computer software package.
The RIC, which is developing the software, is a partner with Advanced NMR of Cambridge, Mass., an MR builder and leader in the venture. An Israeli company, Elscint, is developing the electronic and mechanical interfaces. The system will be assembled and tested at the RIC, which will share royalties on sales when the unit reaches market in 1996. The work has been led in part by physicist Jia-Hong Gao, PhD, an assistant professor and leading authority on MRI. Dr. Gao was recruited last year from Massachusetts Institute of Technology.
In another project, the brain research teams are developing superior ways to analyze images. Using sophisticated mathematical modeling, the researchers play the strengths of one type of imaging technology off the weaknesses of another.
For example, PET is superior in locating events in the brain, but it cannot accurately time how long the events last. Electrical imaging can. So researchers are recording electrical "event-related potentials," the bursts of voltage from brain activity, and combining them with PET images. The result: Soon brain maps will be precise to within 1 millimeter in location and 1 millisecond in duration. "Together, these data will provide models of the neural systems of cognition," said Marty G. Woldorff, PhD, who heads the project.
For its work, the center has won high marks from the Texas Higher Education Coordinating Board, which monitors the state's specially funded research. In 1994, the board ranked the RIC at the top among a half dozen centers of specialized research in Texas and commended its performance and potential in pioneering new technologies. The RIC also is highly regarded by leaders in neuroscience.
"The Texas center is terrific," said Michael I. Posner, PhD, professor at the University of Oregon and leading author and researcher in cognitive psychology. "Its contribution to brain research is enormous already and it is going to grow larger."
Dr. Fox and others also are developing computer data bases and other analytical tools so neuroscientists throughout the world can interpret and share their findings.
Dr. Fox and Jack L. Lancaster, PhD, chief of the RIC's Biomedical Image Analysis Division, developed BrainMap, a data base available on Internet, the worldwide computer network. Now they are developing a data base called SPAMap, which is short for "structural probability anatomy."
Drs. Fox and Lancaster, along with J. Hunter Downs III, PhD, an RIC instructor and graduate of the medical physics program, have developed what is called a "convex hull" method for normalizing brain images. No two brains are the same size or shape so they must be "normalized" for analysis and comparison. The convex hull method is considered one of the most promising steps toward a worldwide standard for analyzing brain function.
Some of the earliest work in brain PET scanning has become the foundation for discoveries at the RIC. Dr. Fox is a good example.
As an assistant professor in the '80s at Washington University School of Medicine in St. Louis, Dr. Fox played an important role in early attempts to understand how the brain handles language tasks such as speaking, and comprehending spoken and written words and sentences. He studied under Michel Ter-Pogossian, MD, inventor of PET, and worked in the early PET experiments.
In 1988, Dr. Fox and a group of researchers headed by another PET pioneer, Marcus E. Raichle, MD, also of Washington University, made several startling discoveries about brain organization for language.
The group found that the language systems use a parallel process rather than a serial process as previously believed They also identified a third major language area in the brain in addition to the two "classical" areas, Broca's and Wernicke's. This newly discovered area of the brain proved to be crucial for processing word meanings, or semantics. Wernicke's area, previously thought to do semantic processing, was reclassified as an area that processes speech sounds. The "generate verbs" task was the first task found to activate the new region, which is situation in front of Broca's area. Subsequently a whole collection of semantics tasks have been shown to work as well. This work is being carried forward at the RIC by Shobini Rao, PhD, a visiting scientist with India's National Institute of Mental Health and Neurosciences.
Dr. Fox also led early studies at Washington University to chart the body's sensory and motor maps. This work is being continued in collaboration with Lawrence Parsons, PhD, assistant professor of cognitive psychology at The University of Texas at Austin. These studies are far more sophisticated than Dr. Fox's early studies of actual and imagined movements. Dr. Parsons has developed a task that produces what he refers to as "implicit movements." In order to judge whether a viewed hand is right or left, the person unconsciously must "move" a mental image of his or her own hand to match the picture. This simple task has provided a more detailed schematic map of the human movement-planning circuits than other methods, Dr. Parsons and his RIC colleagues recently reported in the journal Nature.
Dr. Mayberg's exploration of clinical depression, moods and emotions stems from her earlier studies at Johns Hopkins University. There she reported that patients with depression have reducedbrain blood flow in the cortex.
At the RIC in 1992, Dr. Mayberg began using PET technology to track cerebral glucose. She identified abnormalities in the paralimbic frontal lobe, which is associated with abnormal emotional behavior. Curious, she designed new PET studies involving people without clinical depression. By inducing sadness while the test subjects were in a PET scanner, Dr. Mayberg and her colleague, Mario Liotti, MD, PhD, assistant professor of radiology and neurosurgery, made images of the brain as the subjects became sad. Some people even wept.
"Most PET studies show how stimuli make areas of the brain turn on. We saw areas turn off, specifically in areas almost identical to those seen in depressed patients. In addition we also saw blood flow reduced in a site of the brain Dr. Fox and others had implicated in controlling attention. This is particularly intriguing since depressed people commonly show problems with attention and cognitive processes," she said.
Direct benefits from the imaging experiments are easy to predict, but brain scientists say even greater rewards lie ahead when the parts of the brain puzzle slip into place.
"Take Alzheimer's disease as an example," Dr. Fox said. "Alzheimer's primarily affects memory but it also affects language, attention, coordination and many other brain functions that we are only now beginning to map. If we don't understand all of those things, how are we ever going to design intelligent therapies for Alzheimer's?"
As new imaging devices have opened a window on the brain, the ranks of brain scientists have swelled. Thousands of experiments are being finished daily, raising new questions and inspiring new studies. Dr. Fox said other generations will still be at work with the research begun in this decade.
"I would be surprised if there is ever a complete map of the brain. The idea that we will understand the organization and functions of every area of the brain doesn't have much meaning to me. That's like telling me that we will eventually find the end of the universe."
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