Looking Inside the Black Box

Tim Brady, Kermit Pattison, and Danny Lachance contributed to this story. Angus MacDonald explores the mystery of schizophrenia

Angus MacDonald
Is there a method to the brain's madness? >>> Angus MacDonald III is proving that there is -- and he's providing a map. His innovative research has helped pinpoint areas of the brain that go awry in people with schizophrenia. It also provides clues to genetic and environmental causes.

"It's a miracle that it works," says Angus MacDonald with a hint of awe in his voice. He's speaking about the human brain.

"I mean, who on Earth would put the occipital cortex -- the part of your brain you see with -- at the back of your brain, as far away from your eyes as possible?" asks MacDonald, an assistant professor of psychology. "And who would put the parts of your brain that are doing the heaviest lifting, the deepest thinking, at the front of your brain -- the first part to go through the windshield?"

MacDonald may be incredulous, but he's no skeptic. He knows that if much of the brain's functioning remains a mystery to psychologists, the fault lies not with its design, but with our own incomplete understanding of how the brain works. Indeed, the brain is the ultimate "black box," MacDonald says, a mysterious device that receives inputs from the environment and delivers outputs back to it, but leaves most of us wondering what occurred in between.

That black box effect is especially pronouncedin mental diseases that afflict a staggering percentage of the world's population.MacDonald has spent his career studying schizophrenia, one of the most common and debilitating mental diseases. His work has helped psychologists get inside the black box of afflicted brains in order to understand the neural mechanisms that go awry in those suffering from schizophrenia. It's a journey that has led him to the frontiers of neuroscience.

Going to the source

Schizophrenia is a devastating mental disease that afflicts an estimated one percent of the world's population -- about 6.5 million people. The disorder is usually accompanied by terrifying symptoms, including paranoia, hallucinations, and harassing internal voices.

Aside from the anguish that it brings to those who are afflicted, it is a crushing illness for families and for society as a whole. Unemployment, social withdrawal, and a 100-fold increased risk of suicide are just some of the devastating consequences of the disease. Entirely successful treatment of the illness is rare, and, in MacDonald's words, "a cure to schizophrenia awaits a better understanding of its causes." That's where his studies begin.

One of the disease's most baffling problems, says MacDonald, is the difficulty of understanding why and how it afflicts some people and not others.

"Schizophrenia is such a perplexing illness because it frequently has no antecedents," he says. "You can't predict with much certainty who's going to get it; it seems to come from nowhere and strikes folks from all walks of life."

Fifty years ago, the prevailing view amongst psychologists was Freudian: the disorder was caused by environmental influences such as the "schizophrenia-causing mother." But then another Minnesota researcher, Irving Gottesman, challenged the prevailinorthodoxy about the disease. Gottesman earned international recognition for studies that revealed a genetic predisposition to schizophrenia. Schizophrenia, he boldly argued, was caused by a complex gene system that was triggered by unknown environmental stressors.

The balance between nature and nurture, however, has remained unclear. Indeed, while it is known that schizophrenia is a heritable illness, many people born with a predisposition for the disease never get it. In fact, MacDonald says, "a schizophrenia patient's identical twin has only a 50 percent chance of developing the disorder, despite sharing the same DNA." Moreover, different schizophrenic patients present different symptoms -- some terrifying and some, MacDonald notes, "endearing and wonderful, with bursts of creativity."

The range of both causes and symptoms makes defining schizophrenia and searching for specific treatments exceedingly difficult. "You can find two people who share very few symptoms of the disease. The only thing I can almost guarantee is that they're going to be interesting characters," MacDonald says wryly.

A novel approach

In his wide-ranging research, MacDonald is bringing a battery of tests and measures to bear on the questions surrounding schizophrenia, thereby creating a comprehensive image of the disease. His arsenal includes functional magnetic resonance imaging (fMRI), which enables him to examine the brain patterns of schizophre-nic patients and compare them to those of healthy relatives. Another procedure, electroencephalography (EEG), enables MacDonald and research collaborator Scott Sponheim to measure the brain's electrical activity (event-related potential) in response to stimuli in both healthy and mentally- ill subjects. Together, these and other methods illuminate the brain's mechanisms -- including perception, thinking, and memory -- and how they malfunction. f.M.R.I. image of a brain "You get a pretty coherent story about which brain regions are firing [under certain conditions] and when they're firing in relation to one another," says MacDonald. "Those are important sources of information because they say how the network [of the brain] is interacting."

When these interactions are studied alongside genetic data collected from patients, causes can be linked to symptoms even more firmly. In 2003, for instance, MacDonald and his colleagues showed that one part of the prefrontal cortex functioned abnormally in people with schizophrenia, and that this impairment was associated with a genetic predisposition to the disease. Interestingly, MacDonald has gone on to show that these prefrontal mechanisms are impaired even in healthy relatives of schizophrenics. Such findings can further refine our understanding of the brain and its malfunctions: while genetics may plant the seeds of a disorder such as schizophrenia, other factors, including environmental stressors and cognitive processes, play a role in its onset and development.

Use it or lose it

MacDonald's lab has also developed tasks to measure cognitive mechanisms with possible potential for improving cognitive functioning in people with schizophrenia. One of these tasks, which reveals functional problems associated with the dorsolateral prefrontal cortex, has proven to be a very promising tool in differentiating those who are genetically predisposed to the disorder from those who are not.

Other tasks have treatment potential. In one recent study, for instance, MacDonald and a graduate student demonstrated that patients who participated in a regimen of mental exercises for six weeks showed improvements in cognitive functioning on tests of working memory. Their improvement was also observed on preliminary analyses of fMRI scans: the patients showed increased activation in their left dorsolateral prefrontal cortex during these tests.

If these findings hold up, clinicians of the future might be able to prescribe mental exercises for patients suffering from schizophrenia that will reduce the intensity and frequency of sometimes debilitating symptoms.

"The brain follows the 'use it or lose it' principle," says MacDonald. "You can strengthen connections in the brain by putting a load on them every day. This intensely abstract, executive part of the brain isn't something you're born with, but is something that is plastic and can be modified."

Research on the frontiers

By identifying possible patients through genetic and fMRI analysis, and further refining the analysis through cognitive testing, MacDonald is creating an integrated description of schizophrenia that enhances the possibility for early prediction of the disease and development of concomitant treatment. Studying the disease from multiple angles, he says, has produced knowledge that each angle, independently, could not. Angus MacDonald and students And this is just the beginning. "Before I retire, we will think of this as the dark ages of schizophrenia research," he says. "The kind of information we're going to generate in the next decade is going to make us think of this illness in a new way."

MacDonald's research has also earned him a reputation as a rising star. During his graduate studies at the University of Pittsburgh, he won the Bassell Award for neuroimaging research on schizophrenia. Last year, he won a Young Investigator Award from NARSAD, the mental health research association for neuroimaging research. And this year, the University named him one of three McKnight Land-Grant Professors in the College of Liberal Arts, an award given to the University's most promising junior faculty.

But he's not resting on his laurels. One recent morning found him in the control room outside an MRI scanner in the Center for Magnetic Resonance Research on the East Bank campus.

He was scrolling through a computer screen flickering with images of the brain of a twin. The data are part of a two-year study of the neurological mechanisms behind paranoia, a classic symptom of schizophrenia. In this study, MacDonald and his colleagues are running pairs of identical twins through the fMRI scanner while they play a game (borrowed from economics) designed to measure distrust.

A growing body of evidence suggests that mistrust activates the part of the brain called the insular cortex. MacDonald and his team have hypothesized that the game will produce more activity in this area in subjects with paranoid tendencies. Using twins will provide clues about how much of the behavior is related to genetic structures.

The experiment is just one thread in a broader tapestry of research, but its attention to everything from genetic structures to game playing marks MacDonald's signature approach, one that keeps behavioral geneticists in conversations with cognitive psychologists and even economists -- not to mention all the rest of us.

By crossing those boundaries, Mac- Donald hopes to transform the black box into something like a window. "If you can see how the mechanism works, you can intervene effectively," he says. "You can't fix the car unless you understand how it works."

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This page contains a single entry by cla published on June 26, 2008 4:00 PM.

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