January 2007 | Back to Table of Contents

Pulse

Inside Schizophrenia

Researchers are illuminating the inner workings of a mental illness.

Schizophrenia is a disease cloaked in mystery largely because of the multifaceted nature of its symptoms. Some people exhibit hallucinations and delusional behavior, called “positive” symptoms. Others have so-called “negative” symptoms—a lack of volition, blunted emotions. Still others show signs of “formal thought disorder” or disorganization in thinking. As if that weren’t confusing enough, a person diagnosed with this mental illness may exhibit only one symptom set their entire lives, or they may experience symptoms from all three categories. And no one knows exactly what causes one symptom set to manifest more predominantly than the others.

But researchers are slowly beginning to understand the whys and hows of one predominant symptom: formal thought disorder, when a person speaks incessantly and quickly, switches topics midsentence or at an inappropriate time, or speaks incoherently. “One of the things that patients with schizophrenia have trouble with is using previous context information—using sentences or ideas previously brought forth to construct a coherent conversation, or keeping up with what is being discussed at any given time,” says Angus MacDonald III, Ph.D., assistant professor in the University of Minnesota’s department of psychology.

Mind-Reading Research
MacDonald and his team are using functional magnetic resonance imaging (fMRI) to study the mechanisms behind this symptom. Aware that the prefrontal cortex is the workhorse in context processing, they have been studying the ability of patients with schizophrenia to activate their prefrontal cortex while performing certain executive functioning tasks. In one recent study, which involved 18 never-medicated, first-episode patients with schizophrenia, 12 never-medicated patients with first-episode psychosis, and 28 patients with no psychoses, MacDonald and his team had patients complete a test that measures context-processing ability while they were in an MRI scanner. As they viewed a series of letters that appeared individually on a screen, patients were asked to push a “target” button whenever the letter “A” was followed by the letter “X” and to push a “nontarget” button in all other instances. The test scores and the fMRI images showed that schizophrenic patients had specific deficits in context processing and that those deficits corresponded to prefrontal cortex dysfunction, as indicated by reduced activity in that region of the brain. Researchers did not observe this same dysfunction in the subjects who were not schizophrenic.

MacDonald is hesitant to describe the test as a predictor for schizophrenia. “A predictor implies that if you do poorly on this test, you will develop schizophrenia,” he says. “What that really requires is that you test folks very young and then observe them through a risk period and then determine the extent to which they developed schizophrenia. And that’s not something that we are going to be doing anytime soon.”

That said, the research findings are laying the groundwork for understanding the neuroanatomy of the mosaic of symptoms associated with schizophrenia. He explains that the patients who were having the most difficulty activating the right prefrontal cortex when the task demanded that they rely on previous information in order to perform it were those who had the most problems with formal thought disorders.

Brain Boot Camp
As a follow-up to the findings, which were published in the March 2005 issue of the American Journal of Psychiatry, MacDonald and colleagues have conducted a similar but slightly more sensitive continuous processing test in healthy first-degree relatives of patients with schizophrenia. These individuals are known to be genetically predisposed to the disease. The results showed that compared with a control group with no family history of schizophrenia, the healthy relatives of patients with schizophrenia had a slower rate of response on the test and less activity in the prefrontal cortex when they were deciding how to respond.

MacDonald has since shifted the focus of his research to learning what interventions might enhance prefrontal cortex activity in patients with schizophrenia. He recently finished implementing what he calls a “brain boot camp” for 12 community mental health patients diagnosed with schizophrenia. During the pilot study, MacDonald had patients work on a computer, completing tasks that put a load on the prefrontal cortex such as remembering things that happened during a simple scene and monitoring a digital assembly line for flaws. The idea is to increase the prefrontal cortex’s abilities by giving it a workout.

Compared with patients receiving cognitive behavioral therapy, those in the intervention group were able to not only better perform the tasks they were practicing but also better do tasks they had never done before, he says. “It really demonstrated that you could change prefrontal cortex activity.”

MacDonald and his team eventually hope that the knowledge gained through their research will not only demystify schizophrenia but also improve outcomes for patients. Says MacDonald: “There are so many different things that can go wrong with patients with schizophrenia, and one patient may not bear any similarity to another patient. Once we can understand the functional neuroanatomy of those physical symptoms, it may become self-evident how they are related and why you may have overlapping networks of symptoms among different patients…. Ultimately, that may help to improve their functional outcomes.”—Jeanne Mettner