Inside Out: Looking at schizophrenia’s inner chaos  pg. 5

Results in schizophrenia patients are very different. “In those with schizophrenia, you don’t see increased activity in this part of the brain and you see a higher error rate,” says Park. “But they don’t get all the answers wrong, so it’s not that the area isn’t functioning at all.”

In some studies, even when patients got the right answer, this part of the brain wasn’t activated. This suggests that they don’t seem to need that area to perform the task correctly, she adds.

“So the fMRI literature is in some sense murky right now, because we don’t know what the activation really means in normal individuals versus schizophrenia patients,” says Park. “Overall, it gives the idea that something is wrong with the way they use the brain, though we don’t know yet exactly how.”

Park is collaborating with Meltzer, using fMRI to look at how working memory is affected in schizophrenia patients treated with both an atypical antipsychotic and the drug buspirone, which specifically targets the brain’s serotonin system. In addition, she is exploring the use of other brain imaging technologies with the help of John C. Gore, Ph.D., director of Vanderbilt’s Institute of Imaging Science, and his colleagues.

Park expects that one method, near infrared optical imaging, may prove particularly helpful, since it provides the same kind of information that fMRI does, but has the advantage of allowing the patient to sit up and move more freely while being tested.

Neural circuitry and its genetics

Dr. David A. Lewis has spent years studying neural circuitry in the brain, specifically the prefrontal cortex and related brain regions, and how it is altered in schizophrenia. It was at the University of Pittsburgh where he is director of the Center for the Neuroscience of Mental Disorders, and where Levitt was chairman of the department of Neurobiology at the time, that the two first began their collaborative research into the genetic underpinnings of those alterations.

“David and I partnered with Karoly Mirnics, who was an M.D. neurophysiologist in my lab, and who was also fantastic with computers and data analysis,” Levitt recalls. “We were the first group to use gene microarrays applied to a major brain disorder, and we focused on the dorso-lateral prefrontal cortex, the area that mediates working memory, which is disturbed in schizophrenia.”

Gene microarray studies allow for simultaneous screening of thousands of genes to look for patterns of gene expression. The Pittsburgh group has published a series of papers demonstrating that expression of a certain class of genes—those encoding proteins that control synapse function—is deficient in schizophrenia. Some of these proteins have other roles in the body, but in the brain they play a critical role in the modulation of how neurons communicate with one another.

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