Images of brain activity may hold clues to the onset of schizophrenia in people at high risk for the disease, according to a study headed by psychiatry researchers at the University of North Carolina at Chapel Hill School of Medicine. The new findings appear in the March issue of the Archives of General Psychiatry, a journal of the American Medical Association.
A decline in function in the prefrontal cortex, the “executive” or front part of the brain, is present in high-risk individuals experiencing early symptoms of schizophrenia and may reflect biological changes that precede the onset of diagnosable illness, the study indicates.
Identifying such changes prior to disease onset also may prove useful in determining vulnerability to schizophrenia onset, particularly in those at high risk for the disease, the researchers said.
“We know that individuals who experience symptoms that occur before the disease becomes full-blown demonstrate impaired performance in tasks requiring executive function, attention and working memory, but the neurobiological bases of this remains unclear,” said Dr. Aysenil Belger, the study’s senior author.
“In looking at the brain activity of high-risk people while they performed some of these tasks, we hoped to identify a neurobiological marker of vulnerability to disease onset, a tool we might use to help assess their risk of developing psychotic symptoms,” Belger said. “If such a tool became established, perhaps we could intervene early on in some way to improve whatever pathology it showed.”
Belger is an associate professor of psychiatry in UNC’s School of Medicine and of psychology in UNC’s College of Arts and Sciences.
The study involved functional magnetic resonance imaging, or fMRI. Unlike standard MRI scans that show anatomical structures in black and white, fMRI offers digitally enhanced color images of brain function, depicting localized changes in blood flow and oxygenation.
When particular regions of the brain increase their neural activity in association with various actions or thought processes, they emit enhanced blood oxygen level dependent signals. The signals can be localized in the brain and translated into digital images that portray neural activity level as a ratio of oxygenated to de-oxygenated hemoglobin, the iron-containing pigment in red blood cells. Researchers then can quantify these signals to generate maps of various brain functions.
Fifty-two study participants were divided into four groups: “ultra-high-risk,” where participants experience symptoms but the illness is not full-blown; early schizophrenia, where participants have had the illness less than five years; chronic schizophrenia, where participants have had the illness for more than five years; and healthy age-matched “controls,” for comparison.
Those at ultra-high-risk had been pre-screened for schizophrenia symptoms, revealing that some were showing early emotional, affective and cognitive symptoms such as the blunting of emotion, poor personal relationships, poor hygiene, emotional detachment and false beliefs.
While undergoing fMRI scans, all participants responded to an executive decision test – so-called because decision making and task-appropriate response selection are required – displayed on a computer screen. This test, developed by the study team, requires push-button responses to certain colored squares, circles and objects from everyday life. Each visual cue is presented at a fraction of a second against a white background, and participants must ignore an auditory tone sounded when each cue is presented.
“Of particular interest was the neural activity generated by a series of infrequent circles that were designated as ‘target’ events, which participants were instructed to detect and respond to as quickly as possible by pressing a button,” Belger said.
“Accurate and fast performance on this test requires both the maintenance of attention and vigilance, as well as the ability to rapidly discriminate between target events and other non-target distracters, such as the colored squares and objects.”
The scanner mapped participants’ neural activity in specific brain areas before, during and after the presentation of the visual target events.
“Our goal was to see if the high-risk individuals showed normal brain activity during these executive tasks or whether or not they showed some of the pathology of individuals who already have schizophrenia,” Belger said.
The researchers found that when the healthy people make these types of detections and decisions, they activate frontal and mid-brain regions. Chronic schizophrenia patients showed a significant drop in activation of these regions, “thus it appears that they fail to engage these frontal regions,” said Belger.
“And we found that the high-risk group and early, or first-episode, schizophrenia group are somewhere in between: It looks like these deficits begin even before they are diagnosed and treated. It suggests that this area of the brain that’s important for executive decision-making processes is already altered before disease onset.”
The preliminary study represents a “first pass” at determining feasibility of the tool to map tiny differences between patients and controls, Belger said.
“We need to show that the tool is reliable and that, indeed, it’s detecting something in the population that it’s not detecting in healthy individuals,” she added.
“This is also a cross-sectional study, a comparison between groups. It’s not longitudinal, as we did not study the same individuals over time. Still, the findings are intriguing; they are suggestive. We still need to know how they actually correlate with schizophrenia onset.”
Belger’s UNC co-authors were Dr. Jeffrey Lieberman, who recently left UNC to become chairman of psychiatry at Columbia University; Dr. Diana Perkins, professor of psychiatry, and Dr. Seniha Inan, postdoctoral fellow in psychiatry. Belger, Inan and Dr. Rajendra Morey, clinical associate in psychiatry and behavioral sciences at Duke University Medical Center, are also with the Duke-UNC Brain Imaging and Analysis Center. Dr. Teresa Mitchell, also a co-author, is assistant professor of psychiatry at the University of Massachusetts Medical School.
Funding for the research came from the National Institute of Mental Health, a component of the National Institutes of Health.