UCLA scientists have used a novel three-dimensional mapping technique to identify regions of the brain where people with schizophrenia have significantly less gray matter than their identical twins and the rest of the population.

Tyrone D. Cannon, UCLA’s Staglin Family Professor of Psychology, Psychiatry and Biobehavioral Sciences, and Human Genetics, led the research team that reports schizophrenia patients have significant reductions of gray matter in regions of the brain that integrate, interpret and organize information. The affected areas are called the dorsolateral prefrontal cortex, superior temporal gyrus and superior parietal lobule. The research will be published Feb. 26 in the online edition of Proceedings of the National Academy of Sciences, and March 5 in the print edition.

Cannon and colleagues from UCLA and Finland report their analysis of same-sex twins born in Finland from 1940 to 1957. Cannon has been studying twins who both have schizophrenia, twins where one has schizophrenia, and normal twins who do not have the disease. The researchers were able to use this information to show that some of the gray matter reductions in schizophrenia are caused by genetic factors, and some by environmental factors, and to identify for the first time the precise topography of these two types of changes.

“We are all bombarded with information, but we can organize it and create coherence,” Cannon said. “Typically, we shut a lot of things out. Schizophrenia patients, however, have fewer connections in regions of the brain that synthesize all of the sounds we receive and information we process. They have great difficulty sorting out information, and lack the ability to selectively focus and organize knowledge.

“We have found that while schizophrenia patients appear not to have fewer neurons in the brain, the neurons make weaker connections in regions that synthesize information,” Cannon said. “The reduction in gray matter is highly concentrated to these critical convergence areas.”

The research team studied male and female monozygotic twins — who are genetically identical, sharing 100 percent of their genes — and dizygotic twins, who share 50 percent of their genes. In this study, the scientists studied monozygotic and dizygotic twins where only one of the twins has schizophrenia, and a control group of healthy twins, monozygotic and dizygotic.

The researchers analyzed detailed maps of gray matter for the subjects, using novel brain mapping techniques, and analyzed their DNA. Three-dimensional cortical maps show reduction in gray matter and enable the researchers to calculate the loss of gray matter in those who have schizophrenia. The research was supported by the National Institute of Mental Health and other agencies.

The research team includes Arthur Toga, UCLA professor of neurology; Paul Thompson, UCLA assistant professor of neurology; UCLA graduate students Theo van Erp, Katherine Narr and Rajneesh Dail; UCLA undergraduates Mohammad Khaledy and Chris Zoumalan; and from Helsinki, Finland, psychiatrists Matti Huttunen and Jouko Lonnqvist; physicist Veli-Pekka Poutanen; radiologist Carl-Gustav Standerskjold-Nordenstam; and Jaakko Kaprio, professor of public health.

“We begin life with far more neural connections than we will ever use, but lose huge numbers of the connections among brain cells in late adolescence,” said Cannon, who is director of UCLA’s Center for the Assessment and Prevention of Prodromal States. (The onset of schizophrenia is preceded by a “prodromal phase” marked by behavioral, cognitive and social deterioration.) “In the regions of the brain that govern the synthesis of information, a critical threshold may be required for integrated cognitive activity. If people fall below this threshold, they may be unable to sustain normal cognitive activity; the resulting disintegration of cognition may then manifest as hallucinations, delusions, thought disorder and the other symptoms of schizophrenia.”

Future research may reveal whether schizophrenia patients have many fewer connections to begin with and cross this hypothetical critical threshold during the normal pruning process that occurs during adolescence, or whether they lose connections at a faster rate than normal during adolescence.

The ultimate promise of the recent discovery and related work, Cannon said, is that scientists may eventually pinpoint the molecular mechanisms that cause this loss to occur, and perhaps be able to halt the process to prevent or reduce the loss.

Cannon also is trying to learn the causes of schizophrenia, including the molecules implicated in the disease. His previous research has identified the fundamental importance of genetic factors, showing that schizophrenia is more than 80 percent genetic, and that the environmental influences most likely depend on genetic factors as well.

The trigger to schizophrenia may be related to brain development abnormalities produced in critical periods during gestation, Cannon believes, although the symptoms do not emerge until late adolescence or later.

Identifying the interacting genes that play a role in schizophrenia and the defective or missing protein (or proteins) will be crucial to effectively combating the disease, Cannon said.

“I think we are getting closer conceptually to learning what kinds of proteins are implicated in schizophrenia,” Cannon said. “Most likely, at least one of these proteins is likely to be related to the ability of neurons to sprout and maintain connections.”

Slightly more than one percent of the population is afflicted by schizophrenia, including more than 2 million Americans. Males typically get schizophrenia in their late teenage years, and females in their early 20s.

The symptoms of schizophrenia include hallucinations, delusions, hearing voices, disordered thinking, unusual speech and behavior, and social withdrawal. Seventy percent of patients hear voices, typically making derogatory comments about them, in the third person, Cannon said. Patients commonly have delusions, often involving persecution. Their thinking and speech are disorganized, and they may have a greatly reduced interest in social activities, and a reduced energy level.

If one child has schizophrenia, a second child in that family has a 10 percent risk of getting the disease — nearly 10 times the normal risk, Cannon said.

UCLA study seeks patients who may have early signs of schizophrenia

UCLA’s Center for the Assessment and Prevention of Prodromal States is seeking patients between ages 15 and 35 who want treatment to participate in a two-year research study to track and analyze changes in brain functioning that could be a precursor to schizophrenia. The UCLA center seeks patients for the study who have declined socially or academically during the past year and are starting to have symptoms such as being suspicious, depressed, anxious or nervous; hearing voices or messages; or believing that events have special meaning for them.

Participants in the two-year study will be offered a comprehensive treatment package, as well as a clinical evaluation, neuropsychological testing, magnetic-resonance-based neuroimaging assessments, a psychophysiological examination, a psychosocial evaluation, and collection of a blood sample from the subjects and their biological parents for genetic testing. To participate or receive more information, call Sabrina Lux at the UCLA center: (310) 206-3466.

One of the center’s goals is to develop a reliable basis for predicting who will be afflicted with schizophrenia. Initial funding for the Center for the Assessment and Prevention of Prodromal States was provided by Garen and Sharalyn Staglin.

Cannon hopes his research and that of the center will eventually help produce effective ways to treat and even prevent schizophrenia.

“We hope to develop novel approaches to intervention to, at the minimum, reduce the severity of the illness, or even prevent its onset,” he said.