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Release: Nov. 29, 1999

UI's Andreasen promotes unified concept of schizophrenia

IOWA CITY, Iowa -- Schizophrenia has many different signs and symptoms, ranging from paranoid delusions to apathetic withdrawal. Yet, it remains a question how this one illness can have so many different manifestations -- and how it can more effectively be treated or prevented.

The answer may lie in brain circuitry, where misconnections in how the brain is "wired" together may cause the misconnected thought that typifies schizophrenia, according to a theory developed by Nancy C. Andreasen, M.D., Ph.D., University of Iowa Health Care psychiatrist and director of the UI Mental Health Clinical Research Center. Andreasen recently published her first formal summary of her idea, a unitary model for schizophrenia.

"The clinical story -- the observations of misconnections in how a person with schizophrenia thinks and feels -- matches a brain-related story," said Andreasen, who has studied schizophrenia for more than 30 years. She hopes that by publishing her model more researchers and physicians will consider its implications for treatment and understanding of the illness.

Andreasen's concept of brain circuitry disruption is a neuroscientific update of a theory set forth in the early 1900's by Eugen Bleuler, a psychiatrist who practiced at Burgholzli Clinic in Switzerland. Bleuler ascribed the term schizophrenia (literally, a "mind torn asunder") to the illness in which patients had a substantial inability to think cogently. He underscored this commonality of thought disorder, whether manifested through the paranoid subgroup (in which a person falsely believes persecution or harm is imminent), or the negative subgroup (in which a person is apathetic, silent and devoid of emotion). However, Bleuler did not explain his theory in terms of brain mechanisms.

About five years ago, Andreasen began to take Bleuler's idea a step further and focus on what was "below the surface" rather than the surface signs of schizophrenia. By 1997, using evidence she and other researchers gathered through neuroimaging, she described a "misconnection syndrome" between parts of the brain that causes the cognitive dysfunction of schizophrenia.

"People with schizophrenia are impaired in different cognitive ways such as memory, attention and language," Andreasen said. "Yet neuroimaging studies reveal dysfunction within the cortical regions, cerebellum and thalamus no matter which cognitive function is involved."

The dysfunctional circuit is the cortico-cerebellar-thalamic-cortical circuit. The cerebellum was previously thought to be involved primarily only in coordination of motor activities. But researchers have found that the cerebellum and thalamus also are involved in thought tasks.

Additional evidence suggests the cerebellum has extensive cognitive functions, Andreasen said. For one, it is about one-third larger in humans than in chimpanzees; however, our motor skills are not that much more complex than theirs.

"Five years ago, 95 percent of researchers thought it was wrong to consider the cerebellum as a major factor in schizophrenia," Andreasen said. "Now, that opinion is switched."

Andreasen seeks to understand how the brain of a person with schizophrenia ends up in a misconnected state. Late adolescence, when schizophrenia usually makes it onset, is a major and critical period for brain maturation.

"Between the ages of 15 and 30 the brain completes its final wiring," Andreasen explained. "The axons and dendrites are in place, but there is fine sculpting or pruning to ensure the nerves are connected correctly. In schizophrenia, something seems to go wrong with this pruning, and behind that is some kind of aberrant molecular regulation of late neurodevelopment."

Andreasen will continue to document her concept of a unitary model and attempt to define more precisely the biomolecular mechanism that makes the brain circuitry go wrong.

Her team, in conjunction with researchers at the University of California in San Francisco, will also investigate how brain plasticity -- the ways in which the brain is affected by biological and social environmental factors -- may contribute to schizophrenia treatment.

"While some changes to the brain are irreversible, the brain also has a wonderful capacity to change and adapt," Andreasen said. "For people with mental illness we need to explore how much we can capitalize on brain plasticity to develop treatments that augment pharmaceutical treatments."

Schizophrenia affects approximately 1 percent of the population. Up to 10 percent of affected people eventually commit suicide. Only a tiny percentage of people with schizophrenia are dangerous to others, and people with the condition are overall less prone to violence than the general population. While treatments can be effective, most people with schizophrenia do not fully recover.

"It is interesting and promising to see changes in public attitude toward schizophrenia over the past 15 years," Andreasen said. "Like cancer, people used to talk about schizophrenia in a whisper, but now people are talking about it more openly and raising awareness."

Andreasen's article on a unitary model of schizophrenia was published in the September issue of the Archives of General Psychiatry. Her work was supported in part by three grants and a Research Scientist Award from the National Institute of Mental Health and by an Established Investigator Award from the National Alliance for Research on Schizophrenia and Depression.

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