The Disordered Mind

Researchers tackle the mystery of schizophrenia, a disease that attacks those very qualities that make us human.

By Andy Fell

Scott was 20 when he began to hear voices. Studying for a law degree, he became convinced he was the target of a massive conspiracy. He began to miss class and would either stay in bed all day or wander the streets. His rapidly dwindling number of friends felt he had become depressed and withdrawn. When he did speak, his conversation was confused and bizarre. Eventually he dropped out of school and moved back home. Scott began seeing a psychiatrist and was diagnosed with schizophrenia. He responded well to treatment, which controlled his hallucinations and conspiracy delusions. But he found that being diagnosed with schizophrenia was not exactly a plus at job interviews. Now he holds down a low-level job in a grocery store and is applying to re-enter college.

Scott is fictional. But his story is typical. Schizophrenia, which attacks one person in a hundred, is still a mysterious disease. It attacks those very qualities that make us human: reason, logic, emotional expression, interaction with others. And like other mental illnesses it still carries a stigma. But it is a disease, just like diabetes or breast cancer, and in most cases it can be treated effectively, although not cured.

Schizophrenia is diagnosed from a combination of symptoms. Best known are the psychotic symptoms: auditory hallucinations, delusions that can sometimes be paranoid, and disordered thought that tumbles through the mind in an erratic and confusing way. Then there are what are often called “negative” symptoms that change an individual’s affect or emotional appearance: Patients seem withdrawn and emotionally “flat” or show inappropriate or abnormal emotional responses. People with schizophrenia can exhibit all or some of these symptoms to different degrees.

In the last three decades, psychiatry has made a radical shift from the Freudian approach, in which the mind was considered a black box to be explored through therapy, to the realization that the brain is a body system with its activities rooted in biology, chemistry and physics. A vastly complicated system, it’s true, but ultimately comprehensible.

At UC Davis researchers across campus and at the medical center are working toward that comprehension, seeking the causes of schizophrenia using multiple routes, studying molecular biology, high-tech brain imaging, family genetics, hormonal influences and brain development. They’re also studying less-known features of the disease, such as problems with memory and concentration, that could give clues to its causes.

A better understanding of the causes of schizophrenia could lead to better treatments or prevention strategies; it could also help dispel some of the myths, stigma and discrimination around mental illness. And by researching this complex disease of the brain, we should learn something about how a healthy brain works.

At the UC Davis Center for Neuroscience, Director Edward Jones uses an approach based on the latest methods in molecular biology, imaging and computing. Jones is a principal investigator in a research consortium that includes UC Davis, UC Irvine, Stanford University and the University of Michigan, which was recently awarded a grant of $38 million by the Pritzker Family Philanthropic Foundation to further schizophrenia studies.

"There is little question in my mind that schizophrenia has a basis in defective genes, which put a brain or individual at risk. But that does not mean that the individual is going to contract the disease. That’s where we’re still groping in the dark,” said Jones.

The genetics of disorders like schizophrenia or autism are much more complex than diseases like Huntington’s disease or sickle-cell anemia, which are caused by a single faulty gene, Jones said.

“The best working hypothesis that we have to go on is that schizophrenia is caused by a combination of genes and environment,” he said.

Jones and his collaborators are taking a three-pronged approach to this problem. They are studying how and when genes are expressed—turned on or off—in diseased and healthy brains, building detailed atlases of the brain and studying the genetics of families in which schizophrenia seems to be hereditary.

Using microarray technology, or “gene chips,” consortium researchers are comparing brains from people with schizophrenia and depression alongside brains from healthy people. Microarrays allow scientists to look at the activity of thousands of genes simultaneously—rather like asking for a show of hands instead of polling people individually. The hands that stick up, or the dots that turn green rather than red, are “on” and can be picked out and studied in more detail. Because each dot corresponds exactly to a specific DNA sequence, each can be used to identify which genes are on and which are off at any given time.

Key to the consortium’s approach is a “brain bank” established by Jones and his collaborators at UC Irvine. The collection contains brains from diagnosed, well-documented schizophrenia patients who left their brains to medical research. For each, the collection also includes a matching normal brain from a person of similar age and characteristics. Shortly after death, the brains are quick-frozen with liquid nitrogen and carefully stored to preserve structures and the precious DNA and RNA. Using specialized equipment at the Center for Neuroscience, researchers can pick out pieces of brain as small as a single neuron and look at gene expression using microarrays.

At the same time, Jones’ group is building visual atlases of the brains of humans and rhesus macaques, with funding from the National Institute of Mental Health’s Human Brain Project, the Pritzker Foundation and the W.M. Keck Foundation. Eventually, said Jones, visual maps, genetic information and images created by technology such as magnetic resonance imaging and positron emission tomography will be united in databases that give a comprehensive view of the brain and how it works.

Jones envisages a computer program like an Internet browser that allows researchers to study brain sections, zoom in to microscopic detail, then call up information on expressed genes, MRI images and CAT scans.

Computer scientists from the Center for Image Processing and Integrated Computing at UC Davis are working with Center for Neuroscience researchers to build such “virtual reality” models of the brain. This work is partly supported by a grant from the Keck Foundation.

The consortium is also studying the genetics of families with a history of schizophrenia. The researchers will be able to apply what they have learned from the microarray studies of dead brains to living families, tracing the inheritance of suspect genes and comparing it to patterns of disease in families.

Studying inheritance patterns in affected families is also the approach taken by researchers at the UC Davis Medical Center. Psychologists Bill Kremen and Anne Hoff have been studying cognitive defects, such as memory loss, problem-solving difficulties and attention deficits, in people with schizophrenia and their relatives.

“In the 1970s, mainstream thinking was that cognitive deficits really weren’t present in schizophrenia,” said Kremen. If they were present, they were thought to be secondary to other symptoms. Since then, it has become clear that these are core problems in schizophrenia, he said.

“In many ways, they’re more problematic than psychotic symptoms,” said Hoff. Drugs that control symptoms such as hallucinations and delusions don’t work well against cognitive defects, she said. But at the same time, these cognitive symptoms are giving the researchers a window into how schizophrenia could be inherited.

Schizophrenia is a disease with many different features that vary among patients. It’s hard to tell from examining individual patients which features are fundamental to the disease and which are secondary phenomena; for example, a schizophrenia patient might have difficulty concentrating either because he or she is distracted by hallucinations or because attention deficits are a core symptom of schizophrenia. Secondary phenomena may also be caused by such factors as institutionalization or the side effects of drugs, Kremen said.

Kremen studies the relatives of people with schizophrenia to see if they show any features in common with their sick brother, sister, parent or child. He has found that relatives of schizophrenia patients sometimes have problems with attention and memory that are similar to defects in schizophrenia, though milder.

Although these problems are not enough to cause disease by themselves, and may not even be noticed without specific testing, they are a strong clue that these abnormalities are part of the genetic background of schizophrenia, Kremen said. They also make it easier to trace the genetics of schizophrenia, because they are shared by more family members.

Imaging data supports the hypothesis that healthy people can share brain characteristics with relatives who have schizophrenia, according to Kremen. Studies in which he has participated have shown that the hippocampus, a region of the brain associated with memory, and the thalamus, which is associated with sensation, were smaller in schizophrenia patients and their relatives than in the general population. This effect was most pronounced in families with more than one diagnosed case of schizophrenia.

Kremen agrees with Jones that the molecular genetic information from postmortem studies will contribute to the understanding of schizophrenia and related brain abnormalities in affected families. Eventually, this could lead to treatments for these underlying defects.

“Ultimately, we’re talking about the possibility of preventive intervention in people whose genes put them at risk,” he said.

The ability to detect these borderline or susceptible patients and the development of new drugs to treat them do raise other issues, however. New tests for underlying genetic susceptibility might lead to apparently healthy family members being identified as possible patients. Decisions would have to be made about when a person should be treated.

These shared genetic characteristics will not in and of themselves lead to the disease. Full-blown schizophrenia requires the action of several genes, plus outside environmental factors that act on those genes and trigger the disease. Researchers are not sure what those factors are, although they have some ideas.

One possibility is that the brains of schizophrenia patients are slightly damaged during pregnancy or childbirth. The hippocampus is a very oxygen-sensitive structure, said Kremen, and if childbirth complications reduce oxygen flow to the baby’s brain, it would be one of the first areas affected. Another possibility is that the developing brain is damaged before birth by, for example, a fever in the mother.

To explore some of these possibilities, Kremen is about to join a major project with collaborators at Columbia University and UC San Francisco that is funded by the National Institutes of Health. They will analyze detailed pregnancy, birth and early child-development records collected by the Kaiser Oakland health system in the early 1970s. The data were collected from thousands of families as part of a study of healthcare and not specifically to look for mental illness.

Other UC Davis researchers are looking at influences at a later stage in child development. Psychiatry professor emeritus Irwin Feinberg has spent most of his career learning about sleep. Along the way, that’s led to insights into diseases of the brain, including schizophrenia.

As children grow to adults, the brain continues to develop, Feinberg said, with a major reorganization taking place during adolescence. During that time, nerve connections or synapses are actually removed from the brain. This “synaptic pruning” clears some clutter from the brain by eliminating unnecessary circuits, although it also reduces the brain’s ability to recover from injury.

In 1982, Feinberg proposed that errors in synaptic pruning might create faulty brain circuits leading to schizophrenia. Before the development of this model, schizophrenia had not been thought of as a neurodevelopmental disorder, said Feinberg. Although the exact role of synaptic pruning in schizophrenia is still hazy, it is now widely accepted that brain development plays a role, he said.

Synaptic pruning could be one factor that uncovers a genetic defect leading to schizophrenia, said Feinberg. But he holds out the possibility that, in some individuals, no pre-existing defect—but the pruning process itself—leads directly to disease. “Both are viable working hypotheses,” said Feinberg.

At the UC Davis Psychiatric Research Center at Napa State Hospital, psychologist Anne Hoff is also interested in how developmental changes affect the brain. She is especially interested in the role of the female sex hormone, estrogen, in schizophrenia.

Overall, women with schizophrenia tend to develop the disease a few years later, respond better to treatment and have a different pattern of symptoms than men, Hoff said.

In a few cases, sharp drops in estrogen during the menstrual cycle, at menopause or following childbirth seem to trigger psychosis, she said. That suggests that hormonal changes are one of those environmental factors that can unmask the genetic potential to develop schizophrenia. Fluctuating estrogen levels are a factor in a whole family of diseases that are influenced by pregnancy and the menstrual cycle, including migraine, premenstrual depression, postpartum depression and postpartum psychosis.

In a recent study published in the American Journal of Psychiatry, Hoff, Kremen and their co-workers examined a group of 22 severely mentally ill women who, overall, had lower than normal estrogen levels. The researchers found a link between estrogen level and test scores for memory and concentration, with those with higher levels of the hormone performing better. There was no effect on psychiatric symptoms such as delusions or paranoia.

“Estrogen clearly has a neuroprotective effect” on the brain, said Hoff.

It seems that, just as there is no single schizophrenia gene, there is no one environmental factor that throws the switch and causes the disease to develop in susceptible people. A complex disease likely has complex causes.

Perhaps it’s the very complexity of the human brain that makes us vulnerable to a disease like schizophrenia. Animals just don’t develop the same kinds of disease, says Jones.

“While monkeys may be subject to the same cerebral defects, the readout is going to be different,” he said. Animals lack the mental capabilities to show the clinical syndrome of schizophrenia, and it’s hard to tell whether an animal is having hallucinations or delusions. Social interactions can be easier to measure, but extrapolating from social behavior in animals to behaviors in humans, or vice versa, while it might be intuitively appealing, makes a methodical scientist’s hair stand on end.

“This is why I think it is so important to do the molecular, cellular studies in human brains, because then we can identify the genes, the proteins, and then we can start to develop the animal models. We can’t work backwards from behavior because the behavior is species-specific,” Jones said.

Because schizophrenia is so specifically human, studying it might tell us something about how our minds work. For example, creativity and thought disorder have something in common, Kremen said. In each you put things together in a novel way.

“It’s just that one is more controlled and has a productive outcome, and the other doesn’t,” Kremen said. “It may be that uniquely human characteristics that enable us to be creative also increase the risk of disorganized thought.”

A wider understanding of mental illness and its relationship to the healthy brain is badly needed. Mental illness still carries a pervasive stigma both socially and in employment, even though each year around one in five Americans will experience some sort of mental illness, such as depression, anxiety disorder or schizophrenia. According to a 1999 report by the U.S. Surgeon General, up to two-thirds of people with mental illness don’t seek treatment, at least partly due to that stigma.

That stigma is even reflected in healthcare. Effective drugs to treat schizophrenia are available, but health insurers have imposed stricter limits on coverage of mental health than on “bodily” health, according to the Surgeon General’s report, even though psychiatrists have known since the 1970s that mental illness is not an abstract disorder of the mind but phenomena rooted in the structure and chemistry of the brain. By understanding schizophrenia better, perhaps some of that stigma—the impression that mental illnesses are not “real” illnesses—can be erased. Research may also allow us to create a detailed map of the human mind—a map that perhaps will lead us to a better understanding of ourselves.

Andy Fell writes about the sciences for the UC Davis News Service.