THE UNIVERSITY OF GEORGIA RESEARCH MAGAZINE : www.researchmagazine.uga.edu
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The voices came to stay when she was 25. And then there were other hallucinations a feeling that something unseen was touching her.
I was working on my Ph.D. in English then, said Joan R., a petite middle-aged woman with a pixie haircut and a warm smile. I got alienated from people. I identified more with the chorus in the Greek myths.
Joan suffers from schizophrenia, a devastating mental illness that is much misunderstood by the public and still a puzzle to science.
While Joan now takes medication to control the voices that talked about bad things, she can no longer concentrate long enough to read more than a few sentences and cant remember what she reads; her love of literature is reduced to christening stray cats with names from the Greek and Norse myths.
Schizophrenia means split mind, said L. Stephen Miller, a University of Georgia psychology professor who studies the disease. But it means a split of the mind from reality, not a split of the mind into two parts.
For more than 12 years, Miller has studied how small changes in a persons brain can alter behavior, particularly in schizophrenia and Alzheimers disease. He is among hundreds of researchers around the world who are trying to unravel the underlying biological mechanisms and genetic nature of schizophrenia.
Im interested in looking at what the processes are whatever negatively impacts the brain to cause some aberrant behavior. It might be developmental difficulties that occur in the brain; it might be insults to the brain, Miller said.
Millers research focuses on what psychologists call cognition, which includes many aspects of thinking such as attention, concentration, comprehension, memory and judgment. Cognitive tasks range from simple abilities like making change for a dollar to complex activities that require concentration like playing chess.
The reason that we focus on cognition is because its a window to the function of the brain, Miller said. When we see deficits in cognition, then we infer that to mean deficits in the organization or the structure of the brain in some way the way that the brain functions.
Miller has been examining deficits in cognition caused by schizophrenia. For example, he uses neuropsychological tests to examine social skills and explore how visual information is processed. By using sophisticated medical technology like magnetic resonance imaging, he tries to uncover structural changes and activity in the brain linked to specific mental tasks. All these techniques are aimed at sorting out which behaviors associated with the disease are linked to genetically inherited changes in the brain.
Hallmarks of schizophrenia
The most common misperception of schizophrenia is that it is the same as split personality. Its not.
Instead, people with schizophrenia cant distinguish what is real from what is not. And it strikes one in every hundred people, often during their college years.
To schizophrenics, the world is a jumble they cant comprehend. They hear, see, even smell or feel things that are not there. Speech and thoughts may be incoherent. They may believe their thoughts are being controlled. These are the hallmark symptoms, the ones that respond to medication.
But there are other symptoms that the drugs dont help. A persons ability to feel emotion may be dulled or gone altogether. Combined with eccentric behavior, a person with schizophrenia may become socially isolated.
I did therapy with a patient for two years who really, honestly believed that people were able to hear his thoughts a problem that impacted his life in a thousand ways, Miller said. He wore headphones, he would talk out loud all the time and use profanity to cover-up what he believed other people could hear.
Once thought to be caused by personality defects, bad parenting or demons, scientists now know that schizophrenia has a biological basis: It has to do with faulty brain wiring. Brain abnormalities that occur during development are not evident until late adolescence or early adulthood. The result is a dramatic disturbance in the way a person thinks.
But getting at the underlying biological and genetic mechanisms is a tough problem.
For one thing, scientists believe that multiple genes are involved, with each contributing a small effect. In fact, while schizophrenia runs in families, its not really simply a matter of genetics. Studies of identical twins show that one twin has only a 48 percent risk of developing schizophrenia if the other twin has the disease. Both twins would be expected to have the illness if it were solely a genetic disease because they share the same genes. What is inherited seems to be a genetic vulnerability to the disease, not the disease itself.
Apparently, environmental factors perhaps a virus, poor prenatal nutrition or complications during birth must interact with several genes on different chromosomes for illness to occur. Scientists believe that this interaction of genes and environment somehow disrupts the cell migration and reproduction that occurs during normal brain development.
There are lots of different reasons someone may have schizophrenia. The brain pathology seems to be inherited, probably the result of some neuro-developmental impairment, Miller said. But this is where we get unsure whether its genetic a problem with genes or whether it is due to some insult early on during a critical time in the brain development.
To complicate matters, the very medications that keep the hallucinations, delusions and other symptoms at bay make it difficult to study the link between deficits in cognition and how the brain works.
Miller attempts to isolate the cause by taking parallel paths: studying individuals with related but less severe disorders and studying relatives of schizophrenics. In fact, many scientists now focus more on patients relatives than on the patients themselves.
Along with former doctoral student Tracy Waldeck, now at the National Institute of Mental Health in Washington, D.C., Miller published one of the first studies to examine social skills in people with schizotypal personality disorder a related illness thought to be part of a continuum with schizophrenia as the final and most severe end point.
Individuals with schizotypal personality have many of the same albeit less severe symptoms as individuals with schizophrenia. "There are cognitive, biological and neuroanatomical links between schizophrenia and schizotypal personality disorder," Miller said.
Both disorders share many similarities: the way the brain processes information, a reduced ability to concentrate and structural abnormalities in the brain, to name a few. Theres also a genetic link. Like schizophrenia, SPD runs in families. The main difference is the severity of the deficits and, unlike schizophrenia, people with SPD are usually not taking medications that interfere with cognitive studies.
Scientists had already determined that people with schizophrenia have difficulty dealing with social situations: They may avoid eye contact, speak too loudly or use inappropriate gestures. What Miller and Waldek wanted to find out was whether or how much this trait also affected people with SPD.
Participants in the study both with and without SPD performed three tasks to determine how their social skills stacked up.
First, participants identified the emotions depicted in black and white pictures of adult faces: interest, contempt, fear, shame, disgust, surprise, anger and joy. Next, participants listened to a tape-recorded description of a common social situation and were asked to act out a response. Last, they completed a multiple-choice questionnaire to see if they could identify appropriate social behavior in others.
What the researchers found is that the social skills of people with SPD mirrored those with schizophrenia: They correctly recognize emotions and inappropriate behavior in others but were not as good as those without SPD at choosing an appropriate response to a social situation.
While Miller didnt compare the behaviors of people in this study directly to those of schizophrenics, the study supports the notion that SPD is part of a continuum of related disorders and that studying people with less severe disorders may shed light on schizophrenia.
But to get a handle on the inherited behaviors, Miller took another tack. He and Jeffrey Bedwell, a doctoral student on his research team, set out to study cognitive deficits in relatives of schizophrenics.
Since first-degree relatives parents, children and full siblings share many of the same genes, Bedwell figured that if he studied cognitive performance in relatives of schizophrenics he'd have a good chance of finding traits that could be useful in genetic studies. Those traits may help identify family members who carry schizophrenia genes but have no symptoms and thus improve the chances of finding schizophrenia-related genes. In fact, two studies by other research groups have used this approach successfully to locate genetic regions associated with eye-movement disorders and defects in filtering auditory information, both of which are biologically based markers associated with the disease. Finding genes may lead to new prevention, diagnosis and treatment strategies.
Studying patients is problematic, Bedwell said. Performance differences in neuropsychological tests can be confounded by active symptoms, medication or prolonged hospitalization, which complicate interpretation of genetic brain effects.
Healthy first-degree relatives have few psychopathologies, are not on any anti-psychotic medication and haven't been hospitalized for a psychiatric condition. Any differences in the relatives are likely to be due to genetics because they are like the controls in most every way except for the fact that they share many genes with someone who has schizophrenia, Bedwell said.
Previous research showed that people with schizophrenia have problems with attention, sensory perception, memory, and reasoning, to name a few. Joan, for example, once had a job proofreading manuscripts, but as the schizophrenia got worse, it became a struggle to read and understand a single sentence. She began making errors and eventually lost the job. The faulty wiring in her brain prevented her from keeping the words in her mind long enough to make sense of what she was reading.
Performing a complex mental task like reading requires access to lots of information. Some of that information what the words mean, the feelings they evoke and the pictures they paint comes from long-term storage rather like the hard drive on your computer. Other information is only stored for short periods, more like a computer's RAM. For example, if you cannot keep all the words in this sentence in your mind at once, it will be impossible to understand what the sentence means. That short-term storage called working memory is defective in schizophrenics.
There's indication in the literature that people with schizophrenia have trouble paying attention over a period of time, Bedwell said. But then theres other recent evidence that sustained attention was not the problem, that all along it was a deficit in how visual information is processed.
Miller and Bedwell may be the first to put attention and visual processing head-to-head in one study. Bedwell tailored a set of neuropsychological tests to determine whether the relatives of schizophrenics experience problems with attention or visual perception and whether there was an accelerated age-related decline in performance.
In one test, one to 12 random letters flash on a computer screen every five seconds over a five-minute period and participants say if the letters T or F appear in a grouping. A poor performance on the last third of the test compared to the first third indicates declining attention span. However, stable performance but low accuracy when high numbers of letters appear on the screen points to a deficit in visual processing.
Another task checks working memory and attention. Random letters flash on a computer screen and the test taker presses a button when K is followed by A. The participant keeps the K briefly in mind until the next letter appears, is identified and a response is given. Again the first and last thirds of the test are compared to find any deficits in attention or visual processing.
What I hypothesized was that the ability to process visual information would show an accelerated age-related decline in the relatives, Bedwell said.
And that's what he observed. While the ability to process visual information declined with age for both groups, the decline was much faster in relatives of schizophrenics.
A little bit more controversial are our findings that there is not a difference in sustained attention within those same tasks, Miller said.
Impaired attention has been considered a core deficit in schizophrenia. Finding no difference in relatives compared with controls suggests that attention deficit in schizophrenia may not be passed on genetically. Instead the evidence points to a deficit in visual perception as the inherited trait. This implies that a different place in the brain is involved from the region implicated in attention deficit. It also left Miller and Bedwell with the task of figuring out what aspect of visual processing is problematic.
Seeing is believing
Processing visual information is a complex undertaking.
Imagine a chipmunk darts in front of your car. That triggers a series of events in your brain before you can understand what youve seen. It may seem instantaneous, but from the time the chipmunks image enters your eye until you think, Im about to run over a chipmunk, better slam on the brakes, 50 to 100 milliseconds have passed. Thats about how long you hear the crack of a fastball hitting a bat.
During that instant, the image enters your eye in the form of light, strikes the retina and is translated into electrical impulses. These impulses flow along two pathways from the retina to a visual-processing center at the back of the brain called V1. From V1, the signal travels along these pathways to other visual centers. One set of "wires" - the magnocellular (M) or "where" pathway - carries information about movement and an object's location. A second set of wiring - the parvocellular (P) or "what" pathway - carries information about shape and color. From the various visual centers, the information travels to higher thinking areas of the brain where it is interpreted.
In schizophrenia, it seems theres faulty wiring somewhere along the visual pathway. Previous research indicates that people with schizophrenia and their relatives have a hyperactive M pathway, which may account for the sensory overload and problems filtering stimuli experienced by schizophrenics.
Using a test called backward masking, Bedwell and Miller confirmed that relatives, like schizophrenics, have a deficit in the M pathway.
In the test, letters flash in one of four locations on a computer screen up, down, left or right followed by a mask that covers the entire screen. Researchers vary the lag time between when the subjects see the letter and when the mask appears. Its easy to name the letters without the mask, but harder with the mask. Thats because the mask interrupts the letters image as it travels along the brains visual pathways, causing the signal to stall in one of the visual centers; you dont even know you saw it. The target letter and the mask stimulate a fast M system response and a slower P system response. The test can be used to discriminate the two pathways by asking the test taker to either give the location of the letter relying on the M system or to identify the letter, which uses the P system.
It seems one of the genes that relatives might carry is for a specific type of change in visual processing that is not apparent to them. These very difficult tasks can detect those subtle differences between the groups, Bedwell said.
Diffuse red light selectively suppresses the M system, slowing it down. Knowing that, Bedwell devised the test with two different colored backgrounds either neutral gray or red and compared a persons performance on both backgrounds.
He found that the control group performed worse when the background was red but that relatives performed equally well with both backgrounds. This difference suggests that relatives have a hyperactive M pathway.
If red slows down the magnocellular pathway, then that is what is hurting the controls performance, Bedwell said. And the relatives, as in schizophrenia, have a magno system that goes too fast. Red slows it down to normal levels, so it doesnt really hurt their performance.
Miller and Bedwell are now using functional magnetic resonance imaging or fMRI, (see related story, Mind Reading) to pinpoint the visual areas of the brain that may be responsible for these differences.
Were giving evidence that would suggest where other researchers might want to look to find the genes that turn visual processing on and off, Miller said. The ultimate goal is to find out what causes schizophrenia, what areas are involved, and whether there is any way you can treat it before somebody becomes psychotic and starts seeing things and hearing things and having these strong delusions.
Joan will struggle with her illness for the rest of her life.
I feel Ive settled down now, she said. But she will never complete the dissertation she was writing on Chaucer. And she will probably never hold a job again.
Recovery from schizophrenia like that of Nobel Prize winning mathematician John Nash recently depicted in the movie A Beautiful Mind is rare. The hope for better disease management is earlier detection and a better understanding of how parts of the brain are impacted and change behavior.
Historically, we have made tremendous gains in the understanding of schizophrenia, and yet, we still dont know very much about it, Miller said. Its very difficult for us to see into the mind. We have beautiful pictures of the brain but the mind is still an inference.
more information, contact Stephen
Kathleen Cason is associate director of Research Communications at the University of Georgia. She has degrees in microbiology and plant pathology and is the former editor of the Georgia Department of Technical and Adult Educations Results Magazine.
The Facts on Schizophrenia
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