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Reassembling
Divided Minds December
1996 I was in my room because I was talking to God over the radio and then the sun came out . . . And I couldn't help but cry and cry because I missed my husband in the sky. so my son came down and then I saw God, my son. He was the sun." One of the hallmarks of schizophrenia, a mental illness characterized by hallucinations, paranoia, and a host of what psychiatrists call negative symptoms -- the loss of motivation and the inability to feel pleasure, among them -- is a uniquely disjointed way of talking. While researchers have long been unsure of what, if anything, to make of this trademark incoherence, investigators at Yale are probing "schizophrenese" for clues about the cause of the ailment. And from a series of insights about the geography of this particular form of mental illness, these researchers are beginning to come up with novel methods of treatment. The key is a concept called "working memory": the process by which the brain holds the information it needs to use for a short period -- say, the amount of time a person requires to dial a phone number -- after which the mental slate is wiped clean. (Long-term storage takes place through associative memory.) "Working memory gives us the functional capacity to form plans," says William Sledge, a professor of psychiatry who has studied communication disorders in schizophrenics. "Normally, when we talk, the words are arranged more or less in grammatical fashion because our brains put together a plan for creating each sentence. But schizophrenics can't hold on to this kind of strategy. They get distracted by elements of each word, and as a result, they form sentences that don't make sense to anyone." There is irony in all this. As Sledge explains it, schizophrenics "can understand other people just fine. They seem to have all the rules for grammar in their minds, but they just can't use them to make themselves understood." This occurs, explains neurophysiologist Patricia Goldman-Rakic, because of a breakdown in small groups of nerve cells scattered throughout the prefrontal cortex, which serves as the brain's "executive center" and, in many ways, the seat of human personality. Goldman-Rakic, a professor of neuroscience at the Medical School, has worked with both rhesus monkeys and humans to investigate the basic biology of the disease. She says that a number of experiments demonstrate the link between working memory and schizophrenia. In one key study, for example, a monkey was presented with two empty food containers. An experimenter put a peanut into one, covered them both, and then, after a brief delay, prompted the monkey to choose the container holding the treat. A correct choice was rewarded, and soon, the animal became skilled at the game. However, when certain cells in the monkey equivalent of a prefrontal cortex were destroyed, something very strange happened. If the position of the peanut was suddenly changed, the brain-damaged animal, even though it watched the change taking place, persisted in choosing the old -- and now wrong -- container. "This occurs because we've removed the structure with which information is held in mind," notes Goldman-Rakic. The same kind of wrong-headed persistence is seen among schizophrenics when they take the Wisconsin Card Sorting Test, an assessment tool used by researchers to examine the inner workings of human memory. The test involves matching various cards, each of which is a particular color and contains a number of shapes -- say, a red card with three triangles. The subject decides on precisely how to match the cards and could, for example, choose to group red cards, or those with triangles, or those with three shapes. Once the criteria for matching are established, the subject is rewarded for making the proper choices. But as part of the test, once the subject becomes adept at the task, the experimenter announces that the matches are wrong. The subject must then figure out a new basis on which to group the cards. People whose brains are functioning normally will make the required switch with aplomb, but while schizophrenics can usually accomplish the initial matching task, dealing with change is difficult. "Once they've learned a particular response, they persevere," says Goldman-Rakic. If schizophrenia is, as she, Sledge, and a growing number of other researchers believe, primarily a working memory defect, then such perseverance is precisely what one would predict. Learned, reinforced responses are "stamped into the nervous system" as associative memories, notes Goldman-Rakic, and in the absence of the ability to "update information on a moment-to-moment basis," overriding what is already known becomes impossible. In addition, the susceptibility to interference which is also part of the disease means that "a schizophrenic often can't keep a sentence's subject in mind by the time a verb appears," says the neuroscientist. "Both the thought process and the capacity to speak coherently are derailed." The reason this occurs is that "certain cells aren't doing their jobs," explains Goldman-Rakic. Normally, the neurons involved in working memory are supposed to keep active for a set amount of time even after the information they're designed to convey has departed the scene. But this no longer happens in the schizophrenic, and so out of sight becomes literally out of mind. Modern high-tech methods of watching the brain at work have demonstrated convincingly that there is less activity in a schizophrenic's prefrontal cortex, and Goldman-Rakic, using material from brain banks in Boston and the National Institute of Mental Health in Maryland, has confirmed that this critical cerebral area is indeed reduced in volume. However, her investigations also found that the shrinkage is not due to cell loss; rather, it occurs because the neurons are packed closer together than usual and the individual cells are shrunken and atrophied. Instead of resembling many-branched trees, the neurons look unnaturally pruned. While there are many theories, no one knows why this cortical forest abruptly starts to lose branches. Whatever the reason, the change occurs in late adolescence or early adulthood. The results, almost invariably, are devastating, but not always in the same way. There are many divisions of labor in the prefrontal cortex, and both the degree and location of damage take different forms in each individual. Just how different is clear from the work of Bruce Wexler, an associate professor of psychiatry. Wexler both studies and counsels schizophrenics at the Connecticut Mental Health Center (CMHC), a comprehensive mental health research and treatment facility run jointly by Yale and the state. "Schizophrenia, as it's currently defined on the basis of symptoms, actually includes many illnesses and deficits that we couldn't, until recently, differentiate," says Wexler. Thanks to the availability of high-speed computers, he has been able to devise and analyze a set of what he calls "multidimensional neurocognitive assessments" of people diagnosed with this mental illness. Scientists have learned that there had to be at least two fundamental variations on the schizophrenic theme, for when patients are given medications to curb symptoms, some people are helped by a class of drugs known as the typical neuroleptics, while others find relief through a very different kind of medicine. Wexler and his team administered their battery of tests to CMHC patients in the second group -- those taking a "wonder" drug called clozapine -- and discovered that about all they had in common was a diagnosis. "We found that [in this group] there are at least three subtypes of schizophrenia," says Wexler. One group had difficulty with a series of assessments that measured a person's ability to tell the difference between sounds, and then remember that difference for varying lengths of time. The tests could be relatively easy, as in one in which a subject heard sounds a third of a second apart and had to determine whether they were the same. The tests could also be tough, as in another during which a person heard three tones and, after a noise-filled pause that could last as long as nine seconds, had to determine if a new sound matched any of the original tones. A second group could handle the tone tests, which were primarily assessments of working memory, but failed a "shopping list" exam in which a subject was read a list of 16 common items, and then asked to repeat them. A subject had five tries to memorize the list. A few schizophrenics, however, managed to remember everything, a mastery, says Wexler, that only one out of five "normal" people ever achieve. "I don't believe that the people we tested can have the same disorder. They may look similar to a clinician, but at the brain level, it's another story." Wexler's testing procedures confirm what a growing number of researchers have suspected: that schizophrenia is a family of diseases. But what makes the psychiatrist's work of more than academic interest is its ability to zero in on precisely which brain functions are compromised. "The medications we have available are good at treating symptoms like hallucinations, but the drugs don't help remedy the cognitive deficits," says Wexler. "In fact, they may make some of them worse." The assessment profiles that Wexler's lab can now generate may allow clinicians to find dosage levels of drugs that alleviate some of schizophrenia's classic problems without causing what one researcher called a "chemical lobotomy." Efforts are underway at Yale to find better medications, and in places such as Goldman-Rakic's lab, research is being aimed at discovering the fundamental processes by which the cells involved in working memory keep information on-line. "We're not on the threshhold of a drug discovery," Goldman-Rakic admits. "But we're on a path, and there's great hope through basic research." In the shorter term, however, other intervention strategies could have more immediate payoffs. Wexler, for example, has recently finished a pilot study in which he devised a series of training tasks aimed at improving a schizophrenic's compromised mental abilities. A typical task involved looking at a number and a word displayed for one second on a computer screen, and then, after a two-second interval, trying to recall both. Initially, new word and number pairs appeared for a minute and a half, and in the course of training sessions that were held five times a week for ten weeks, both the display and the interval times grew shorter while the task time increased to eight minutes. As improvements in performance warranted, tasks in the training program became progressively more difficult as well. At first, none of the 22 patients in Wexler's study could handle the work, but after ten weeks, 16 of them matched or exceeded the performance on memory and perception tasks of a group of nonschizophrenics. When six patients were tested six months later, half retained the gains they had made. Perhaps this kind of training improves the functioning of nerve cells. Perhaps the "exercise" pushes neurons to branch out and make alternate connections. New ways of watching the brain at work, particularly magnetic resonance imagery, may enable scientists to understand not only where working memory becomes derailed, but how the process can be put back on track. Meanwhile, though, the large state mental hospitals, once essentially warehouses for the mentally ill, are closing and disgorging a steady stream of people, many of whom are schizophrenic and ill-equipped to function in a society that is equally ill-prepared to deal with them. "The long-term institutionalizations of the past have generally been very destructive," says John Strauss, a professor of psychiatry who has led efforts to change the way schizophrenics are viewed -- and treated -- by society. Until the middle of this century, Strauss notes, parents of children who developed the disease would be given a diagnosis, then told to drop the son or daughter off at a mental institution, regard the child as dead, and get on with their own lives. That was the accepted wisdom, but in the 1970s Strauss and a team of colleagues looked at data collected for the World Health Organization's International Pilot Study of Schizophrenia. "We were able to show that at least some people improved," he says. "This is a very heterogeneous disease with a very heterogeneous outcome. There's been a tendency to dehumanize and depersonalize schizophrenics, but that's bad science, and bad for everyone involved. I've interviewed many patients, and I can tell you that we're talking here about people with goals who are struggling to make sense of life. I don't know any basket cases." Diagnosis, in his view, was not prognosis. Among Strauss's statistics, one of the strongest predictors of a good outcome was "previous social relations." Having held a job was also an indication that a patient had a reasonable likelihood of getting better. On the other hand, social isolation is a predictor of poor outcome. Says Larry Davidson, an assistant professor of psychology who directs the clinical care program at the Connecticut Mental Health Center: "We can help patients find the right medication, but they need more than pills." Enabling the mentally ill to get back into the community requires a number of linked strategies. One CMHC approach, known as cognitive behavioral psychotherapy, involves having schizophrenics explain why they hear voices. "If they can come to understand that it's just their brains playing tricks on them, and not God, the devil, or the CIA talking, there's the potential that symptoms will decrease and patients will be able to cope more adaptively," says Davidson. Psychiatric rehabilitation also demands jobs, community support, decent housing, and, as Strauss has shown, friends. To help meet that need, Davidson and others at the CMHC have developed what they call the Partnership Program, a statewide effort to provide regular companionship for schizophrenics. "This is a very poignant illness," says psychiatrist William Sledge. "It typically begins in the bloom of life -- in either late-adolescence or early adulthood -- and then strikes down that sense of youthful promise. Because schizophrenia is, we believe, an illness of thinking and communication, it gets at the core of what defines us as human." The fundamental failure of working memory that Yale researchers are uncovering can bring with it an isolation that may trigger further episodes of psychosis, more hospitalization, and suicide. Something as simple as friendship, says Davidson, can help break this cycle. In some cases, the companions are schizophrenics who are relatively far along in the recovery process. The friends may also be volunteers who have never had the ailment. Those people in the first group demonstrate that recovery is indeed possible; those in the latter group show their companions that "there are other things to think about besides mental illness," says a participant. "Life isn't one big horror." Davidson is quick to note that the Partnership Program does not offer a miracle cure. It does, however, seem to cut down on relapses. "The experience enhances the quality of a schizophrenic's life in the community," he says. "Having a friend can provide a reason to get well." |
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Yale
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