March 19, 1999

Schizophrenia has long bewildered psychiatrists and terrified the layperson, seeming to appear without warning to devastate developing minds poised on the threshold of adult life.

But according to Robin Murray, M.B., symptoms of schizophrenia are apparent well before the first full-blown episode of the disease. In connection with his research on schizophrenia, Murray, a professor of psychological medicine at the Institute of Psychiatry in London, England, received the Dean Award from the American College of Psychiatrists (ACP) at the ACP's 36th annual meeting in San Francisco in February.

Murray's department carried out two major, prospective studies that elucidated precursors to schizophrenia. One study involved 50,000 people, another 5,000 people. In the larger study about 190 people developed schizophrenia, and in the other study about 30 people did so, according to Murray.

His research has led him to conclude that "symptoms of schizophrenia don't suddenly arise in adolescence, but have their origins much earlier in life." Major risk factors include having had a relative with schizophrenia and having suffered perinatal complications. As children, persons prone to develop schizophrenia are "more likely to be a bit solitary, their I.Q.s on average are five points lower than the rest of the population, they are more likely to have minor problems with coordination, and more likely to have social anxiety," said Murray. "Although the people in our sample didn't become psychotic until their early 20s," they were deviant from age 6 and became more abnormal as they approached adolescence. Psychosis does not "suddenly erupt at age 22 or 23," Murray added.

The advent of brain-imaging technology has proven an invaluable tool for scientists such as Murray. At the ACP meeting, he displayed brain scans depicting the activation of distinct parts of the brain in response to a person's listening to sounds, listening to speech, thinking of words, and moving fingers on the right hand.

One of the most fascinating aspects of Murray's work has been the use of such scans to investigate how people with schizophrenia experience auditory hallucinations, which many say they find among the most disturbing symptoms of the disorder. One theory of these hallucinations is that people who suffer from schizophrenia mistake internal thinking for audible speech. The notion is that of "inner speech going wrong," said Murray.

Murray and colleagues decided to look at Broca's area in the brain's frontal cortex, because that is "where people generate words in their brain," explained Murray. They also decided to look at the auditory cortex within the brain's temporal lobes to see the contrast between the process of verbal thinking versus heard speech in normal people and auditory hallucinations versus heard speech in people with schizophrenia.

The scientists took 12 people with severe schizophrenia and observed their brain function through magnetic resonance imaging. They found that when the subjects reported auditory hallucinations (by holding up a finger), Broca's area was activated, which would be expected, but also found that the auditory cortex was activated. Even more fascinating, said Murray, was that in people with schizophrenia who listened to audible speech while experiencing auditory hallucinations, there was no additional activation of the auditory cortex. In other words, explained Murray, the schizophrenic brain reacts as if unable to distinguish between its own internally generated speech and actual, audible speech.

In normal people, there is activation of Broca's area when they think of words, but there is no activation of the auditory cortex. When normal people who are thinking words are then exposed to audible speech, there is a dramatic activation of the auditory cortex visible as a lit-up area on the MRI.

If the brains of people with schizophrenia react to imagined internal speech in virtually the same way as they do actual speech, perhaps people with schizophrenia also have trouble identifying their own interior voice as being their own, Murray speculated. To test this hypothesis, Murray's colleagues had people with schizophrenia and normal people speak into a microphone and listen to their own voices slightly distorted.

People with schizophrenia were not good at recognizing their own, slightly distorted external voice as being their own voice, while normal people quickly identified the voice as their own albeit slightly distorted. Although not conclusive, the exercise strengthened Murray's belief that in schizophrenia, the brain experiences imagined speech as audible speech and is unable to identify internally generated speech as coming from within the brain.

Murray noted that research on twins has revealed a significant genetic element in schizophrenia. Among monozygotic twins, there is a concordance of about 40 percent, that is, if one twin develops schizophrenia, the other twin will also do so about 40 percent of the time. In dizygotic twins and among nontwin siblings concordance falls to about 1 percent.

But despite relatively clear evidence for a genetic role in schizophrenia, the precise genetic mechanisms are many and complex and have yet to be elucidated.

"What we do know is that there are no big genes for schizophrenia," remarked Murray. Based on current knowledge, it appears that variants in a number of disparate genes contribute together to neuro-developmental abnormalities that may then put someone at risk for schizophrenia.

He gently chided the field of psychiatric genetics for seeking genes that cause schizophrenia rather than genes that may contribute to risk factors for the disorder.

"Cardiologists don't look for genes for coronary artery disease," observed Murray. "Cardiologists search for genes for risk factors for coronary artery disease."-R.B.K.