Evidence Mounting for Role of Fetal Damage in Schizophrenia
By DANIEL GOLEMAN
Published: May 28, 1996
A DRAMATIC change is afoot in the scientific understanding of schizophrenia, a devastating mental illness with 2.5 million victims in the United States alone. The first symptoms usually appear when people are in their late 20's, but neuroscientists now believe that the seeds of the disorder are often sown during fetal development.
That is when the brain is wired up; nerve cells grow and divide, building connections with each other. The basic flaw in the brains of many schizophrenics seems to be that certain nerve cells migrate to the wrong areas when the brain is first taking shape, leaving small regions of the brain permanently out of place or miswired. Such errors in neural architecture may have one or more causes, which remain to be discovered. One speculation is that brain misconnections might develop when the mother catches a virus early in pregnancy.
The chief symptoms of schizophrenia include apathy, a blunting of emotions, delusions and the hearing of internal voices. Once these symptoms begin, they typically wax and wane for the rest of a person's life.
The origins of the disorder have long been mysterious. Once attributed to poor communication within families, the condition is now recognized as a disease of the brain, as seen in differences between schizophrenic and normal brains.
The idea that these differences arise during fetal development, said Dr. David Shore, chief of the Schizophrenia Research Branch at the National Institute of Mental Health in Bethesda, Md., "is one of the leading candidates for explaining how the changes we see in the brains of schizophrenics might have come about."
But that theory does not solve the entire puzzle. "Schizophrenia is probably many different kinds of problems that converge on the same syndrome, not just a single disease," said Dr. Daniel Weinberger, chief of the clinical Brain Disorders Branch of the National Institute of Mental Health. "But based on the weight of evidence, half or more of schizophrenia seems to be due to abnormalities in fetal brain development."
Evidence for that new theory comes from several different sources, including autopsies of patients' brains, family movies taken when patients were as young as 2 years old and epidemiological data.
One of the more convincing reports, based on tissue from autopsies and published this month in The Archives of General Psychiatry, showed neurons out of place in the prefrontal areas of 7 of 20 brains from patients with schizophrenia and in none of the 20 brains from people without the disorder. The study is the fourth of its kind to report wayward cells in various parts of the cortex in people with schizophrenia.
The out-of-place cells are unexpectedly large residues of the neural subplate, a structure that guides other neurons to their proper sites. The subplate forms about the fourth month of pregnancy. It gradually disappears almost entirely within the first month of life, having performed its task of aiming neurons toward their location in the cortex.
"The migration of brain cells through the neural subplate occurs almost entirely in the second trimester of fetal development," said Dr. Steven G. Potkin, a psychiatrist at the University of California at Irvine and a co-author of the study, with Dr. William E. Bunney and Dr. Edward Jones.
"If you disrupt this migration, cells end up in the wrong place or have faulty connections -- and that's what we found in the brains of the schizophrenic patients," Dr. Potkin said. "The maldistribution of these cells suggests an abnormality in the subplate."
Experiments on cats by Dr. Carla Shatz, a neuroscientist at the University of California at Berkeley, has shown that making cuts in the subplate at an equivalent period in the development of the cat brain produces cortical cells that are miswired or out of place.
Just what might cause the neural subplate to fail to perform its duties is a matter of surmise. Dr. Potkin speculated that "there may be a wide range of causes, from a faulty genetic mechanism to environmental insults, like the mother having a virus that penetrates the placenta, all of which interfere with the operation of the neural subplate during the critical months of fetal brain development."
One nagging question for proponents of the new theory is why no symptoms of schizophrenia appear for two decades or more if the brain abnormalities are present from birth.
One answer is that there are, indeed, signs of coming trouble throughout life but that they are subtle and easily missed. The British Medical Research Council tracked every child born in Britain in the first week of March 1946, assessing them every two years or so until they reached the age of 43. Dr. Robin Murray, a British psychiatrist, found subtle childhood differences among those who later developed schizophrenia.
At most milestones of neurological development -- analyzed by looking at things like when each infant first sat up and teacher ratings of each child's performance -- the development of the schizophrenic group, on average, was delayed.