Jan 10, 1999

Questions and Comments
Mary Herman: Dissecting the Secrets of the Human Brain by Ruth Levy Guyer, Ph.D.
Mary Herman, Neuropathologist

Mary Herman looks for the structural changes in the brain that cause schizophrenia and other serious mental disorders.

Mary Herman, M.D.  
Schizophrenia is a frightening disease. Some people imagine that insects are crawling under their skin; others hear voices urging them to jump off buildings. Unless they receive effective treatment, people with schizophrenia can spend much of their energy managing wild and often terrifying fantasies, and coping with the chaos in their brains. Mary Herman, who studies the brains of people who had schizophrenia when they died, says that the disease often simply overpowers its victims.

Herman is a neuropathologist. She studies how the brains of people with schizophrenia and other severe neurological disorders differ from the brains of apparently healthy people, both in structure and in the ways they function. To become a neuropathologist, Herman attended the University of Wisconsin in Madison as both an undergraduate and a medical student. She earned a B.S. degree in 1957 and an M.D. in 1960. For 25 years, she and her husband Lucien Rubinstein did research on brain tumors at Stanford University in California and at the University of Virginia in Charlottesville. But when her husband died several years ago, Herman decided to change her research focus.

A close relative had struggled with obsessive-compulsive disorder all his life. Herman had become curious about this and other diseases of the nervous system, and she shifted her research focus away from tumors and toward diseases of the brain. She has worked at the National Institute of Mental Health in Bethesda, Md., since 1991. She is also a consultant neuropathologist for the D.C. Medical Examiner’s Office and a teaching associate at D.C. General Hospital.

Many Causes
Schizophrenia is one of the diseases that Herman now studies. Researchers still do not have a clear understanding of what causes schizophrenia, although they do know that many factors play a role. One factor may be a person’s genes, says Herman. Neurogeneticists, who study the possible hereditary basis of brain disease, have reported that the gene or genes for schizophrenia may be carried on particular chromosomes. So far, none of those findings has turned out to be definitive.

Other scientists focus on various environmental factors as the possible triggers of schizophrenia. They believe that viruses, toxins, too little oxygen, malnutrition, or perhaps radiation can damage DNA or cells in the brain sometime during an individual’s life and cause the symptoms of schizophrenia. And, although the stage may be set early—even in utero—for the development of the disease, the signs and symptoms of schizophrenia typically do not show up until an individual is a young adult.

Sorting out which factors lead to schizophrenia in any one person is very difficult. For example, when all members of a set of identical twins or triplets develop schizophrenia, genes surely seem to be involved. But the truth may be more complex.

In Sweden, for example, three brothers—identical triplets—all developed similar hearing problems when they reached age 11, and all developed schizophrenia within an eight-month period when they were 20. The scientists studying the brothers note that the men seem to have been marked for similar diseases by "a precise time-programmed series of events."

But was one gene or were several genes defective in the single fertilized egg from which the brothers developed? Or did a virus or some other factor in the shared environment of their mother's womb induce the diseases in all three?

Whatever the cause, schizophrenia can be devastating. For people with untreated or untreatable schizophrenia, the world can stop making sense. They may be overwhelmed by superstitions and magical thinking. They may believe that they are receiving messages from voices coming through the fillings in their teeth, or that actors on their television screens are spying on them. One of the Swedish triplets, for example, heard voices coming from the forest and was sure that his chest was on fire. Another thought his mother and brothers were breaking through his skin to take over his body, and the third was convinced that he could reliably forecast events in the future.

Human brain preserved in formaldehyde

These bizarre perceptions and behaviors are powerful evidence that something has gone terribly wrong in the neural circuits of the brain. Nerve cells (also called neurons) communicate with each other by releasing chemicals known as neurotransmitters. Communication among neurons is responsible for thoughts, movements, learning, speech, and all the other activities that people engage in. But when the patterns of communication among neurons are disturbed, speech can be impaired, movements can become awkward, and thoughts can get tangled.

Schizophrenia is an extreme example of neuronal communication gone haywire. The person's thoughts and feelings no longer fit together in an orderly fashion. This phenomenon gave the disease its name, a hybrid of the Greek words "skhizo," meaning split and "phrenia," meaning mind.

In addition to the mental chaos, people with untreated schizophrenia typically have difficulty planning and carrying out everyday activities. They may not be able to do what once was routine and may even lose interest in life. Their IQs may drop and their memories may fail them.
  Close work. Herman (right) and a colleauge examine brain tissue.

Developmental Disorder
Herman and other researchers suspect that schizophrenia is the result of a developmental defect—some damage that struck the brain during its early development. As a neuropathologist, Herman has dissected and studied the brains of people who were diagnosed with various neurological diseases, including schizophrenia, before they died. Schizophrenia differs from diseases such as Alzheimer’s and Parkinson’s, which are said to be degenerative because they involve a progressive destruction of brain tissue.

Several types of evidence support the hypothesis that schizophrenia is a developmental disorder. One is that physical changes in the brains of people who had schizophrenia when they died do not show the hallmarks of degenerative diseases. For example, Herman says, the brains of people with schizophrenia do not show "gliosis"—the accumulation of nonneuronal, star-shaped cells left in the brain after neurons have died. Gliosis is a typical sign of degenerative diseases.

A second kind of physical evidence that schizophrenia is a developmental disorder rather than a degenerative process is that the brains of people with schizophrenia show a small amount of shrinkage in the gray and white matter of the medial temporal lobe. This region of the brain lies above the ear on either side of the brain and forms part of each half of the cerebral cortex. The extent of the shrinkage usually remains constant no matter how many years or decades the person had the disease, says Herman. And if schizophrenia were a degenerative disease rather than a developmental one, the brain would continue shrinking as the patient aged and the disease progressed.

A third piece of evidence comes from experiments with rats. Barbara Lipska, one of Herman’s co-workers, has used a chemical toxin to destroy a small part of the hippocampus in the brains of newborn rats. The hippocampus, the most ancient part of the cerebral cortex in evolutionary terms, is a curved structure in each half of the brain that lies within the temporal lobe. Rats with hippocampal damage develop some schizophrenia-like behaviors, but not until they reach puberty, which suggests that the effects of an early developmental lesion may not be obvious until later in life.

Finally, family movies document that some children who seemed normal for decades, but who later developed schizophrenia, actually moved awkwardly and behaved in quirky ways in the first two years of their lives. Something was abnormal early in life, even though it may have gone largely unnoticed.

The Shape of the Brain
The search by Herman and other scientists for developmental defects that may cause schizophrenia is a bit like the search for a needle in a haystack, because crowded into every human brain are more than 10 billion nerve cells. Each neuron makes connections with 1,000 to 10,000 other neurons, to form hundreds of trillions of connections, called synapses. With so many cells and so many synapses tying them together, it is not surprising that much can go wrong in the human brain.

Brain images: even healthy twins have distinctive brains.  
When Herman and her colleagues study preserved and frozen sections of brains of people who had schizophrenia when they died, they find that the overall organization of their brains is not markedly different from the organization of healthy brains. In general, says Herman, few mental illnesses are associated with easily observable structural changes.

But subtle differences do exist. The minor shrinkage of brain tissue volume is one example, and it is balanced by a 5 to 10 percent enlargement of the brain’s fluid-filled cavities, called ventricles. Scientists first detected these differences with imaging techniques—positron emission tomography, magnetic resonance imaging (MRI), computerized tomography, and single photon computed tomography. The most convincing data that subtle physical changes occur in the brains of people with schizophrenia come from studies of sets of identical twins, only one of whom has schizophrenia. The twins are referred to as discordant for schizophrenia because one has the disease and the other does not. Interestingly, the twin who has schizophrenia has a smaller volume of brain tissue and larger ventricles than does the healthy twin, a difference that researchers can observe in MRI scans.


MRI scans of the brains of identical twins. The twin on the right has schizophrenia, but the twin on the left does not. Note that the twin with schizophrenia has larger ventricles.

The imaging studies of the brains of living people and the studies of brains taken at autopsy indicated to Herman that the entorhinal cortex was an important region of the brain to examine. Now, by using a variety of stains and other analytical procedures, she is cataloging the cell types of the entorhinal cortex to determine how many of each there are and to identify the kinds of molecules that different cell types display on their surfaces or carry inside. Researchers have already identified some 300 different markers and at least 100 different neurotransmitters that are associated with cells in the brain.

Recently, Herman has focused her research on a particular area of the brain called the entorhinal cortex. "The entorhinal cortex connects with other important brain regions [including the hippocampus] and is a way station that is likely to be affected early in schizophrenia," she says.

Slicing Brains. This technician is sectioning frozen brain tissue.  
In the course of her research, Herman has learned that two of the layers of the entorhinal cortex look unusual in the brains of people who had schizophrenia. These layers contain fewer neurons than normal, and the number of surface binding sites—called receptors—for the neurotransmitter neurotensin in the nerve cells in those layers seems to be fewer than normal.

What exactly is the nature of the link between these physical and chemical changes in the brain and the ways people with schizophrenia behave? Herman says much sifting of the information about neuronal abnormalities remains to be done before those questions can be answered.

Additional Resources

For more information about the Herman's work and her fellow workers, try the homepage for the Clincal Brain Disorders Branch of the National Institute for Mental Health.

The National Alliance for Research on Schizophrenia and Depression
has a good web site, and the National Alliance for the Mentally Ill has quite a bit of information--do a search of "schizophrenia" using their search engine. Also search Healthfinder for a good collection of government information.