Copyright 1995 National Alliance for the Mentally Ill NOTE: The following article by Manuel F. Casanova, M.D., is reprinted from The Decade of the Brain (vol. 5, issue 2). Dr. Casanova is a professor of psychiatry and neurology and a consultant in pathology at the Medical College of Georgia. As a result of his clinical, research, and teaching endeavors, he has received several distinguished appointments including that of Scientific Expert for the Armed Forensic Sciences at The George Washington University. Dr. Casanova is also a Stanely Scholar. --editor

My work to find the major center of brain abnormality accounting for schizophrenia began seven years ago when Joel Kleinman, M.D., and Daniel Weinberger, M.D., invited me to join the National Institute of Mental Health and their research into the organic basis for mental diseases. A review of past studies of the causes of schizophrenia revealed that many publicized pathological discoveries proved ephemeral. However, one finding seemed promising: that abnormalities of the tissue connecting the cerebral hemispheres (corpus callosum) may contribute to a dysfunctional interhemispheric transfer of information in schizophrenic patients.

Earlier attempts to pinpoint the abnormalities were inconclusive, but I suspected that imprecise measuring techniques could have obscured subtle traces of tissue loss and that use of a computerized image analysis system to measure preselected anatomical regions would yield more precise results than manual measurement techniques. Scans could be magnified, contrast enhanced, and color coded and quantified with modern image analysis and extrapolation via radiologic films.

To explore corpus callosum abnormalities in persons with schizophrenia, we analyzed the length, area, thickness, and shape of its three major subdivisions--genu, body, and splenium--in a population of monozygotic twins discordant for schizophrenia. Because both the schizophrenic patients and their normal twins shared the same genes, we expected any structural brain differences between them to be attributable to the schizophrenic process.

Our study found a significant distortion of the middle segment of the corpus callosum in the twins with schizophrenia. It was difficult to show pictorially the abnormalities in the corpus callosum of the twins with schizophrenia because this tissue can be distorted by either a flattening or an upward-downward bowing of its middlemost segment. To better understand the nature of the conformational change, our group measured the mean curvature of the corpus callosum in the same patient population. The mean curvature--the net change of an angle per length of line--is a unit of measurement that reflects how much a linear structure bends.

Our investigation showed that the shape distortion of the corpus callosum in patients with schizophrenia was due to an upward bowing that has been associated with enlarged ventricles, or ventriculomegaly. There is a direct correlation between the mean curvature of the corpus callosum and the size of the ventricles. Two basic facts are important to this discussion. First, the brain is enclosed within the skull, an unyielding covering of bone. Second, the brain abhors a vacuum. These conditions mean that dead tissue is often liquified and reabsorbed; and when that happens, an enlarged ventricle remains as a tombstone to recall past injury. Ventriculomegaly in schizophrenia therefore strongly suggests a previous episode of brain-tissue damage. It certainly seemed appropriate to conclude from our first few experiments that schizophrenia is an organic brain disorder.

As a next step and with the hope of finding an abnormality that could account for the ventriculomegaly of persons with schizophrenia, we studied the volume of large portions of their brains. Magnetic resonance imaging of patients and controls and analyses with our computerized image system revealed that a shortage of gray matter produced the volumetric defect. It is not yet certain, but it is possible that the reduction in volume may result from the loss of small cells, or interneurons, which would selectively affect the gray matter. If our hypothesis is correct, it implies a malfunction of information-processing within the temporal lobes of schizophrenic patients, even though signal transmission between different cortical centers and the temporal lobes remains normal. This scenario suggests that an affected patient would be able to receive information normally, but he or she would misinterpret it. We still had not determined which of many anatomical structures within the temporal lobe was abnormal in schizophrenia.

Of the possible sites, the part of the brain associated with social adaptation, emotion, and motivation--the limbic system--seemed the most likely to be affected by the disease because malfunctions of these functions are typical in schizophrenia. I decided to continue searching for signs of the disease in the limbic regions. The introduction of computerized-image analysis into psychiatry allowed us to show that persons with schizophrenia had smaller than normal temporal lobes, an abnormality that seemed to be restricted virtually to the gray matter.

To determine the cause of this abnormality, we studied the temporal lobes of seventeen patients with schizophrenia and an equal number of age-matched controls after we subdivided them into various anatomical levels so we could selected the patient and control that were most representative at each level. Qualitative examination of the contours of the subjects' temporal lobes suggested major conformational changes in the medial aspects as well as in the posterior-superior portion of those with schizophrenia. Because the superior portion of the temporal lobe is involved in the regulation of language and language provides a mirror for the way the brain formulates its thoughts, disturbances in language may reflect a more pervasive defect in the way we think. Keep in mind that the medial aspect of the temporal lobe modulates the flow of information into the limbic system, which--as noted--helps regulate our social behavior, emotional values, and drives.

Several additional studies by our group have corroborated our findings. In the first, magnetic resonance images of the posterior temporal lobe of patients with schizophrenia were examined, and abnormalities in size and shape were found in the language center--or superior portion--of their temporal lobes. These abnormalities at this site are similar to those found in other developmental disorders, such as dyslexia. Furthermore, measurement of opiate nerve endings having psychotic properties (sigma receptors) in postmortem brain material has shown abnormalities in or near the brain language region of schizophrenic patients. We have also done quantitative shape analyses of brain tissue from the anterior portions of temporal lobes of deceased persons who had schizophrenia.

The analyses show alterations--thinning and other distortions--in the medial section (entorhinal cortex) of the temporal lobe. Anthropologists know that this brain region underwent a remarkable territorial expansion on the way up the evolutionary scale. The expansion reached its culmination in the human brain, which indicates the functional importance of the entorhinal cortex within our species. Brain-tissue abnormalities similar to those we are discussing have been observed--although to a lesser degree--in some depressed patients who have committed suicide. Perhaps variations in the severity of these abnormalities may result in a wide spectrum of mental disorders. Our studies indicate two brain-disease sites: the language area of the superior portion of the temporal lobe and the middle section, or entorhinal cortex. Because few, if any, functions other than language have been attributed to the superior region of the temporal lobes, we will here discuss only the entorhinal cortex.

Dysfunction in the entorhinal cortex may explain some of the nonlanguage symptomatology of persons with schizophrenia. At the microscopic level the entorhinal cortex subdivides into several regions that, together, provide a belt of gray matter that separates the limbic system from areas of more recent evolutionary origin within the temporal lobe. The entorhinal cortex may provide passage for information necessary for memory, mood, and drive as well as information related to our sensory perception of the environment. Brain abnormalities--specifically lesions of the prefrontal cortex in humans--result in a disorder of attention, loss of spontaneous activity, and dulling of affect. The prominent interconnections of the entorhinal cortex with the prefrontal lobe may therefore explain some of the symptomatology observed in schizophrenic patients. Recent behavioral studies of monkeys with surgically induced lesions have confirmed the information-processing capacity of this region of the brain. Bilateral lesions in caged monkeys produce substantial memory impairment, a fall through the social echelons, changes in sexual activity, and lessened aggressive behavior. Intriguing data on entorhinal cortex function was derived from electrical stimulation of the human brain.

Almost 125 years ago, Dr. Wilder Penfield electrically stimulated specific parts of epileptic patients' brains and elicited responses he thought of as their past experiences or memory traces. His subjects often told of hearing or watching someone else's actions and speech. It is interesting that, from all the possible responses related by these patients, some were never described, such as activities during which the patient himself or herself spoke, thought, or performed a skilled behavior. We now know that the phenomenon described by Penfield was not the recollection of past experiences, but instead it represented hallucinations that evolved from the patient's personality, cognitive state, and expectations. Normal nerve development early in life assigns a key role to dopamine, a neurotransmitter essential for controlling nerve activity. Because studies with primates show the importance of nerve activity in the early development of the entorhinal cortex, it is possible that the abnormalities of the entorhinal cortex in patients with schizophrenia reflect an early injury from hyperactive dopamine stimulation.

This hypothesis is supported by additional studies claiming abnormalities in other terminal fields of the ventral area (VTA). Reports of disturbances in the columnar arrangement of these cells, decreased blood flow to the prefrontal cortex, and the well-detailed abnormalities of dopamine receptors in the striatum are all consistent with VTA brain injury in schizophrenia. This article summarizes our research during the last few years. Most importantly, the knowledge we've gained substantiates an organic basis for schizophrenia.

Our research has also shown that much of the pathology in schizophrenia is found at two specific sites in the gray matter of the temporal lobes, the hippocampus (entorhinal cortex) and the posterior-superior aspect of the temporal lobe. Additional neuroimaging and postmortem work have confirmed our findings. Our studies have led us to believe that schizophrenia is a genetically determined illness with a clinical expression either due to or modified by brain damage during gestation. Variabilities in the expression of the illness may be caused by other disease and environmental influences. We hope our research has produced testable hypotheses that will lead investigators to further probe the nature of temporal lobe lesions in persons with schizophrenia. Are they due to lack of oxygen (hypoxia)? A virus? A cellular metabolic defect? Are these the main sites of disease, or are they the byproduct of a lesion somewhere else? We hope that when the underlying pathology of schizophrenia is revealed and understood, new therapeutic interventions and the prevention of the disease itself will follow. by Manuel F. Casanova, M.D Transmitted: 95-06-07