Structural Abnormalities in the Cerebral Cortex of Chronic Schizophrenic Patients Daniel R.
Weinberger, MD;
Torrey, MD; Andreas N. Neophytides, MD; Richard Jed Wyatt,
E. Fuller
\s=b\ Enlarged cerebral ventricles in chronic schizophrenic patients suggest a process of mild cerebral atrophy occurs in
To see if this process involves the cerebral cortex, the widths of the Sylvian fissure, the interhemispheric fissure, and three cortical sulci were measured blindly on computerized tomography (CT) scans of 75 chronic psychiatric patients and 62 asymptomatic volunteers, all less than 50 years of age. A total of 19 of the 60 patients with chronic schizophrenia had at least one abnormality. All 15 patients with other diagnoses were within the some.
control range. Comparing those chronic schizophrenic patients with abnormalities to those without them, there were no significant differences in age, length of illness or treatment, and length of hospitalization. From this and ventricular size data, two thirds of the chronic schizophrenics had some cerebral structural abnormality. Ventricular enlargement did not correlate significantly with cortical abnormalities. Therefore, more than one etiology may account for the structural abnormalities found in chronic schizophrenic patients. (Arch Gen Psychiatry 36:935-939, 1979)
for
in the brains of and controversial history. Neuropathological studies, most of which were done during the first half of the century, claimed many abnormal findings. These studies were inconclusive, however, because of methodological limitations and because the findings were either "nonspecific" or not present in all patients with schizophrenia.14 Pneumoen-
search structural abnormalities Theschizophrenic long patients has
a
Accepted for publication May 21, 1979. From the Laboratory of Clinical Psychopharmacology, Division of Special Mental Health Research, Intramural Research Program (Drs Weinberger, Torrey, and Wyatt), National Institute of Mental Health, St Elizabeths Hospital, Washington, DC; and the Department of Neurology (Dr Neophytides), New York University School of Medicine. Reprint requests to National Institute of Mental Health, William A. White Building, St Elizabeths Hospital, Washington, DC 20032 (Dr Weinberger).
MD
cephalography studies also claimed abnormal findings in schizophrenic patients, specifically ventricular enlarge¬ ment and cortical atrophy.""8 Although most pneumoencephalography studies corroborated these findings, the failure to use adequate controls and the possibility of pneumoencephalography artifacts have made the results of these studies difficult to interpret. The advent of computerized tomography (CT) intro¬ duced a safe and reliable method for studying cerebral morphology during life that can be applied to large samples of patients as well as to healthy subjects. Using this
method, we found ventricular size in a group of 58 chronic schizophrenic patients less than 50 years old to be signifi¬ cantly greater (P < .0001) than in a similarly aged group of 56 healthy subjects." Ventricular size in 35 (40%) of the
chronic schizophrenic patients studied exceeded the upper limit of the control range; in 31 (53%) it was outside 2 SDs of the control mean. This finding did not seem to result from the effects of various forms of treatment. It was assumed to represent mild cerebral atrophy. The present study was undertaken to examine whether atrophy also involves the cerebral cortex. Our hypothesis was that enlarged fissures and sulci visible on a CT image and indicative of cortical atrophy would be found in
schizophrenic patients.
SUBJECTS AND METHODS Patients The methods of patient selection and diagnosis have been previously described." Briefly, all patients were volunteers less than 50 years old from either a clinical research or a general psychiatric division of St Elizabeths Hospital, Washington, DC. The CT scans from 75 patients (mean age, 31 years) were available for the present study. (These patients include the 73 patients previously studied," plus two new admissions to the research division.) Using Research Diagnostic Criteria (RDC),1" patients' conditions were diagnosed prior to scanning as follows: acute
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Fig 1.—Normal (top left) and abnormal (top right) Sylvian structures and normal (bottom left) and abnormal (bottom right) sulci and interhemispheric fis¬ sure.
schizophrenia (three patients); subacute schizophrenia (four patients); chronic schizophrenia (defined as RDC chronic or subchronic) (60 patients); schizoaffective disorder (four patients); and affective disorders (three patients). One patient had a diagnosis of mental retardation (etiology unknown). The extent of the medical evaluation performed on each patient has also been previously
described."
Control
Subjects
The CT scans from 62 healthy, asymptomatic volunteers less than 50 years old (mean age, 30 years), who were studied for other research projects at the National Institutes of Health, were available for the present study. A total of 54 had first-degree relatives with Huntington's disease but had no clinical manifesta¬ tions of the illness themselves. The remaining eight were volun¬ teers between the ages of 40 and 50 years who were free of similar genetic risk. An earlier study11 found no obvious differences between the scans of the subjects at risk for Huntington's disease and those of a group of normal volunteer subjects with no known genetic risk for Huntington's disease. Methods The procedure for CT scanning has been previously described." With the exception of those of eight controls, all scans were performed by the same machine. The scans, in the form of either self-developing prints or transparencies, were coded and mixed randomly. From each scan, the following cuts were selected for blind measurement: a slice showing the Sylvian fissures at their largest (usually at the level of the third ventricle); a slice showing the interhemispheric fissure at its broadest; and a cut showing the sulci on the superior surface of the cerebrum (usually the same level as the interhemispheric fissure slice) (Fig 1). Apical cuts with distorted sulci ("apical artifact"1-') were not considered. Calipers were used to make the following determinations: the maximum
width of the widest Sylvian structure (fissure or cistern13); the maximum width of the interhemispheric fissure; and the mean width of the three broadest sulci. Measurements from the trans¬ parencies were multiplied by 1.25 (minification factor involved in reducing from print to transparency), and all dimensions were expressed to the nearest millimeter. If a structure was not measurable, it was assigned a value of less than 1 mm (< 1 mm). On nine scans, all of chronic schizophrenic patients, cortical measurements could not be made because of movement artifacts. For statistical purposes, the structures on these scans were
assigned values of less than
1
mm.
RESULTS
Figures 2 to 4 illustrate the distribution of values for the width of fissures and sulci for chronic schizophrenic patients and control subjects. The groups differ signifi¬ cantly in the proportion of widths found for the Sylvian fissure (Fisher Exact < .005), for the interhemispheric fissure (P < .05), and for the cortical sulci (P < .01). Group differences were not found for the patients with other
diagnoses.
For a structural abnormality of the cerebral cortex to be considered present in an individual, at least one of the following criteria had to be met: a Sylvian fissure width of 3 mm or greater, an interhemispheric fissure width of 3 mm or greater, or a mean sulcal width of 2 mm or greater. Using these criteria, 19 (32%) chronic schizophrenic patients were found to have an abnormality. Only two of these patients had a history of past or present alcohol abuse. Six patients met more than one of the criteria; only two patients met all three. More patients (11 cases) had an abnormality of the Sylvian fissure than of any other structure. Of the 13 patients with only one cortical abnor-
Downloaded From: http://archpsyc.jamanetwork.com/ by a Penn State Milton S Hershey Med Ctr User on 05/25/2015
Table 1.—Cortical Abnormalities in Chronic Schizophrenic Patients*
SYLVIAN FISSURE
80
Patients
D CONTROL SUBJECTS (N 62) ICHRONIC SCHIZOPHRENIC =
60 40
With
=
31.1
Mean age ± SD, yr Mean length of illness, yr Mean length of hospitalization,
20
11.0
Fig 2.—Sylvian
control
±
31.0 ± 8.6 10.7 ± 7.6
8.9 8.1
5.1 ± 6.5 8.7 ± 4.1
yr_ Mean ventricular size WIDTH
Without
Abnormality Abnormality (N = 19)(N = 41)
(N 60)
PATIENTS
(VBRf)
7.0
±
1.6
±
7.4 3.1
* All intergroup comparisons not significant. fVBR indicates ventricular-brain ratio (see text).
(
fissure width for chronic Exact < .005).
schizophrenic and
subjects (Fisher
Table 2.—Relationship Between Cortical Abnormalities and Ventricular Enlargement* Patients
80
INÎERHEMISPHERIC FISSURE
With Cortical Abnormalities
«60
CONTROL SUBJECTS
(N=62)
40
=
(VBRt Without
21
31
20 41
29 60
> 8.1) enlarged
ventricles Total
20-
Total
Patients With enlarged ventricles
1 CHRONIC
SCHIZOPHRENIC PATIENTS (N 60)
Without Cortical Abnormalities
19
* 2 .01, not significant. tVBR indicates ventricular-brain ratio. =
Weinberger, MD;
Torrey, MD; Andreas N. Neophytides, MD; Richard Jed Wyatt,
E. Fuller
\s=b\ Enlarged cerebral ventricles in chronic schizophrenic patients suggest a process of mild cerebral atrophy occurs in
To see if this process involves the cerebral cortex, the widths of the Sylvian fissure, the interhemispheric fissure, and three cortical sulci were measured blindly on computerized tomography (CT) scans of 75 chronic psychiatric patients and 62 asymptomatic volunteers, all less than 50 years of age. A total of 19 of the 60 patients with chronic schizophrenia had at least one abnormality. All 15 patients with other diagnoses were within the some.
control range. Comparing those chronic schizophrenic patients with abnormalities to those without them, there were no significant differences in age, length of illness or treatment, and length of hospitalization. From this and ventricular size data, two thirds of the chronic schizophrenics had some cerebral structural abnormality. Ventricular enlargement did not correlate significantly with cortical abnormalities. Therefore, more than one etiology may account for the structural abnormalities found in chronic schizophrenic patients. (Arch Gen Psychiatry 36:935-939, 1979)
for
in the brains of and controversial history. Neuropathological studies, most of which were done during the first half of the century, claimed many abnormal findings. These studies were inconclusive, however, because of methodological limitations and because the findings were either "nonspecific" or not present in all patients with schizophrenia.14 Pneumoen-
search structural abnormalities Theschizophrenic long patients has
a
Accepted for publication May 21, 1979. From the Laboratory of Clinical Psychopharmacology, Division of Special Mental Health Research, Intramural Research Program (Drs Weinberger, Torrey, and Wyatt), National Institute of Mental Health, St Elizabeths Hospital, Washington, DC; and the Department of Neurology (Dr Neophytides), New York University School of Medicine. Reprint requests to National Institute of Mental Health, William A. White Building, St Elizabeths Hospital, Washington, DC 20032 (Dr Weinberger).
MD
cephalography studies also claimed abnormal findings in schizophrenic patients, specifically ventricular enlarge¬ ment and cortical atrophy.""8 Although most pneumoencephalography studies corroborated these findings, the failure to use adequate controls and the possibility of pneumoencephalography artifacts have made the results of these studies difficult to interpret. The advent of computerized tomography (CT) intro¬ duced a safe and reliable method for studying cerebral morphology during life that can be applied to large samples of patients as well as to healthy subjects. Using this
method, we found ventricular size in a group of 58 chronic schizophrenic patients less than 50 years old to be signifi¬ cantly greater (P < .0001) than in a similarly aged group of 56 healthy subjects." Ventricular size in 35 (40%) of the
chronic schizophrenic patients studied exceeded the upper limit of the control range; in 31 (53%) it was outside 2 SDs of the control mean. This finding did not seem to result from the effects of various forms of treatment. It was assumed to represent mild cerebral atrophy. The present study was undertaken to examine whether atrophy also involves the cerebral cortex. Our hypothesis was that enlarged fissures and sulci visible on a CT image and indicative of cortical atrophy would be found in
schizophrenic patients.
SUBJECTS AND METHODS Patients The methods of patient selection and diagnosis have been previously described." Briefly, all patients were volunteers less than 50 years old from either a clinical research or a general psychiatric division of St Elizabeths Hospital, Washington, DC. The CT scans from 75 patients (mean age, 31 years) were available for the present study. (These patients include the 73 patients previously studied," plus two new admissions to the research division.) Using Research Diagnostic Criteria (RDC),1" patients' conditions were diagnosed prior to scanning as follows: acute
Downloaded From: http://archpsyc.jamanetwork.com/ by a Penn State Milton S Hershey Med Ctr User on 05/25/2015
Fig 1.—Normal (top left) and abnormal (top right) Sylvian structures and normal (bottom left) and abnormal (bottom right) sulci and interhemispheric fis¬ sure.
schizophrenia (three patients); subacute schizophrenia (four patients); chronic schizophrenia (defined as RDC chronic or subchronic) (60 patients); schizoaffective disorder (four patients); and affective disorders (three patients). One patient had a diagnosis of mental retardation (etiology unknown). The extent of the medical evaluation performed on each patient has also been previously
described."
Control
Subjects
The CT scans from 62 healthy, asymptomatic volunteers less than 50 years old (mean age, 30 years), who were studied for other research projects at the National Institutes of Health, were available for the present study. A total of 54 had first-degree relatives with Huntington's disease but had no clinical manifesta¬ tions of the illness themselves. The remaining eight were volun¬ teers between the ages of 40 and 50 years who were free of similar genetic risk. An earlier study11 found no obvious differences between the scans of the subjects at risk for Huntington's disease and those of a group of normal volunteer subjects with no known genetic risk for Huntington's disease. Methods The procedure for CT scanning has been previously described." With the exception of those of eight controls, all scans were performed by the same machine. The scans, in the form of either self-developing prints or transparencies, were coded and mixed randomly. From each scan, the following cuts were selected for blind measurement: a slice showing the Sylvian fissures at their largest (usually at the level of the third ventricle); a slice showing the interhemispheric fissure at its broadest; and a cut showing the sulci on the superior surface of the cerebrum (usually the same level as the interhemispheric fissure slice) (Fig 1). Apical cuts with distorted sulci ("apical artifact"1-') were not considered. Calipers were used to make the following determinations: the maximum
width of the widest Sylvian structure (fissure or cistern13); the maximum width of the interhemispheric fissure; and the mean width of the three broadest sulci. Measurements from the trans¬ parencies were multiplied by 1.25 (minification factor involved in reducing from print to transparency), and all dimensions were expressed to the nearest millimeter. If a structure was not measurable, it was assigned a value of less than 1 mm (< 1 mm). On nine scans, all of chronic schizophrenic patients, cortical measurements could not be made because of movement artifacts. For statistical purposes, the structures on these scans were
assigned values of less than
1
mm.
RESULTS
Figures 2 to 4 illustrate the distribution of values for the width of fissures and sulci for chronic schizophrenic patients and control subjects. The groups differ signifi¬ cantly in the proportion of widths found for the Sylvian fissure (Fisher Exact < .005), for the interhemispheric fissure (P < .05), and for the cortical sulci (P < .01). Group differences were not found for the patients with other
diagnoses.
For a structural abnormality of the cerebral cortex to be considered present in an individual, at least one of the following criteria had to be met: a Sylvian fissure width of 3 mm or greater, an interhemispheric fissure width of 3 mm or greater, or a mean sulcal width of 2 mm or greater. Using these criteria, 19 (32%) chronic schizophrenic patients were found to have an abnormality. Only two of these patients had a history of past or present alcohol abuse. Six patients met more than one of the criteria; only two patients met all three. More patients (11 cases) had an abnormality of the Sylvian fissure than of any other structure. Of the 13 patients with only one cortical abnor-
Downloaded From: http://archpsyc.jamanetwork.com/ by a Penn State Milton S Hershey Med Ctr User on 05/25/2015
Table 1.—Cortical Abnormalities in Chronic Schizophrenic Patients*
SYLVIAN FISSURE
80
Patients
D CONTROL SUBJECTS (N 62) ICHRONIC SCHIZOPHRENIC =
60 40
With
=
31.1
Mean age ± SD, yr Mean length of illness, yr Mean length of hospitalization,
20
11.0
Fig 2.—Sylvian
control
±
31.0 ± 8.6 10.7 ± 7.6
8.9 8.1
5.1 ± 6.5 8.7 ± 4.1
yr_ Mean ventricular size WIDTH
Without
Abnormality Abnormality (N = 19)(N = 41)
(N 60)
PATIENTS
(VBRf)
7.0
±
1.6
±
7.4 3.1
* All intergroup comparisons not significant. fVBR indicates ventricular-brain ratio (see text).
(
fissure width for chronic Exact < .005).
schizophrenic and
subjects (Fisher
Table 2.—Relationship Between Cortical Abnormalities and Ventricular Enlargement* Patients
80
INÎERHEMISPHERIC FISSURE
With Cortical Abnormalities
«60
CONTROL SUBJECTS
(N=62)
40
=
(VBRt Without
21
31
20 41
29 60
> 8.1) enlarged
ventricles Total
20-
Total
Patients With enlarged ventricles
1 CHRONIC
SCHIZOPHRENIC PATIENTS (N 60)
Without Cortical Abnormalities
19
* 2 .01, not significant. tVBR indicates ventricular-brain ratio. =
