Brain Morphology and Schizophrenia A Magnetic Resonance Imaging Study of Limbic, Prefrontal Cortex, and Caudate Structures
Alan Breier, MD; Robert W. Buchanan, MD; Ahmed Elkashef, MD; Robert C. Munson; Brian Kirkpatrick, MD; Fouad Gellad, MD \s=b\ We used magnetic resonance imaging to examine the morphologic characteristics of the amygdala/hippocampus, prefrontal cortex, and caudate nucleus in 29 healthy volunteers matched for age, gender, and head of household socioeconomic status and 44 patients with chronic schizophrenia. Total volumes of these structures were determined from 3-mm contiguous coronal sections. Schizophrenic patients, compared with healthy controls, had significantly smaller right and left amygdala/hippocampal complex volumes, smaller right and left prefrontal volumes, and larger left caudate volumes. A secondary analysis revealed reductions in the right and left amygdala and the left hippocampus. In addition, prefrontal white matter, but not gray matter, was reduced in the schizophrenic patients. Moreover, the right white matter volume in schizophrenic patients was significantly related to right amygdala/hippocampal volume (r=.39), data that provide preliminary support for a hypothesis of abnormal limbic-cortical connection in schizophrenia. We studied the implications of these data for the pathophysiology of schizophrenia. (Arch Gen Psychiatry. 1992;49:921-926)
neuroanatomic localization
the
of site(s) responsible The for the pathophysiology of schizophrenia has mained elusive. re¬
The most reproducible finding in the brain literature of schizophrenia has been that of morphologic enlarged ventricular spaces demonstrated in computed tomographic (CT) studies. At present, more than 35 controlled CT studies have reported enlarged ventricular brain ratios and other evidence of enlarged ventricles in schizophrenia with a relatively small number of negative or inconclusive findings.1,2 However, the pathophysiologic importance of enlargement of the ventricular system is unknown. Moreover, although it has been suggested that enlarged ventricles reflect loss of brain tissue, it is unclear whether the putative tissue loss is generalized or focal and, if the latter, which brain regions are specifically affected. The advent of magnetic resonance imaging (MRI) has al¬ lowed a detailed morphologic assessment of discrete brain structures so that it is now possible to determine whether re¬ gions hypothesized to be involved in the pathophysiology of schizophrenia have abnormal morphologic features. In ad-
Accepted for publication June 8, 1992. From the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore (Drs Breier, Buchanan, and Kirkpatrick and Mr Munson); National Institute of Mental Health Neuroscience Center at St Elizabeth's Hospital, Washington, DC (Dr Elkashef); and the Department of Radiology, University of Maryland School of Medicine, Baltimore (Dr Gellad). Reprint requests to the Maryland Psychiatric Research Center, PO Box 21237, Baltimore, MD 21228 (Dr Breier).
dition to confirming enlarged ventricular spaces in schizo¬ phrenic patients,3"9 several, although not all, recent MRI stud¬ ies have found evidence for reductions of temporal cortex,6-912 amygdala/hippocampal complex,3-5-13 and frontal cortex14 in schizophrenic patients. The MRI data indicating morpho¬ logic abnormalities of the amygdala / hippocampus and fron¬ tal lobe in schizophrenia are of particular interest because of several lines of converging biochemical,15"18 pharmacolog¬ ie,15-19-20 and functional imaging21"28 evidence that strongly
suggests that these structures, either alone or in concert, may be involved in the pathophysiology of schizophrenia.29,30
Although
not
as
extensively investigated
as
prefrontal
and limbic regions, there is growing interest in the exam¬ ination of the morphologic characteristics of the basal gan¬ glia in schizophrenia. The basal ganglia have been shown to play an important role in complicated human behaviors, including emotions and cognition.31-32 In addition, recent in vivo neuroimaging33-34 and postmortem3539 data suggest that this region may be involved in the pathophysiology of schizophrenia as well. A small number of recent studies have found specific basal ganglia structures to be abnor¬ mally enlarged in schizophrenia,1 u" data that require rep¬ lication. Moreover, the basal ganglia are components of neural circuits that have connections to cortical and limbic regions, the so-called basal ganglia-thalamocortical cir¬ cuits.41 Thus, a primary lesion in this region could have sec¬ ondary effects on other components of the circuit that to¬ gether may produce symptoms and signs of schizophrenia. We used MRI to examine the total volume of the amygdala/hippocampal complex, prefrontal cortex, and caudate nucleus in 44 outpatients with chronic schizophre¬ nia and 29 healthy controls. In addition, volumes of sub¬ components of these structures, namely, prefrontal gray and white matter, amygdala, hippocampus, and head and body of the caudate, were assessed. Prefrontal white mat¬ ter volume is of interest because abnormalities in this tis¬ sue may suggest partial deafferentation of prefrontal cor¬ tex from other brain regions, such as the limbic system. To examine this hypothesis, we assessed the relationship be¬ tween prefrontal white matter volume and amygdala/ hippocampal complex volume.
SUBJECTS
AND METHODS
Subjects
Forty-four schizophrenic patients and 29 healthy volunteers participated in the study. The patients were stable, neuroleptictreated outpatients in the Maryland Psychiatric Research Center Outpatient Program, Baltimore, and had a DSM-III-R diagnosis of schizophrenia disorder, chronic type. They had a mean (±SD) of 14±7 years of illness and 6±7 previous hospitalizations. Diag¬ noses were determined by two research psychiatrists in a bestestimate diagnostic conference in which all available sources of
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Healthy
Controls (n=29)
Schizophrenic
Patients (n=44)
No. males
20
(69)
29 (66)
Age,
34.4±8
35.8±7
3±1
3±1
3±1
4±1
y
Head of household socioeconomic statust
Personal socioeconomic status
173.7+10
Height, cm Weight, kg
79.8±16
Head circumference, cmt
No. (%)
right-handed
171.7±10 79.9±15
57.2±2
57.7±2.3
24 (83)
35 (80)
•Unless otherwise noted, values are mean±SD. tSocioeconomic status was rated from 1 to 5, with higher numbers representing poorer socioeconomic status (patients, n=39).
tPatients, n=39; controls, n=23.
information, including direct
assessment using the Structured Clinical Interview for (SCID) DSM-UI-R,i2 family informant information, and past psychiatric records, were utilized. Patients were excluded if they had a concurrent history of alcohol and /or other substance abuse, history of severe head trauma, or a neu¬ rologic disorder. They were in good health, as determined by a physical examination, electrocardiography (ECG), and screening blood work. The patients' personal and sociodemographic char¬ acteristics are presented in Table 1. External head circumference was determined with the inion and the superior nasion ridge as posterior and anterior landmarks, respectively. Head circumfer¬ ence was obtained after commencement of the study and, there¬ fore, was available for only 39 patients and 23 controls. The 29 healthy volunteers were selected from the general pop¬ ulation through neighborhood newspaper notices and flyers. They matched the schizophrenics on age, gender, and head of household socioeconomic status (SES). Head of household as op¬ posed to personal SES was selected as a matching variable because the illness process of schizophrenia may cause decre¬ ments in personal SES. Thus, controls who were matched on per¬ sonal SES with schizophrenics would likely have abnormally low SES and represent a skewed control group.43 The controls had no past or current Axis I or Axis II psychiatric illnesses, as deter¬ mined by SCID42 and Structured Interview for the DSM-III Per¬ sonality Disorders (SIDP)44 interviews, respectively, and had no history of head trauma or neurologic and /or medical illness. In addition, they had no first-degree family history of psychosis, which was determined from clinician interviews of controls. Their personal and sociodemographic characteristics are presented in Table 1. As shown, the patients and control groups were closely matched, and no significant differences between these variables were noted, with the exception of personal SES (f=4.4, P