Maureen Kushner

Schizophrenia as a chronic active brain process: a study of progressive brain structural change subsequent to the onset of schizophrenia

Brain structural deviation is known to be present in chronic patients with schizophrenia when compared with normal age-matched individuals. While the assumption is that these differences are based on a neurodevelopmental disturbance, whether they are static or continue to change throughout the disease process remains unknown. The following report describes a prospective follow-up study of first episode cases of schizophrenic illness. Analyses of MRI evaluations on an approximate annual basis for a minimum of four years are presented on 50 patients and 20 controls. Computer-assisted image analysis measuring the volume of several brain regions, using the program ANALYZE (Mayo Clinic), was performed on all scans. Patients were compared with controls for the rate of change over time in size of structures. No differences were found for the volumes of the caudate nucleus, temporal lobes, or hippocampus; and no changes in the degree of cerebral laterality were detected. However, there was a significant difference in the rate of change in the overall volumes of left and right hemispheres (P < 0.0004 and 0.001, respectively), right cerebellum (P < 0.02) and area of the isthmus of the corpus callosum (P < 0.05). The left cerebral ventricle had significantly greater enlargement over time when measured on coronal slice sequences (P < 0.02), but was not detected by axial views. These findings suggest that a subtle active brain process may be continuing through the first few years of a schizophrenic illness causing greater than the normal adult cortical deterioration. Further studies using other methods of image analysis and over a longer period of time are needed to determine the course and nature of this biologic process.

A prospective follow-up study of brain morphology and cognition in first-episode schizophrenic patients: Preliminary findings

Brain morphological abnormalities have been reported in several independent investigations of chronic schizophrenic patients. The present study is a prospective 4-year follow-up of first-episode schizophrenic patients to determine whether some of these abnormalities may be a consequence of regional brain structural change over time after the onset of a first psychotic episode. Whole hemisphere, temporal lobes, superior temporal gyrus, hippocampus, caudate, corpus callosum, and lateral ventricles were measured in a series of MRI scans taken over a 4-year period in 20 patients and five controls. Total volume reduction was noted in both hemispheres to a greater degree in patients than controls. When adjusted for total brain size, left ventricular enlargement occurred in patients, but not controls, over time. These preliminary data suggest that subtle cortical atrophy may be occurring over time after the onset of illness.

The timing of brain morphological changes in schizophrenia and their relationship to clinical outcome

The present study is an examination of ventricular and temporal lobe size in 50 DSM-III-R first-episode schizophreniform or schizoaffective patients who were ill for less than 6 months. Two-year clinical follow-up and magnetic resonance imaging (MRI) scan analyses are also reported from data collected on an initial group of 30 first-episode schizophrenic patients and controls. Left ventricular enlargement, which was present in our previously published report of first-episode cases of schizophrenia, is not present to the same extent in this larger group of schizophreniform patients closer to the onset of their illness, and no temporal lobe volume reduction was detected. However, lateral ventricular size at the time of the first-episode was generally correlated with outcome--the larger the ventricles, the poorer the outcome. No mean change in ventricular or temporal lobe size was found at rescanning 2 years later, but the degree of ventricular change was inversely correlated with the number of hospitalizations and the amount of time spent in hospital; it did not correlate with temporal lobe size. When rescanned, some patients showed change greater than 20% in ventricular size and 10% in temporal lobe size. Thus, these findings need further evaluation by serial scans over a longer time period before it can be determined that no progression of brain structural abnormalities is occurring as part of the pathology of schizophrenia, even in a subgroup of patients.

Asymmetries in the superior temporal lobe in male and female first-episode schizophrenic patients: measures of the planum temporale and superior temporal gyrus by MRI

Schizophrenia has been hypothesized to be associated with an underlying brain developmental anomaly, specifically affecting normal brain asymmetries. The most pronounced asymmetries are present on the superior surface of the temporal lobes, the left plane, as measured along the sylvian fissure (planum temporale) being longer than the right in the majority of normal individuals. These asymmetries encompass Wernickes area, the anatomical substrate for language, and have been found to be less pronounced in individuals with developmental language problems, i.e. dyslexia. Since disordered language is one of the hallmarks of schizophrenia, the present study focuses on the planum temporale and related superior temporal gyrus. Eighty-five first-episode schizophrenic patients and 40 controls had measurements of the sylvian fissure taken from coronal slices. The pattern of asymmetry in controls was for the right length to be longer than the left in anterior slices, and for left to be longer than right in posterior slices (corresponding to the planum temporale). Schizophrenic patients as a group demonstrated less asymmetry (R > L) in anterior slices, and female patients showed a trend for less (L > R) asymmetry in posterior slices. In contrast to the report of Barta et al. (1990), the volume of the anterior superior temporal gyrus did not differ from controls in first-episode schizophrenic patients. Neither the presence of formal thought disorder nor auditory hallucinations defined a subgroup of patients with reduced size or lateralization of the planum temporal or superior temporal gyrus.

Familial thyroid disease and delayed language development in first admission patients with schizophrenia

One hundred consecutive first admission patients with a DSM-III-R diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder were compared with 100 randomly selected community controls. Childhood histories of physical, medical, and perinatal trauma, as well as physical and cognitive development, were examined by structured interviews with all available mothers of patients and controls. The prevalence of specific psychiatric disorders and several medical illnesses among first degree and more distant relatives was determined by family history questionnaires. The patient group did not have an excess of childhood head injuries, serious infections, or perinatal/birth complications compared with controls. With social class level taken into account, it was found that the acquisition of reading skills occurred significantly later in patients than controls. Family histories of schizophrenia and thyroid disorders were significantly more frequent among patients than controls. These data fail to indicate any childhood physical or medical environmental trauma that could lead to an increased risk for schizophrenia, although patients were substance abusers to a greater extent than controls. This study also confirms the already known contribution of familial factors and suggests an association of the inheritance of thyroid disorders with schizophrenia. Delayed development of reading skills suggests that precursers of illness may appear early in life before psychosis is evident.

Association of brain structural change with the heterogeneous course of schizophrenia from early childhood through five years subsequent to a first hospitalization

Fifty first-episode patients with schizophrenia were followed for 5 years subsequent to their first hospitalization. The course of illness was charted prospectively and premorbid childhood histories were obtained retrospectively at the initial evaluation, and MRI scans were obtained initially and at each follow-up. Fifteen different life-time patterns of illness course emerged, although none were specifically associated with structural brain change. A deterioration in premorbid scores was positively correlated with larger ventricular volume at the first hospitalization, and the larger the ventricles, the less the subsequent change in ventricular size thereafter. An analysis to see whether initial hemispheric and ventricular size could predict different course types only revealed that patients with an acute onset and complete recovery had significantly smaller ventricles than all others. No differences emerged for initial hemispheric size. Thirty-four percent of patients individually showed some association of brain ventricular size and 28% hemisphere volume reductions with fluctuation in psychotic symptoms. Paradoxically, most showed larger ventricles and smaller hemispheres to be associated with clinical improvement, rather than the predicted reverse. These latter data question the notion that the structural brain changes seen over time in some patients are related to poor outcome, although small ventricular size in those patients with acute onset may be predictive of recovery. Thus, brain structural change is occurring early in the course of illness and may be a consequence of the process leading to resolution.

Gender differences in corpus callosum size in first-episode schizophrenics

Previous studies indicate differences between schizophrenics and normals in thickness and overall size of the corpus callosum, particularly in female subjects. The present study compares the area of the corpus callosum as measured by magnetic resonance imaging (MRI) in men and women experiencing first-episode cases of schizophrenia. The corpus callosum area is also correlated with measures of neuropsychological function. The results of this study suggest that women who are first-episode schizophrenic patients have a smaller total corpus callosum area than female controls, with no difference noted for men. In normal controls, a larger corpus callosum was associated with better cognitive function, whereas in schizophrenics, no such relationship emerged.

Increased prevalence of cavum septum pellucidum in schizophrenia

A previous report that the presence of a cavum septum pellucidum was significantly more common in schizophrenic patients than in control subjects (DeGreef et al., 1992) stimulated the present study of an independent but similar population of first admission schizophrenic patients. A high prevalence of this developmental anomaly (44.8%) was found in the patients (n = 85), although it could also be detected in 29.8% of similarly aged control subjects (n = 47). This finding was not associated with corpus callosum, ventricular, or temporal lobe size or asymmetries.

Left ventricular enlargement associated with diagnostic outcome of schizophreniform disorder

In a recent publication (DeLisi et al 1992) we reported data showing no significant ventricular enlargement or temporal lobe volume reduction in 50 schizophreniform patients compared with controls. As a result, we concluded that either there was a progressive component to the degree of ventficular enlargement detected in chronic patients, or patients with a first hospitalization for schizophreniform disorder (who tend to be functioning well until < 6 months prior to hospitalization) are not the subgroup of schizophrenic patients who have significant brain pathology. Though these explanations cannot yet be ruled out, a third, equally important one was overlooked; that is, only a portion of schizopbreniform patients (those with less than. 6 months of symptoms) may be destined to be diagnosed as definite schizophrenia with time, ~.d thus only a smaller proportion of the 50 p~ti¢~ts may be expected to have ventricular enlargement than would be seen if a similar sample of schizophrenic subjects of longer illness :lu~:atioa were studied. Thus, the overall difle:ences in the schizophreniform group as a whole may not be significantly different from controls. However, if the initial scans of those that were later di-

Lack of evidence for linkage to chromosomes 13 and 8 for schizophrenia and schizoaffective disorder

A previous report [Blouin et al., 1998: Nat Genet 20:70-73] suggesting linkage to chromosomes 13q32 and 8p21 in families with schizophrenia led us to investigate these regions in a large set of 301 multiplex families with schizophrenia. Multipoint analyses failed to reveal evidence for linkage to any portion of chromosome 13, while only a weakly positive score was present on 8p using the identical marker reported in the earlier report. Failure to confirm the Blouin et al claims in a substantially larger cohort adds emphasis to the inconsistency of the findings concerning linkage in schizophrenia. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:235-239, 2000.