Michael Sakuma

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.

Cerebral ventricular change over the first 10 years after the onset of schizophrenia

Whether the brain structural abnormalities seen in schizophrenia are progressive is controversial. We previously reported on a longitudinal study of 50 first-episode patients with schizophrenia and 20 controls who had serial MRI scans during the first 5 years of illness. Greater enlargement of lateral ventricles and reduction of hemispheric volume was observed over time in the patients compared with controls. The present study obtained MRI scans from 26 of these patients and 10 controls at a follow-up 10 years subsequent to their first evaluations. The initial, 4-5th and 10th year scans were examined for the degree of change in ventricular and hemispheric volume. Significantly greater ventricular enlargement during the second 5 years was detected in the patient cohort compared with controls (P<0.05) with nine of the patients having ventricular enlargement (as measured by percent change) occurring at a rate exceeding that of any of the controls from years 1 through 10. The rate of ventricular change during the first 5 years was significantly correlated with age at first hospitalization, and ventricular enlargement in years 5-10 was correlated with the amount of time spent in hospital. Paradoxically, greater change in ventricles over time was correlated with better, not worse, outcome at the 10th year of follow-up with regard to the presence of symptoms. These data suggest heterogeneity in the course of brain change whereby some patients may exhibit active structural brain change only early in their illness or not at all after their first episode, while others continue to exhibit ventricular change spanning the decade subsequent to their first episode. Despite these differences among patients, the present study fails to detect any relationship of ventricular enlargement to poorer outcome as has been reported by other investigators.

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.

Language processing and memory in ill and well siblings from multiplex families affected with schizophrenia

The present study was designed to extend the investigation of genetic factors for schizophrenia to cognitive and linguistic signs of central nervous system dysfunction. Of 51 siblings studied from 19 schizophrenia multiplex families, 37 had a DSM-III-R diagnosis of schizophrenia or related schzophrenia spectrum disorder and 14 were well. Controls were 17 unrelated healthy individuals within the same social class and age range. Subjects were tested on measures of memory, attention, reading and expressive language ability. Schizophrenic and spectrum disorder siblings were significantly more impaired in tests of auditory discrimination and memory than their well siblings or controls and displayed significantly reduced syntactic complexity to their speech. While well siblings did not differ from controls on most measures, some aspects of language complexity were reduced. A familial effect was observed for tests of reading ability, attention, some syntactic measures, and short-term memory, although these were not the measures that distinguished patients from controls in this cohort, the scores were not correlated among the ill sibling pairs, and poorer scores did not segregate with schizophrenia within these families. Thus, while some measures of language, memory and attention are deviant in patients with schizophrenia, they may not be heritable and directly related to the genetics of the disorder. Instead, they may be a manifestation of, rather than a vulnerability to, the illness.

Functional asymmetries in schizophrenia and their relationship to cognitive performance.

Previous accounts of cerebral dominance in schizophrenic patients have been conflicting. While many studies report decreased patterns of functional laterality in schizophrenic subjects, others report increases or no differences. Conceptual differences in the definition of laterality and its effects on behavior may be a reason for the poor concordance among studies. The present report addresses some of these problems and examines the hypothesis that schizophrenia may be associated with an alteration in normal patterns of functional laterality. In addition, the relationship between patterns of laterality and cognitive functioning was assessed. Twenty-one schizophrenic patients and 24 control subjects, all right-handed, were compared on two neuropsychological batteries, one designed to test cerebral dominance and the other, cognitive performance. Cerebral dominance was measured by two dichotic listening tests (verbal and nonverbal) and three motoric tests. Cognitive ability was assessed with a comprehensive neuropsychological battery. Schizophrenic and control subjects differed significantly in performance on laterality measures, but they did not differ in patterns of functional laterality when performance was taken into account. In addition, it was shown that the relationship between cognitive ability and laterality is complex, with some aspects of laterality appearing to be beneficial to cognitive ability.

Longitudinal neuropsychological findings from Stony Brook first episode study

comprehensive neuropsychological test battery during the midluteal phase (one time), and blood levels of estrogen and progesterone were collected weekly over the four week period. Average estrogen levels were positively and strongly associated with cognitive performance across all domains, including verbal and nonverbal abilities. Perceptual-motor speed (Symbol Digit Modalities Test), verbal memory (WMS Associate Learning. CVLT), and visual memory (WMS Visual Reproduction, Benton VRT) showed the strongest relationships (0.77 ~r.~0.8l; p<O.OOOOl). Average estrogen levels were also inversely correlated with the BPRS negative symptom scale (rho=-0.44, p<O.05), but not with pos itive symptoms. It appears that estrogen is more strongly related to cognitive abilities than to symptomatology. These data may have implications for hormone replacement therapy in schizophrenic patients. Supported by Napa State Hospital, California Department of Mental Health, NARSAD, and MH30854.