Incidence of ectopic gray matter in patients with schizophrenia and healthy control subjects studied with MRI.

Magnetic resonance imaging scans were visually inspected to investigate the incidence of gray matter heterotopia (GMH) in a group of 55 schizophrenic patients and a group of 75 control subjects. No GMHs were found in the control subjects. In the patient group, 1 GMH was found, an incidence of 1.8%.

Cavum septi pellucidi in normals and patients with schizophrenia as detected by magnetic resonance imaging.

Cavum septi pellucidi (CSP) is a cavity between the two leaflets of the septum pellucidum. CSP is a developmental anomaly, yet the pathologic implications, if any, of an abnormally large CSP remain unclear. The reported incidence of CSP among normal populations varies greatly from 0.15% to 85%. Several studies have suggested that there is a higher incidence of CSP in patients with schizophrenia. We conducted a thin-slice magnetic resonance imaging study to evaluate the prevalence of CSP in a sample of 75 controls and 55 patients. There was a high incidence of small CSP among both groups: 58.8% in the controls and 58.2% in the patients, suggesting that a small cavum could be considered a normal variant; however, the patient group had significantly higher incidence of large CSP (20.7%) compared to the normal group (3%). The patients with large CSP were all male.

Magnetic resonance imaging of brain anomalies in fetal alcohol syndrome.

OBJECTIVE: Postmortem studies of fetuses, infants, and young children with fetal alcohol syndrome (FAS) have demonstrated a variety of severe central nervous system (CNS) anomalies. We undertook this magnetic resonance study (1) to assess the spectrum of CNS anomalies that occur in a clinical sample of typical patients with FAS who are medically stable; and (2) to examine the relationship between CNS and facial anomalies. METHODOLOGY: Magnetic resonance imaging was performed on a series of 10 patients (4 children, 3 adolescents, and 3 adults) who met criteria for FAS. We systematically evaluated each scan for brain anomalies and compared total brain tissue volume with that of healthy child, adolescent, and adult control subjects. RESULTS: Six patients had some type of midline anomaly, ranging from partial to complete callosal agenesis (three patients) to hypoplastic corpus callosum (one patient), cavum septi pellucidi (three patients), and cavum vergae (two patients). These midline anomalies were associated with a greater number of facial anomalies. Other brain anomalies identified included micrencephaly, ventriculomegaly, and hypoplasia of the inferior olivary eminences. CONCLUSION: Patients with classic FAS have a high incidence of midline brain anomalies. This finding is consistent with the concept that the midline CNS is a developmental field that is particularly susceptible to the teratogenic effects of alcohol. Furthermore, patients with more severe facial dysmorphologic characteristics are more likely to have midline brain anomalies. In addition, we observed a high incidence of micrencephaly with a wide range of severity.

Lack of an association between delayed memory and hippocampal and temporal lobe size in patients with schizophrenia and healthy controls.

The purpose of the present study was to investigate putative neural substrates of long-term (delayed) memory in schizophrenia and young healthy controls. Ten "low" and 10 "high" memory patients were selected from a large sample of DSM-III-R diagnosed schizophrenia spectrum patients, based on composite verbal and nonverbal delayed recall memory scores. Ten "low" and 9 "high" memory individuals were also selected from a larger sample of young healthy controls. Magnetic resonance imaging scans were acquired on a 1.5-T GE Signa scanner using a SPGR sequence (repetition time = 24 msec, echo time = 5 msec). Hippocampal volumes were computed from manual tracings (intraclass correlation = .96), and temporal lobe and whole brain tissue volumes were obtained using a semiautomated technique. In both the patient sample and controls, there was no significant relationship between delayed memory ability and hippocampal, temporal lobe, or whole brain volume. The integration of results from this study, and from studies on normal aging and Alzheimer's disease, supports a model suggesting that hippocampal size may be an indicator of long-term memory ability, but only when hippocampal measures reflect aging and degenerative hippocampal atrophy. If the hippocampal measures reflect individual differences in hippocampal size prior to the onset of hippocampal atrophy, then hippocampal size does not appear to predict long-term memory ability.

Reversibility of brain tissue loss in anorexia nervosa assessed with a computerized Talairach 3-D proportional grid.

We describe the results of our follow-up magnetic resonance imaging (MRI) study of underweight patients with anorexia nervosa, using rigorous methodology to control for head position across time. All subjects first underwent an initial scan and rescan to verify that our computerized three-dimensional co-planar grid method for volume measurement was reliable and accurate, regardless of head positioning. After a period of several months, subjects had a follow-up scan to assess for changes that may have occurred following significant weight gain. Ventricular and total brain volume measurements from the initial scans were compared with the scans from an age- and sex-matched normal control group to determine whether we could replicate previous findings of ventricular enlargement compared with controls and whether brain volume is reduced compared with controls. Anorexic subjects had significantly larger ventricles when compared with normal controls but did not differ significantly in total brain volume. Using a repeated measures analysis of variance, a priori contrasts compared the initial/rescan pair volumes with each other and the initial/rescan pair volumes with the follow-up volume. These analyses showed that ventricular and total brain volumes derived from the initial/rescan pair were nearly identical, but that at follow-up ventricular volume decreased significantly and total brain volume increased significantly after weight gain.

Pattern of brain morphology in patients with schizophrenia and large cavum septi pellucidi.

Cavum septi pellucidi (CSP) is a midline developmental anomaly shown to have increased incidence in patients with schizophrenia. The etiology of CSP may involve dysgenesis of the temporal lobes. This study evaluated the pattern of brain changes in three groups: 1) normal control subjects, 2) schizophrenic subjects without large CSP, and 3) schizophrenic subjects with large CSP. Patients without large CSP had decreased total brain, frontal, and temporal lobe volumes; patients with the anomaly had more pronounced right > left asymmetry and volume decrement limited to the left temporal lobe. These findings indicate that patients with schizophrenia and large CSP may show a different pattern of disturbed brain morphology than patients without this abnormality.

Automatic atlas-based volume estimation of human brain regions from MR images.

OBJECTIVE: MRI offers many opportunities for noninvasive in vivo measurement of structure-function relationships in the human brain. Although automated methods are now available for whole-brain measurements, an efficient and valid automatic method for volume estimation of subregions such as the frontal or temporal lobes is still needed. MATERIALS AND METHODS: We adapted the Talairach atlas to the study of brain subregions. We supplemented the atlas with additional boxes to include the cerebellum. We assigned all the boxes to 1 of 12 regions of interest (ROIs) (frontal, parietal, temporal, and occipital lobes, cerebellum, and subcortical regions on right and left sides of the brain). Using T1-weighted MR scans collected with an SPGR sequence (slice thickness = 1.5 mm), we manually traced these ROIs and produced volume estimates. We then transformed the scans into Talairach space and compared the volumes produced by the two methods ("traced" versus "automatic"). The traced measurements were considered to be the "gold standard" against which the automatic measurements were compared. RESULTS: The automatic method was found to produce measurements that were nearly identical to the traced method. We compared absolute measurements of volume produced by the two methods, as well as the sensitivity and specificity of the automatic method. We also compared the measurements of cerebral blood flow obtained through [15O]H2O PET studies in a sample of nine subjects. Absolute measurements of volume produced by the two methods were very similar, and the sensitivity and specificity of the automatic method were found to be high for all regions. The flow values were also found to be very similar by both methods. CONCLUSION: The automatic atlas-based method for measuring the volume of brain subregions produces results that are similar to manual techniques. The method is rapid, efficient, unbiased, and not subject to the problems of rater drift or potentially poor interrater reliability that plague manual methods. Consequently, this method may be very useful for the study of structure-function relationships in the human brain.

Symptom dimensions and brain morphology in schizophrenia and related psychotic disorders.

The heterogeneity of symptoms in schizophrenia may reflect heterogeneity of underlying pathophysiological mechanisms. Factor analytic studies have consistently identified three symptom factors, psychotic, negative and disorganized, as independent dimensions of schizophrenic psychopathology. This study examined the relationship of these symptom dimensions with volumes of specific brain regions. One-hundred and sixty-six schizophrenia spectrum patients were clinically evaluated with the Comprehensive Assessment of Symptoms and History (CASH) and scanned with a 1.5 Tesla magnetic resonance imaging scanner. Regions of interest (ROIs) were manually traced on 5 mm and 3 mm coronal slices by a single technician, blind to all aspects of subject identity. Correlations between ROI volumes and indices of symptom severity were determined. Analyses of covariance were then used to test for specific relationships between each of the three symptom dimensions and ROI volumes. Tests were made of each dimension, controlling for all others. Overall symptom severity was significantly correlated with larger ventricle volumes (lateral, third and temporal horns) and smaller temporal lobe, hippocampal and superior temporal gyral volumes. Both psychotic and negative symptom severity predicted increased third ventricular volume. Psychotic symptom severity uniquely predicted decreased superior temporal gyral volume as well as increased temporal horn volume. Within the psychotic symptom dimension, hallucinations alone predicted left superior temporal gyral volume. No significant associations between disorganized symptoms and any ROIs were demonstrated. These results provide clues to the localization of specific brain regions underlying symptom clusters in schizophrenia, and provide further validating evidence for the construct of independent dimensions of psychopathology within schizophrenia and related psychotic disorders.

Gray matter heterotopias in schizophrenia.

Gray matter heterotopias (GMHs) are a type of neuronal migration anomaly in which collections of normal neurons are abnormally located secondary to an arrest of radial migration. They are often manifested clinically by seizures and cognitive, motor, and language deficits. Through magnetic resonance imaging, we have observed two cases in patients presenting with symptoms of schizophrenia, but no neurological abnormalities, and otherwise normal scans. While the incidence of GMH among normal individuals is unknown, it is possible that this particular anomaly may occur in schizophrenic patients at a higher rate than in the normal population. Furthermore, neuronal migration abnormalities may be involved in the pathogenesis of the disorder among a small subset of patients with schizophrenia.

Effects of diagnosis, laterality, and gender on brain morphology in schizophrenia.

OBJECTIVE: Structural neuroimaging and neuropathological studies have demonstrated a variety of aspects of brain morphology that appear to distinguish schizophrenic patients from comparison subjects (diagnostic effects), a predominance of left-sided pathology (laterality effects), and a greater likelihood of brain abnormality among males (gender effects). However, findings have been inconsistent across studies, perhaps reflecting limited power due to small study group sizes. The goal of this study was to examine diagnostic, laterality, and gender effects of brain morphology as assessed by magnetic resonance imaging in a large, carefully evaluated group of schizophrenic and comparison subjects. METHOD: One hundred two patients with schizophrenia (DSM-III-R) (70 men and 32 women) and 87 normal comparison subjects, chosen to be equivalent to the patients in terms of familial socioeconomic background, underwent magnetic resonance imaging with a 1.5-tesla scanner. All regions of interest were outlined manually by an experienced technician on all slices in which they were visualized. Region of interest volumes were compared across groups, and age, sex, and stature were controlled. RESULTS: Schizophrenic patients were found to have larger lateral and third ventricles and smaller thalamic, hippocampal, and superior temporal volumes than comparison subjects. No significant differences were demonstrated for intracranial, cerebral, cerebellar, temporal lobe, caudate nuclei, or temporal horn volumes. There were no significant Laterality by Diagnosis effects and no significant Gender by Diagnosis effects for any of the regions of interest. CONCLUSIONS: Many, but not all, of the hypotheses informed by earlier studies regarding diagnostic effects were confirmed, while hypotheses regarding gender and laterality interactions with diagnosis were not supported.

Frontal leukotomy and related psychosurgical procedures in the era before antipsychotics (1935-1954): a historical overview.

OBJECTIVE: This article provides an overview of the history of psychosurgery as a treatment for psychiatric illnesses. METHOD: The author reviewed articles describing psychosurgery between 1935 and 1954 in order to summarize surgical techniques, clinical indications for surgery, patient selection, complications, and outcome. RESULTS: Patients were operated on for a wide variety of psychiatric illnesses. Initially, a large number of uncontrolled studies reported considerable therapeutic benefit in at least one-third of the patients operated on. Complications with the early surgical techniques included hemorrhage, seizures, infection, and personality changes. Surgical techniques proliferated in hopes of achieving greater therapeutic benefit while minimizing detrimental side effects. As psychosurgery became more widely accepted, its principal supporters began to use it as a routine therapy. A number of uncontrolled and controlled short-term studies supported the efficacy of psychosurgery, but long-term controlled studies showed mixed results. CONCLUSIONS: Psychosurgery was promoted as a treatment for patients who had shown little or no response to less drastic therapies. In the context of an era when no efficacious treatments were available for psychosis, its use was understandable. However, its history illustrates the importance of critical evaluation of new treatments in the context of long-term controlled outcome studies, the natural course of specific illnesses, and an understanding of brain physiology.

Abnormalities in midline attentional circuitry in schizophrenia: evidence from magnetic resonance and positron emission tomography.

The syndrome of schizophrenia presents with a complex array of symptoms that are difficult to explain at the neural level. Data collected using magnetic resonance (MR) and positron emission tomography (PET) suggest that this complex array could occur as a consequence of misconnections and mismatches in midline circuitry that is reticular-thalamic-cingulate-cortical. MR studies have shown a variety of abnormalities, including callosal agenesis, cavum septi pellucidi, decreased thalamic size, decreased frontal size, and changes in signal intensity in white matter tracts between the thalamus and the frontal cortex. PET studies using a dichotic listening paradigm suggest that patients suffering from schizophrenia have brain blood flow abnormalities consistent with a difficulty in focusing or shifting attention, which may reflect the functional substrate of the anatomic abnormalities.

Regional brain abnormalities in schizophrenia measured with magnetic resonance imaging.

OBJECTIVE: To determine general and regional indices of structural brain abnormality in schizophrenia. DESIGN: Case-control comparison study. SUBJECTS: Fifty-two patients diagnosed as having schizophrenia according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, were compared with 90 healthy volunteers recruited from the community. MEASUREMENTS: Structural brain images were acquired using magnetic resonance; measurements were obtained using three-dimensional visualization of volume-rendered brains and an automated atlas-based dissection of specific regions. General measures included the volume of total brain tissue, total cerebrospinal fluid (CSF), and CSF within the ventricular system. Regional measures included the volume of tissue and CSF in the frontal, temporal, parietal, and occipital lobes and the cerebellum. RESULTS: Compared with the controls, the patients had a smaller average volume of total brain tissue and a greater average volume of total and ventricular CSF. A specific relative decrease in brain tissue was found only in the frontal lobes, although the volume of CSF was greater in patients than in controls in all brain regions. CONCLUSION: In addition to the generalized brain abnormalities observed in schizophrenia, a regional abnormality may be present in frontal regions. Since the frontal lobes integrate multimodality information and perform a variety of "higher" cognitive and emotional functions that are impaired in schizophrenia, the frontal abnormality noted is consistent with the clinical presentation of the illness. Impaired frontal function and a disruption in its complex circuitry (including thalamocortical projections) may explain why patients with schizophrenia often have significant deficits in formulating concepts and organizing their thinking and behavior.

Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging.

Schizophrenia is a complex illness characterized by multiple types of symptoms involving many aspects of cognition and emotion. Most efforts to identify its underlying neural substrates have focused on a strategy that relates a single symptom to a single brain region. An alternative hypothesis, that the variety of symptoms could be explained by a lesion in midline neural circuits mediating attention and information processing, is explored. Magnetic resonance images from patients and controls were transformed with a "bounding box" to produce an "average schizophrenic brain" and an "average normal brain." After image subtraction of the two averages, the areas of difference were displayed as an effect size map. Specific regional abnormalities were observed in the thalamus and adjacent white matter. An abnormality in the thalamus and related circuitry explains the diverse symptoms of schizophrenia parsimoniously because they could all result from a defect in filtering or gating sensory input, which is one of the primary functions of the thalamus in the human brain.

IQ and brain size in schizophrenia.

In a previous study of normal control subjects, positive correlations were demonstrated between intelligence, as measured by the Wechsler Adult Intelligence Scale-Revised, and various measures of brain size, as assessed by magnetic resonance imaging (Andreasen et al., 1993). The goal of this study was to see if these findings generalized to schizophrenia. Corresponding analyses were performed in a group of DSM-III-R schizophrenic patients (50 men and 22 women) and compared with a subset of those normal control subjects (32 men and 27 women) who were equivalent to the patient group in their age and the educational and socioeconomic background of their families of origin. Full Scale IQ score was found to be uncorrelated with any of the regions of interest for the patient group as a whole. When subjects were divided by sex, the female patients were found to have a pattern of correlations similar to that of normal control subjects, while no such relationship was apparent among the male patients. These differences did not appear to be attributable to variability in symptom severity. Thus, there appear to be gender-related differences in brain structure/function relationships in schizophrenic patients versus normal control subjects.

Evaluating and validating two methods for estimating brain structure volumes: tessellation and simple pixel counting.

Developments in imaging technology have made three-dimensional visualization of internal brain structures possible with excellent resolution. Since improved visualization implies improved measurement, these advances hold promise to more accurately measure the volumes of internal structures. As new technologies and techniques emerge, evaluating the relative benefits of measurement methods becomes necessary. We compared and evaluated two methods of estimating volumes from images of brain structures. One method counted pixels within a region of interest, while the other method tessellated the surface between tracings on adjacent slices. Our study assessed both measurement error for true phantom volumes and method disparity for in vivo structures in a randomly selected sample of subjects (n = 100). For our comparisons, we focused on the temporal lobe, ventricular system, and hippocampus. Bias, independence of measurement errors and maximal discrimination of individual differences are properties that are relevant to validating and evaluating measurements of cerebral structure. Pixel counting proved to be the more robust of the two methods, being less sensitive to nuisance-interactions between size of object, shape, and slice thickness. Clinical and research applications of imaging techniques may have distinctive but overlapping needs when evaluating and validating new developments in imaging.

Positive and negative symptoms of schizophrenia: past, present, and future.

The "group of schizophrenias," normally referred to with a single nominative, is phenomenologically heterogeneous. Its symptoms represent multiple psychological domains, including perception, inferential thinking, language, attention, social interaction, emotion expression, and volition. Studies of psychopathology have simplified this complex array in several ways; one has been a subdivision into positive and negative symptoms. Reports by our group and others suggest that the symptoms of schizophrenia fall into three natural dimensions: positive symptoms subdivided into psychotic and disorganized dimensions, while a third negative dimension also emerges. Since these dimensions have impressive consistency across studies, future work must examine their relationship to clinically relevant concepts such as prognosis or etiology and examine four different aspects: longitudinal course, neural mechanisms, relationship to treatment, and interrelationships in other pathological conditions.

Techniques for measuring sulcal/gyral patterns in the brain as visualized through magnetic resonance scanning: BRAINPLOT and BRAINMAP.

A method for measuring sulcal and gyral patterns, using data derived from magnetic resonance (MR) scanning, is described. This method can be applied through two newly developed computer programs, BRAINPLOT and BRAINMAP. These programs provide quantitative measures of brain surface pattern. The method has been validated with postmortem brains, phantoms, and human MR data. The method is robust to detecting differences in brain surface anatomy between atrophic and nonatrophic brains. It appears to offer an efficient, fully automated, and accurate method for analyzing the large amounts of information generated through in vivo neuroimaging techniques.

The neuropsychology of the prefrontal cortex.

Single photon emission computed tomography with the xenon inhalation technique is used to compare activation of regional cerebral blood flow in frontal brain regions during the performance of four widely used neuropsychological tests: the Continuous Performance Test, the Wisconsin Card Sorting Test, the Tower of London, and Porteus Mazes. Healthy normal volunteers performing these tasks show significant increases in frontal regions during the Continuous Performance Test, the Wisconsin Card Sorting Test, and the Tower of London, but not the Porteus Mazes. Activation produced by the Continuous Performance Test and the Tower of London are mesial and bilateral and may reflect stimulation of midline attentional circuits. The Wisconsin Card Sorting Test produces a left dorsolateral area of prefrontal activation. These findings indicate that regional activation of the frontal lobes occurs in response to cognitive challenges produced through performance of standard neuropsychological tests.