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Objective: The goal of this study was to investigate brain white matter abnormalities by using diffusion tensor imaging in patients with schizophrenia or schizoaffective disorder close to illness onset. Method: Ten patients experiencing a first episode of schizophrenia or schizoaffective disorder and 13 healthy volunteers received diffusion tensor imaging and structural magnetic resonance imaging examinations. Voxel-wise analysis was used to compare fractional anisotropy maps in the white matter of the two groups following intersubject registration to Talairach space. Results: Compared with healthy volunteers, patients demonstrated lower fractional anisotropy in the left internal capsule and left-hemisphere white matter of the middle frontal gyms and posterior superior temporal gyms. There were no areas of significantly higher fractional anisotropy in patients compared with healthy volunteers. Conclusions: These findings suggest that white matter pathology is present early in the course of schizophrenia and may be less pronounced than has been found in previous diffusion tensor imaging studies of patients with chronic illness. Further, these data are consistent with hypotheses regarding frontotemporal dysfunction and the failure of left-hemisphere lateralization in the pathophysiology of schizophrenia.

Objective: The authors investigated volumetric alterations of the anterior hippocampal formation in patients experiencing a first episode of schizophrenia relative to healthy comparison subjects. Method: From contiguous 1.5-mm coronal magnetic resonance images, the hippocampal formation was divided into posterior and anterior segments, and the anterior hippocampal formation was separated from the amygdala. Volumes of the posterior and anterior hippocampal formation and amygdala were computed in 46 (31 male and 15 female) patients experiencing a first episode of schizophrenia and in 34 (21 male and 13 female) healthy comparison subjects. Twenty-four patients were antipsychotic naive at the time of the scan. Results: Patients had significantly reduced total (right plus left) anterior hippocampal formation volume relative to healthy comparison subjects but did not differ in volumes of either the posterior hippocampal formation or amygdala. Similar findings were obtained when analyses were restricted to the antipsychotic-naive subgroup of patients. Conclusions: These findings suggest that volumetric abnormalities of the hippocampus-amygdala complex may be specific to the anterior hippocampal formation in patients experiencing a first episode of schizophrenia and are consistent with hypotheses regarding abnormal frontolimbic connectivity playing a role in the pathophysiology of the disorder.

Objective: Functional neuroimaging studies have identified a role for the cerebellum in the neuropsychology of schizophrenia. Few studies, however, have examined the relationship between cerebellar size and neuropsychological functioning in schizophrenia. The authors' goal was to examine this relationship in patients and healthy comparison subjects. Method: Total cerebellar volume was computed from magnetic resonance images in 48 male and 33 female patients experiencing a first episode of schizophrenia and in 14 male and nine female healthy comparison subjects. Patients and comparison subjects completed a comprehensive neuropsychological assessment encompassing six domains of functioning: executive, motor, language, visuospatial, memory, and attention. A global domain of functioning was computed as the mean of these six domains. Results: Larger cerebellar volume correlated significantly with better global functioning in healthy subjects but not among patients with schizophrenia; this relationship was significantly stronger in healthy subjects than in patients. Additional analyses revealed significant associations between cerebellar volume and visuospatial, executive, and memory functions in healthy volunteers but not among patients. Conclusions: The cerebellum plays a role in higher cognitive functions in healthy individuals, and normal associations between cerebellar size and function are absent in patients experiencing a first episode of schizophrenia. These findings are consistent with neurobiological models implicating the cerebellum in the pathogenesis of schizophrenia.

Objective: Despite evidence for hippocampal structural abnormalities in patients with schizophrenia, their functional correlates remain largely unknown. This study investigated the neuropsychological correlates of hippocampal volume in 43 men and 32 women experiencing a first episode of schizophrenia. Method: Posterior and anterior hippocampal volumes were computed from contiguous 3.1-mm magnetic resonance images and examined in relationship to six domains of neuropsychological functioning. Significant structure-function associations were investigated by examining the correlations between functioning and individual hippocampal slice volumes across the long axis of the hippocampus after interpolation to 10 equally spaced slice positions. Results: Among men, worse executive and motor functioning correlated significantly with smaller anterior, but not posterior, hippocampal volume. The relationship between executive and motor functioning and hippocampal volume was not linear, however, when examined across the long axis of the hippocampus. Anterior hippocampal volume was more strongly correlated with both executive and motor functioning than with either memory or language functioning in men. None of the correlations between either posterior or anterior hippocampal volumes and the neuropsychological domains was significant among women. Anterior hippocampal volume was more strongly correlated with motor functioning in men than in women. Conclusions: Anterior hippocampal abnormalities associated with deficits on tests considered sensitive to frontal lobe functions implicate a defect in the integrated system linking frontal and mesiotemporal lobe regions. These findings further suggest that there are sex differences in structure-function relations in schizophrenia such that men may have more pronounced frontolimbic system abnormalities. (Am J Psychiatry 2002; 159:217-226)

Research indicates that depression in the elderly may be linked to heterogeneous pathogenic conditions, including deep white matter hyperintensities and subcortical gray matter hyperintensities. The study controlled for effects of gender, age and height, and was conducted within an inpatient-outpatient geriatric psychiatric hospital facility.

Objective: The purpose of this study was to examine the relationship between signal hyperintensities - a probable marker of underlying pathology - on [T.sub.2]-weighted magnetic resonance brain scans and neuropsychological test findings in elderly depressed and normal subjects. Method: Elderly subjects with a DSM-III-R diagnosis of major depression (N = 41) and normal elderly comparison subjects (N = 38) participated in a magnetic resonance imaging study (1.0-T) of signal hyperintensities in periventricular, deep white matter, and subcortical gray matter. Hard copies of scans were rated in random order by research psychiatrists blind to diagnosis; the modified Fazekas hyperintensity rating scale was used. Cognitive performance was independently assessed with a comprehensive neuropsychological battery. Clinical and demographic differences between groups were assessed by t tests and chi-square analysis. Relationships between neuropsychological performance and diagnosis and hyperintensities and their interaction were analyzed by using analysis of covariance, with adjustment for age and education. Results: Elderly depressed subjects manifested poorer cognitive performance on several tests than normal comparison subjects. A significant interaction between hyperintensity location/severity and presence/absence of depression on cognitive performance was found: depressed patients with moderate-to-severe deep white matter hyperintensities demonstrated worse performance on general and delayed recall memory indices, executive functioning and language testing than depressed patients without such lesions and normal elderly subjects with or without deep white matter changes. Conclusions: Findings validate cognitive performance decrements in geriatric depression and suggest possible neuroanatomic vulnerabilities to developing particular neuropsychological dysfunction in depressed subjects.

Objective: This study examined the pathomorphology of the caudate nuclei in first-episode schizophrenic patients with minimal previous neuroleptic exposure. Method: Magnetic resonance imaging (MRI) of the brain was used to examine longitudinally the caudate pathomorphology in 29 first-episode schizophrenic patients and 10 healthy comparison subjects. MRI scans were obtained after the subjects entered the study and at 18-month follow-up. The patients were treated with standardized neuroleptic regimens during the 18-month period. Volumetric assessments of the cerebral cortex, lateral ventricles, and caudate nuclei were performed on [T.sub.1]-weighted coronal brain sections. In addition, the patients were systematically evaluated for psychopathology at baseline and during treatment. Results: Caudate volumes increased 5.7% in the patients during the 18-month treatment interval, whereas they decreased 1.6% in the comparison subjects over the same time period. Greater amounts of antipsychotic medication received by patients before the first scan and younger age at the time of the first scan were associated with larger increases in caudate volume. Conclusions: Caudate enlargement occurs early in the course of treatment in young first-episode schizophrenic patients. This may be a result of an interaction between neuroleptic treatment and the plasticity of dopaminergic neuronal systems in young patients.

The goal of this study was to determine whether patients experiencing their first episode of schizophrenia differ from healthy subjects in regional cerebral hemispheric volumes or asymmetries. Method: Regional volumes corresponding to prefrontal, premotor, sensorimotor, occipitoparietal, and temporal lobes in each hemisphere were measured on contiguous coronal magnetic resonance images in 70 patients experiencing their first episode of schizophrenia and in 51 healthy comparison subjects. Results: Patients did not differ from the comparison subjects in regional or total hemispheric volumes, but they had abnormal hemispheric asymmetries. Subjects in the comparison group had significant lateral asymmetries in each region: their occipitoparietal and sensorimotor regions were larger on the left, and their pre-motor, prefrontal, and temporal regions were larger on the right. Patients lacked lateral asymmetries and showed significantly less asymmetry than healthy subjects in occipitoparietal, premotor, and prefrontal regions. Absence of the normal asymmetry was more common among patients initially diagnosed with the undifferentiated than with the paranoid subtype of schizophrenia and was associated with more severe negative symptoms among men. Asymmetries were related to sex and handedness regardless of diagnosis; specifically, dextral men showed more asymmetry than nondextral men or dextral women. Conclusions: The absence of normal hemispheric asymmetries suggests an anomaly in the development of laterally specialized cerebral systems in schizophrenia, and this may be associated with an initial presentation of nonparanoid psychosis.