Hippocampal deformities in the unaffected siblings of schizophrenia subjects.

BACKGROUND: Neuroanatomical abnormalities have been reported in schizophrenia subjects and their relatives and may be related to genetic vulnerability. The objective of this study was to further elucidate hippocampal deformities as a marker of genetic vulnerability for schizophrenia. METHODS: Magnetic resonance scans were collected in 13 pairs of schizophrenics and their unaffected siblings from families with multiple affected members, in 12 schizophrenics from families without another affected member, and in 10 healthy controls. Hippocampal volume and shape were compared using large-deformation high-dimensional brain mapping. RESULTS: Decreases in hippocampal volume, covaried for total cerebral volume, were observed in the schizophrenia subjects from families with multiple affected members, as well as in their unaffected siblings. Shape analysis demonstrated that both groups of schizophrenia subjects, as well as the unaffected siblings, could be distinguished from the controls; however, no significant difference in hippocampal shape was found between the schizophrenia subjects and their unaffected siblings. Visualization of the pattern of hippocampal shape deformity in both groups of schizophrenia subjects and in the unaffected siblings showed inward deformities of the head of the hippocampus. CONCLUSIONS: Deformations of hippocampal anatomy may be related to the genetic vulnerability of acquiring schizophrenia.     

Abnormalities of thalamic volume and shape in schizophrenia

OBJECTIVE: Postmortem and neuroimaging studies of schizophrenia have reported deficits in the volume of the thalamus and its component nuclei. However, the pattern of shape change associated with such volume loss has not been investigated. In this study, alterations in thalamic volume, shape, and symmetry were compared in subjects with and without schizophrenia. METHOD: T(1)-weighted magnetic resonance scans were collected in 52 schizophrenia and 65 comparison subjects matched for age, gender, race, and parental socioeconomic status. High-dimensional (large-deformation) brain mapping was used to assess thalamic morphology. RESULTS: Significant differences in thalamic volume, deformities of thalamic shape at the anterior and posterior extremes of the structure, and a significant exaggeration of thalamic asymmetry (i.e., left smaller than right) were found in the schizophrenia subjects. After covarying for total cerebral volume, the difference in thalamic volume became insignificant. When information about thalamic shape was combined with previously collected information about hippocampal shape, the discrimination between schizophrenia patients and comparison subjects was improved. CONCLUSIONS: Thalamic volume was smaller than normal in schizophrenia patients, but only proportionate to reductions in reduced total cerebral volume. The presence of changes in thalamic shape and asymmetry suggest greater pathologic involvement of individual nuclei at its anterior and posterior extremes of the thalamic complex.     

Early DAT is distinguished from aging by high-dimensional mapping of the hippocampus. Dementia of the Alzheimer type

OBJECTIVE: To determine the feasibility of using high-dimensional brain mapping (HDBM) to assess the structure of the hippocampus in older human subjects, and to compare measurements of hippocampal volume and shape in subjects with early dementia of the Alzheimer type (DAT) and in healthy elderly and younger control subjects. BACKGROUND: HDBM represents the typical structures of the brain via the construction of templates and addresses their variability by probabilistic transformations applied to the templates. Local application of the transformations throughout the brain (i.e., high dimensionality) makes HDBM especially valuable for defining subtle deformities in brain structures such as the hippocampus. METHODS: MR scans were obtained in 18 subjects with very mild DAT, 18 healthy elderly subjects, and 15 healthy younger subjects. HDBM was used to obtain estimates of left and right hippocampal volume and eigenvectors that represented the principal dimensions of hippocampal shape differences among the subject groups. RESULTS: Hippocampal volume loss and shape deformities observed in subjects with DAT distinguished them from both elderly and younger control subjects. The pattern of hippocampal deformities in subjects with DAT was largely symmetric and suggested damage to the CA1 hippocampal subfield. Hippocampal shape changes were also observed in healthy elderly subjects, which distinguished them from healthy younger subjects. These shape changes occurred in a pattern distinct from the pattern seen in DAT and were not associated with substantial volume loss. CONCLUSIONS: Assessments of hippocampal volume and shape derived from HDBM may be useful in distinguishing early DAT from healthy aging.     

Hippocampal shape deformity analysis in obsessive–compulsive disorder

Abnormalities of orbital prefrontal cortex and caudate nuclei have, thus far, been the main findings regarding the pathophysiology of obsessive–compulsive disorder (OCD). On the other hand, neuroimaging studies have failed to reach a consensus with regard to the issue of hippocampal abnormalities in OCD patients. Shape analysis may facilitate a resolution of the discordance among these former studies by detecting local structural changes, thus enhancing power to discriminate structural differences. It has been suggested that neural circuitry interconnecting brain areas may critically influence the shape of neuroanatomical structures, serving as a rationale for better sensitivity of shape analysis compared to volume analysis, especially in detecting abnormalities of neural circuitry. Shape analysis of the hippocampus was performed in 22 matched pairs of OCD patients and normal control subjects. As a result, we observed a bilateral hippocampal shape deformity including the most prominent characteristic of downward displacement of the head. The hippocampal structural alteration observed in this study indicates that this structure may play a role in the pathophysiology of OCD. Also, further considering the hippocampal neural connections specific to its surface topography, these surface deformities may reflect developmental alterations in these patients with regard to the neural circuitry involving hippocampus.     

Increased duration of illness is associated with reduced volume in right medial temporal/anterior cingulate grey matter in patients with chronic schizophrenia

It is unclear whether the neuroanatomical abnormalities associated with schizophrenia change over the course of the disorder. We addressed this issue by examining whether the magnitude of structural brain abnormalities in patients with chronic schizophrenia was related to their duration of illness. Thirty-nine subjects with schizophrenia (34 male, 5 female, range of illness duration 2-31 years) were scanned using magnetic resonance imaging. Images were segmented into grey and white matter, cerebrospinal fluid and dura/blood vessels using the Structural Magnetic Resonance Toolkit (SMaRT). Voxel-based analysis identified brain areas whose volume varied significantly with time since the first onset of psychosis. Right medial temporal, medial cerebellar and bilateral anterior cingulate grey matter volume, and white matter volume in the right posterior limb of the internal capsule, were all negatively correlated with illness duration (p < 0.002). Conversely, illness duration was positively correlated with the volume of the right globus pallidus (p < 0.002). These correlations were not a function of chronological age or age at illness onset. The inverse correlation between right frontal, temporal and cerebellar volumes and the time since the onset of schizophrenia could reflect progressive tissue loss following the first episode of the disorder.     

Temporal pole morphology and psychopathology in males with schizophrenia

A dysfunction of the paralimbic system has been implicated in the pathophysiology of schizophrenia. The temporal pole (TP) is a relevant component of the paralimbic circuit. Functional and structural imaging studies have shown circumscribed abnormalities in the TP. Subjects were 30 controls and 30 schizophrenia patients. Cortical surface size and gray matter volume of the TP were accurately measured to explore the morphology of the TP cortex and the relationship of TP measures to clinical variables in patients with schizophrenia. Correlations between structural measures and clinical dimensions, duration of illness, and cumulative neuroleptic exposure were determined. Neither macroscopic abnormalities in the TP nor differences in the pattern of asymmetry were demonstrated. The TP volume was correlated negatively to the psychotic and disorganized dimension scores. No other significant correlations were found. No morphological abnormalities in the TP were found in patients with schizophrenia. Interestingly, a reduction in the TP volume, a higher-order multimodal association cortex, was associated with the severity of disorganized and psychotic symptoms.     

Automated ROI-based brain parcellation analysis of frontal and temporal brain volumes in schizophrenia

Structural MRI studies of schizophrenia have yielded a diversity of findings. To help characterize regional gray matter changes in schizophrenia, we used an automated region of interest (ROI)-based approach that targeted frontal and temporal regions in schizophrenia patients. The sample compromised 43 schizophrenia patients (21 chronic patients, 22 unmedicated first episode patients), 20 first episode non-schizophrenia psychosis patients and 47 comparison subjects. Automated regional volume measurement was performed in 22 ROIs, including frontal and temporal cortical subregions and hippocampus. Correlations between volume measures, duration of illness and clinical scores were evaluated. Chronic schizophrenia patients showed gray matter volume differences in left dorsolateral prefrontal cortex (DLPFC) and right supplementary motor area (SMA). First episode psychosis patients presented smaller right anterior cingulate cortex (ACC) and left DLPFC than comparison subjects. Disorganization scores and duration of illness correlated negatively with gray matter volume of DLPFC and SMA in chronic schizophrenia patients. Using an automated ROI-based method, we found volume reductions in lateral and medial frontal regions in both first episode and chronic schizophrenia. The automated ROI-based method can be used as a valid and efficient tool for quantification of regional gray matter volume in schizophrenia in multiple ROIs across the brains of large numbers of subjects.     

Structural magnetic imaging of the hippocampus in early onset schizophrenia.

BACKGROUND: Previous literature suggests that hippocampal volume reductions in schizophrenia may occur either during adolescence or at the point of transition to overt psychosis. The authors tested these hypotheses by examining the hippocampal formation in adolescents with recent onset schizophrenia. METHODS: We compared the volumes of the left and right hippocampus, obtained using stereologic methods from magnetic resonance brain images, from 40 adolescents with recent onset schizophrenia to those of an equal number of matched healthy control subjects. Symptoms were rated using the Positive and Negative Syndrome Scale. RESULTS: Compared with control subjects, adolescents with schizophrenia had reduced whole brain volume. After adjusting for brain volume, no group differences were observed in hippocampal volume. Duration of illness was negatively correlated with the volume of the left hippocampus. We found no effect of pregnancy and birth complications or family history of psychosis on hippocampal volumes. There was a negative correlation between severity of psychopathology and hippocampal volumes, which was significant for negative symptoms. CONCLUSIONS: Specific hippocampal volume reductions in early onset schizophrenia do not seem to predate the onset of or to occur at the point of transition to psychosis but may develop in adolescence during the early stages of the illness.     

Hippocampus and amygdala volumes in schizophrenia and other psychoses in the Northern Finland 1966 birth cohort

Structural brain differences have been reported in many studies with schizophrenia, but few have involved a general population birth cohort. We investigated differences in volume, shape and laterality of hippocampus and amygdala in patients with schizophrenia, all psychoses and comparison subjects within a large general birth cohort sample, and explored effects of family history of psychosis, perinatal risk and age-at-onset of illness. All subjects with psychosis from the Northern Finland 1966 birth cohort were invited to a survey including MRI scan of the brain, conducted in 1999-2001. Comparison subjects not known to have psychosis were randomly selected from the same cohort. Volumes of hippocampus and amygdala were measured in 56 subjects with DSM-III-R schizophrenia, 26 patients with other psychoses and 104 comparison subjects. Small hippocampal volume reductions in schizophrenia (2%) and all psychoses (3%) were not significant when adjusted for total brain volume. The shape of hippocampus in schizophrenia did not differ significantly from comparison subjects. Right hippocampus and amygdala were significantly larger than the left in all groups. Mean amygdala volume in schizophrenia or all psychoses did not differ from comparison subjects. Patients with family history of psychosis had larger hippocampus than patients without. Neither perinatal risk nor age-at-onset of illness had any effect on hippocampal or amygdala volumes. Small hippocampal volume reduction in schizophrenia and all psychoses was not disproportionate to reduced whole brain volume in this population-based sample. Perinatal events that have been suggested as of etiological importance in structural pathology of psychosis had no effect.     

Volume reduction of the left planum temporale gray matter associated with long duration of untreated psychosis in schizophrenia: a preliminary report

A longer duration of untreated psychosis (DUP) in schizophrenia is reported to lead to a poorer clinical outcome, possibly reflecting a neurodegenerative process after the onset of overt psychosis. However, the effect of DUP on brain morphology in schizophrenia is still poorly understood. In this study, we used magnetic resonance imaging to investigate the relation between DUP and volumetric measurements for the superior temporal sub-regions (Heschl's gyrus, planum temporale, and caudal superior temporal gyrus), the medial temporal lobe structures (hippocampus and amygdala), and the frontal lobe regions (prefrontal area and anterior cingulate gyrus) in a sample of 38 schizophrenia patients (20 males and 18 females) whose illness duration was less than five years. We found a significant negative correlation between DUP and the volume of gray matter in the left planum temporale even after controlling for age, age at illness onset, and duration and dosage of neuroleptic medication. There was no such correlation for the other brain regions including each sub-region of the prefrontal cortex (the superior frontal gyrus, middle frontal gyrus, inferior frontal gyrus, ventral medial prefrontal cortex, orbitofrontal cortex, and straight gyrus). When subjects were divided into two groups around the median DUP, the long-DUP group had a significantly smaller planum temporale gray matter than the short-DUP group. These findings may reflect a progressive pathological process in the gray matter of the left planum temporale during the initial untreated phase of schizophrenia, whereas abnormalities in the medial temporal regions might be, as has been suggested from previous longitudinal findings, relatively static at least during the early course of the illness.     

High-dimensional mapping of the hippocampus in depression

OBJECTIVE: Abnormalities of the hippocampus may play a role in the pathophysiology of depression, but efforts to identify a structural abnormality in this brain structure among depressed patients have produced mixed results. Previous research may have been limited by exclusive reliance on measures of hippocampal volume. High-dimensional brain mapping is a new analytic method that quantitatively characterizes the shape as well as volume of a brain structure. In this study, high-dimensional brain mapping was used to evaluate hippocampal shape and volume in patients with major depressive disorder and healthy comparison subjects. METHOD: By using magnetic resonance imaging, brain scans were obtained from 27 patients with major depressive disorder and 42 healthy comparison subjects. High-dimensional brain mapping generated a series of 10 variables (components) that represented hippocampal shape, and hippocampal volumes were also computed. Analysis of variance techniques were used to compare depressed patients and comparison subjects on hippocampal shape and volume. RESULTS: While the depressed patients and comparison subjects did not differ in hippocampal volume, there were highly significant group differences in hippocampal shape. The two groups did not overlap on a discriminant function computed from a model comprising the 10 components. The pattern of hippocampal surface deformation in the depressed patients suggested specific involvement of the subiculum. CONCLUSIONS: Patients with major depression may have structural abnormalities of the hippocampus that can be detected by analysis of hippocampal shape but not volume. A specific defect in the subiculum could have widespread effects throughout neurocircuits that appear to be abnormal in depression.     

Hippocampal changes in patients with a first episode of major depression

OBJECTIVE: Previous work suggests that patients with unipolar depression may have structural as well as functional abnormalities in limbic-thalamic-cortical networks, which are hypothesized to modulate human mood states. A core area in these networks is the hippocampus. In the present study, differences in volumes of hippocampal gray and white matter between patients with a first episode of major depression and healthy comparison subjects were examined. METHOD: Thirty patients with a first episode of major depression and 30 healthy comparison subjects who were matched for age, gender, handedness, and education were examined with high-resolution magnetic resonance imaging. RESULTS: Male patients with a first episode of major depression had significantly smaller hippocampal total and gray matter volumes than healthy male comparison subjects. Both male and female patients showed significant alterations of left-right asymmetry and significant reductions of left and right hippocampal white matter fibers in relation to healthy comparison subjects. Hippocampal measurements were not significantly correlated with clinical variables, such as age at onset of illness, illness duration, or severity of depression. CONCLUSIONS: These results are consistent with findings of structural abnormalities of the hippocampal formation in patients with major depression that were more pronounced in male patients. The authors' findings support the hypothesis that the hippocampus and its connections within limbic-cortical networks may play a crucial role in the pathogenesis of major depression.     

Asymmetry analysis of deformable hippocampal model using the principal component in schizophrenia

The hippocampus is thought to play an important role in learning and memory processing, and impairments in memory, attention, and decision making are found commonly in schizophrenia. Although many studies have reported decreases in hippocampal volume in the left hemisphere in schizophrenia, regionally specific hippocampal volume loss has not been revealed consistently using volume analysis. Recently, many studies have analyzed shape asymmetry using 3-D models; however, inconsistent results have been reported, mainly due to methodologic differences. We therefore used an active, flexible, deformable shape model for surface parameterization, and compared shape asymmetry based on principal component analysis (PCA) in the hippocampi of schizophrenic patients with those of the normal controls. Although the overall pattern of the statistical results did not change according to the number of principal components, the reconstructed results based on six major components were much more distinguishable. Although the left hemispheric hippocampal volume was larger than the right hemispheric was in this study, the difference was not significant. In shape asymmetry analysis, the right hemisphere hippocampus was bilaterally larger than the left hemisphere hippocampus was in the head of the superior CA1 and smaller in the tail and head of the inferior CA1. The asymmetry in the schizophrenia group was statistically smaller than that in the control group through reduction of the left hemisphere hippocampus volume.     

Selective bilateral hippocampal volume loss in chronic schizophrenia.

BACKGROUND: The hippocampus is implicated in the pathophysiology of schizophrenia; however, volumetric changes are subtle and have limited diagnostic specificity. It is possible that the shape of the hippocampus may be more characteristic of schizophrenia. METHODS: Forty-five patients with chronic schizophrenia and 139 healthy control subjects were scanned using magnetic resonance imaging. Hippocampi were traced manually, and two-dimensional shape information was analyzed. RESULTS: Two shape factors were found to be adequate to represent variance in the shape of the hippocampus. One of these factors, representing volume loss behind the head of the hippocampus, provided a degree of discrimination between patients with chronic schizophrenia and healthy control subjects; however, overall hippocampal volume following appropriate adjustment for brain volume showed a similar level of discrimination. Patients with chronic schizophrenia were best characterized using these two measures together, but diagnostic specificity was only moderate. CONCLUSIONS: This study identified that less of the hippocampus was distributed in its posterior two-thirds in patients with chronic schizophrenia, and specifically in the region just posterior to the hippocampal head. Group discrimination on the basis of hippocampal volume and shape measures was moderately good. A full three-dimensional analysis of hippocampal shape, based on large samples, would be a useful extension of the study.     

Shape differences in the corpus callosum in first-episode schizophrenia and first-episode psychotic affective disorder

OBJECTIVE: The corpus callosum, the largest white matter tract in the brain, is a midline structure associated with the formation of the hippocampus, septum pellucidum, and cingulate cortex, which have been implicated in the pathogenesis of schizophrenia. Corpus callosum shape deformation, therefore, may reflect a midline neurodevelopmental abnormality. METHOD: Corpus callosum area and shape were analyzed in 14 first-episode psychotic patients with schizophrenia, 19 first-episode psychotic patients with affective disorder, and 18 normal comparison subjects. RESULTS: No statistically significant corpus callosum area differences between groups were found, but there were differences in the structure's shape between the patients with schizophrenia and the comparison subjects. A correlation between width and angle of the corpus callosum was found in patients with affective disorder. CONCLUSIONS: Corpus callosum shape abnormalities in first-episode psychotic patients with schizophrenia may reflect a midline neurodevelopmental abnormality.     

Anterior hippocampal volume reduction in male patients with schizophrenia

Quantitative high resolution magnetic resonance imaging (MRI) was utilized to measure anterior, posterior, and total hippocampal volumes in 27 male patients with chronic schizophrenia and 24 male controls. To optimize measurement techniques, hippocampal volumes were: (1) acquired with 1.4-mm slices; (2) excluded with the amygdala; (3) normalized for position; and (4) corrected for total intracranial volume (ICV). The results of a linear mixed effects regression analysis, which made it possible to analyze total anterior and total posterior hippocampal volumes separately, indicated that the anterior hippocampus was significantly smaller in the schizophrenic group relative to the control group. There were no significant group differences with respect to posterior hippocampal volumes, and no significant correlations between hippocampal volumes and illness duration. A significant lateralized asymmetry was also noted in both groups with the right hippocampal volume being larger than the left. These preliminary findings support a significant anterior hippocampal volume reduction in men with schizophrenia as well as a similar hippocampal volume asymmetry in both male controls and schizophrenics.     

Brain morphometry in female victims of intimate partner violence with and without posttraumatic stress disorder.

BACKGROUND: To examine neuroanatomical morphometry in adult female victims of intimate partner violence with and without posttraumatic stress disorder. METHODS: Seventeen nonvictimized comparison subjects and 22 victims of intimate partner violence, 11 with and 11 without posttraumatic stress disorder, were studied. Using quantitative magnetic resonance imaging, three mesial temporal lobe areas were measured: hippocampus, amygdala, and parahippocampal gyrus. Additionally, whole brain morphometry provided fluid, gray, and white matter volumes of the cortex and cerebellum for exploratory analyses. Relationships of morphometric measures to symptoms, abuse history, and neuropsychological function were examined. RESULTS: Intimate partner violence subjects with posttraumatic stress disorder did not demonstrate significantly smaller hippocampal or other mesial temporal lobe volumes. Overall, intimate partner violence subjects had smaller supratentorial cranial vaults and smaller frontal and occipital gray matter volumes relative to nonvictimized comparison subjects. Supratentorial cranial vault volume was negatively correlated with severity of childhood physical abuse, but not with intimate partner violence or posttraumatic stress disorder severity. Trails B performance was negatively correlated with frontal gray matter volume. CONCLUSIONS: These findings are inconsistent with prior reports of smaller hippocampal volumes in patients with posttraumatic stress disorder. Rather, the findings point to cerebral abnormalities that may reflect the influence of early trauma on neurodevelopmental processes or denote brain morphometric characteristics of persons at increased risk for serious psychosocial adversity.     

Functional imaging of memory retrieval in deficit vs nondeficit schizophrenia

BACKGROUND: Neuroimaging studies have provided evidence of abnormal frontal and temporal lobe function in schizophrenia. Frontal cortex abnormalities have been associated with negative symptoms and temporal lobe abnormalities with positive symptoms. The deficit and nondeficit forms of schizophrenia were predicted to differ in prefrontal cortical activity, but not in medial temporal lobe activity. METHODS: Regional cerebral blood flow was studied using oxygen 15 positron emission tomography during 3 different memory retrieval conditions in 8 control subjects, 8 patients with the deficit syndrome, and 8 patients without the deficit syndrome. Behavioral and positron emission tomography data were analyzed using a mixed-effects model to test for population differences. RESULTS: In all memory conditions, frontal cortex activity was higher in patients without the deficit syndrome than in patients with the deficit syndrome. During the attempt to retrieve poorly encoded words, patients without the deficit syndrome recruited the left frontal cortex to a significantly greater degree than did patients with the deficit syndrome. The 2 schizophrenia subtypes did not differ in the activity or recruitment of the hippocampus during memory retrieval. CONCLUSION: Frontal cortex function during memory retrieval is differentially impaired in deficit and nondeficit schizophrenia, whereas hippocampal recruitment deficits are not significantly different between the 2 schizophrenia groups.     

Voxel-based morphometry of patients with schizophrenia or bipolar I disorder: a matched control study

Controlled trials provide critical tests of hypotheses generated by meta-analyses. Two recent meta-analyses have reported that gray matter volumes of schizophrenia and bipolar I patients differ in the amygdala, hippocampus, or perigenual anterior cingulate. The present magnetic resonance imaging study tested these hypotheses in a cross-sectional voxel-based morphometry (VBM) design of 17 chronic schizophrenia and 15 chronic bipolar patients and 21 healthy subjects matched for age, gender and duration of illness. Whole brain gray matter volume of both the schizophrenia and bipolar groups was smaller than among healthy control subjects. Regional voxel-wise comparisons showed that gray matter volume was smallest within frontal and temporal regions of both patient groups. Region of interest analyses found moderately large to large differences between schizophrenia and healthy subjects in the amygdala and hippocampus. There were no group differences in the perigenual anterior cingulate. When schizophrenia and bipolar groups were directly compared, the schizophrenia group showed smaller gray matter volumes in right subcortical regions involving the right hippocampus, putamen, and amygdala. The hippocampal and amygdala findings confirm predictions derived from recent meta-analyses. These structural abnormalities may be important factors in the differential manifestations of these two functional psychotic disorders.     

Reduced left angular gyrus volume in first-episode schizophrenia

OBJECTIVE: Research suggests that the normal left-greater-than-right angular gyrus volume asymmetry is reversed in chronic schizophrenia. The authors examined whether angular gyrus volume and asymmetry were abnormal in patients with first-episode schizophrenia. METHOD: Magnetic resonance imaging scans were obtained from 14 inpatients at their first hospitalization for psychosis and 14 normal comparison subjects. Manual editing was undertaken to delineate postcentral, supramarginal, and angular gyri gray matter volumes. RESULTS: Group comparisons revealed that the left angular gyrus gray matter volume in patients was 14.8% less than that of the normal subjects. None of the other regions measured showed significant group volume or asymmetry differences. CONCLUSIONS: Patients with new-onset schizophrenia showed smaller left angular gyrus volumes than normal subjects, consistent with other studies showing parietal lobe volume abnormalities in schizophrenia. Angular gyrus pathology in first-episode patients suggests that the angular gyrus may be a neuroanatomical substrate for the expression of schizophrenia.