The Disrupted-in-Schizophrenia-1 Ser704Cys polymorphism and brain morphology in schizophrenia.

The Disrupted-in-Schizophrenia-1 (DISC1) polymorphism is a strong candidate for a schizophrenia-susceptibility gene as it is widely expressed in cortical and limbic regions, but the effect of its genotype variation on brain morphology in schizophrenia is not well known. This study examined the association between the DISC1 Ser704Cys polymorphism and volumetric measurements for a broad range of fronto-parietal, temporal, and limbic-paralimbic regions using magnetic resonance imaging in a Japanese sample of 33 schizophrenia patients and 29 healthy comparison subjects. The Cys carriers had significantly larger volumes of the medial superior frontal gyrus and short insular cortex than the Ser homozygotes only for healthy comparison subjects. The Cys carriers tended to have a smaller supramarginal gyrus than the Ser homozygotes in schizophrenia patients, but not in healthy comparison subjects. The right medial superior frontal gyrus volume was significantly correlated with daily dosage of antipsychotic medication in Ser homozygote schizophrenia patients. These different genotype effects of the DISC1 Ser704Cys polymorphism on the brain morphology in schizophrenia patients and healthy comparison subjects suggest that variation in the DISC1 gene might be, at least partly, involved in the neurobiology of schizophrenia. Our findings also suggest that the DISC1 genotype variation might have some relevance to the medication effect on brain morphology in schizophrenia.

The association of genotypic combination of the DRD3 and BDNF polymorphisms on the adhesio interthalamica and medial temporal lobe structures.

Abnormal neurodevelopment in midline structures such as the adhesio interthalamica (AI), as well as in the medial temporal lobe structures has been implicated in schizophrenia, while its genetic mechanism is unknown. This magnetic resonance imaging study investigated the effect of the genotypic combination of the dopamine D3 receptor (DRD3) Ser9Gly and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms on the AI length and volumetric measures of the medial temporal lobe structures (amygdala, hippocampus, and parahippocampal gyrus) in 33 schizophrenia patients and 29 healthy controls. The subjects with a combination of the Ser/Ser genotype of DRD3 and Met-containing genotypes of BDNF (high-risk combination) had a shorter AI than those without it in the healthy controls, but not in the schizophrenia patients. The subjects carrying the high-risk combination had a smaller posterior hippocampus than those without it for both diagnostic groups. These genotypic combination effects on brain morphology were not explained by the independent effect of each polymorphism. These findings suggest the effect of gene-gene interaction between the DRD3 and BDNF variations on brain morphology in midline and medial temporal lobe structures, but do not support its specific role in the pathogenesis of schizophrenia.

Association between absence of the adhesio interthalamica and amygdala volume in schizophrenia.

Abnormal neurodevelopment in midline structures such as the adhesio interthalamica (AI) has been reported in schizophrenia, but not consistently replicated. We investigated the prevalence and anterior-posterior length of the AI in 62 schizophrenia patients (32 males, 30 females) and 63 healthy controls (35 males, 28 females) using magnetic resonance imaging. We also explored the relation between the AI and volumetric measurements for the third ventricle, medial temporal structures (amygdala, hippocampus, and parahippocampal gyrus), superior temporal sub-regions, and frontal lobe regions (prefrontal area and anterior cingulate gyrus). The AI was absent in 24.2% (15/62) of the schizophrenia patients and in 9.5% (6/63) of the controls, showing a significant group difference. For the length of the AI, schizophrenia patients had a shorter AI than controls, and males had a shorter AI than females. The subjects without an AI had a significantly larger third ventricle and smaller parahippocampal gyrus than the subjects with an AI for both groups. We found a significant diagnosis-by-AI interaction for the amygdala. The schizophrenia patients without an AI had a smaller bilateral amygdala than those with an AI, whereas the AI was not associated with the volume of the amygdala in the control subjects. These findings suggest that the absence of AI in schizophrenia could be a marker of developmental abnormalities in the neural network including the thalamus and connected amygdaloid regions, which may play an important role in the pathogenesis of schizophrenia.

Prevalence of large cavum septi pellucidi and its relation to the medial temporal lobe structures in schizophrenia spectrum.

Magnetic resonance imaging was used to evaluate the prevalence of the cavum septi pellucidi (CSP) in 154 schizophrenia patients, 47 schizotypal disorder patients, and 163 healthy controls. We also explored the relation of a large CSP (> or =6 mm) with medial temporal lobe structures. No significant difference was found in the prevalence of the CSP (76.0% of the schizophrenia patients, 81.6% of the controls, and 85.1% of the schizotypal patients) or the large CSP (6.5% of the schizophrenia patients, 7.4% of the controls, and 10.6% of the schizotypal patients) among the groups, but patients with a large CSP (10 schizophrenia and 5 schizotypal patients) had smaller volumes of bilateral amygdala and left posterior parahippocampal gyrus than patients without it. In the control subjects, the large CSP did not affect the volumes of the medial temporal lobe structures. These findings might reflect neurodevelopmental abnormalities in midline and associated limbic structures of the brain in schizophrenia spectrum.

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.

Parietal lobe volume deficits in schizophrenia spectrum disorders.

There has been little attention given to whether parietal lobe structural deficits are present in patients with schizophrenia and related personality disorders. The current study was designed to examine parietal volume alterations between schizophrenia and schizotypal personality disorder. Twenty-five patients with schizotypal disorder, 53 patients with schizophrenia, and 59 healthy volunteers were scanned using high-resolution magnetic resonance imaging (MRI). Volume measurements of the postcentral gyrus (PoCG), precuneus, superior parietal gyrus (SuPG), supramarginal gyrus (SMG), and angular gyrus (AGG) were performed on consecutive 1-mm coronal slices. Gray matter volumes were reduced in all parietal subregions in patients with schizophrenia compared with healthy controls. White matter volumes were also reduced in the SuPG and PoCG. In contrast, the schizotypal subjects had gray matter reductions only in the PoCG, while other regions were not affected. In addition, there was a lack of normal significant-leftward asymmetry in the SMG in schizophrenia. These findings demonstrate that volume reductions in the somatosensory cortices are common morphological characteristics in schizophrenia spectrum disorders. The additional volume alterations in schizophrenia may support the notion that a deficit in the posterior parietal region is critical for the manifestation of overt psychotic symptoms.

Temporal lobe gray matter in schizophrenia spectrum: a volumetric MRI study of the fusiform gyrus, parahippocampal gyrus, and middle and inferior temporal gyri.

Although several brain morphologic studies have suggested abnormalities in the temporal regions to be a common indicator of vulnerability for the schizophrenia spectrum, less attention has been paid to temporal lobe structures other than the superior temporal gyrus or the medial temporal region. In this study, we investigated the volume of gray matter in the fusiform gyrus, the parahippocampal gyrus, the middle temporal gyrus, and the inferior temporal gyrus using magnetic resonance imaging in 39 schizotypal disorder patients, 65 schizophrenia patients, and 72 age and gender matched healthy control subjects. The anterior fusiform gyrus was significantly smaller in the schizophrenia patients than the control subjects but not in the schizotypal disorder patients, while the volume reduction of the posterior fusiform gyrus was common to both disorders. Volumes for the middle and inferior temporal gyri or the parahippocampal gyrus did not differ between groups. These findings suggest that abnormalities in the posterior region of the fusiform gyrus are, as have been suggested for the superior temporal gyrus or the amygdala/hippocampus, prominent among the temporal lobe structures as a common morphologic substrate for the schizophrenia spectrum, whereas more widespread alterations involving the anterior region might be associated with the development of full-blown schizophrenia.

Morphologic alterations of the parcellated superior temporal gyrus in schizophrenia spectrum.

Morphologic abnormalities of the superior temporal gyrus (STG) as well as its sub-regions such as Heschl's gyrus (HG) or planum temporale (PT) have been reported in schizophrenia patients, but have not been extensively studied in schizotypal subjects. In the present study, magnetic resonance images were acquired from 65 schizophrenia patients, 39 schizotypal disorder patients, and 72 healthy controls. Volumetric analyses were performed using consecutive 1-mm coronal slices on the temporal pole (TP) and superior temporal sub-regions [planum polare (PP), HG, PT, rostral STG, and caudal STG]. The HG was significantly smaller in schizophrenia patients compared with controls but not in schizotypal patients, while volume reductions of the left PT and bilateral caudal STG were common to both disorders. The TP gray matter was larger in female schizotypal patients compared with female schizophrenia patients. There were no significant group differences in the PP and rostral STG volume. In the subgroup of early phase schizophrenia patients (illness duration <1.0 year), smaller volumes for the left PP and rostral STG were correlated with hallucinations and delusions. Our findings suggest that morphologic changes in the posterior regions of the STG are common to the schizophrenia spectrum, whereas less involvement of the HG, and possibly the PP and rostral STG might be related to the sparing of schizotypal patients from developing overt psychosis.

Verbal memory deficits in a preadolescent case of lesions of the left parahippocampal gyrus associated with a benign tumor.

The authors report cognitive functions of a 13-year-old boy with a cavernous angioma occupying the posterior left parahippocampal gyrus (PHG) and part of the left fusiform gyrus but not hippocampus. Neuropsychological examinations soon after the removal of the tumor showed selective deficits in semantic memory function, as evaluated by the Category Fluency Task and the Wechsler Memory Scale-Revised, while visual memory, attention, and IQ were not affected. These observations suggest the involvement of the PHG in the processing of semantic memory and provide an insight into the neural substrates underlying the distinct cognitive deficits in some of the psychiatric diseases such as schizophrenia.

Prefrontal abnormalities in patients with simple schizophrenia: structural and functional brain-imaging studies in five cases.

Simple schizophrenia is an uncommon disorder with unknown pathophysiology, and its position in the current diagnostic system is ambiguous. Brain-imaging studies may help to elucidate its pathophysiology. Five patients fulfilling both ICD-10 criteria for simple schizophrenia and DSM-IV criteria for simple deteriorative disorder underwent computed tomography, magnetic resonance imaging, and single photon emission computed tomography. These scans were assessed individually by visual inspection as well as automatically by comparison with scans in normal controls or other schizophrenia subtype patients using voxel-based image analyses. Three of the five simple schizophrenia patients had findings of atrophy and reduced cerebral perfusion in the frontal areas. Voxel-based analyses also showed prefrontal grey matter deficits and hypoperfusion in simple schizophrenia patients compared with the controls. Although this study is limited by the small number of patients with simple schizophrenia, the results suggest that simple schizophrenia, or at least this subpopulation, may have rather homogeneous morphological and functional deficits in the prefrontal cortex. It is also suggested that simple schizophrenia may occupy an extreme position of the schizophrenic continuum where the prefrontal deficits and negative symptoms are most purely manifested.

Differential contributions of prefrontal and temporolimbic pathology to mechanisms of psychosis.

Common abnormalities within the schizophrenia spectrum may be essential for the pathogenesis of schizophrenia, but additional pathological changes may be required for the development of full-blown schizophrenia. Clarifying the neurobiological similarities and differences between established schizophrenia and a milder form of schizophrenia spectrum disorder would potentially discriminate the pathophysiological mechanisms underlying the core features of the schizophrenia spectrum from those associated with overt psychosis. High-resolution MRIs were acquired from 25 patients with schizotypal disorder, 53 patients with schizophrenia and 59 healthy volunteers matched for age, gender, handedness and parental education. Volumetric measurements of the medial temporal structures and the prefrontal cortex subcomponents were performed using consecutive 1-mm thick coronal slices. Parcellation of the prefrontal cortex into subcomponents was performed according to the intrinsic anatomical landmarks of the frontal sulci/gyri. Compared with the controls, the bilateral volumes of the amygdala and the hippocampus were reduced comparably in the schizotypal and schizophrenia patients. The parahippocampal gyrus volume did not differ significantly between diagnostic groups. Total prefrontal grey matter volumes were smaller bilaterally in the schizophrenia patients than in the controls and the schizotypal patients, whereas the schizotypal patients had larger prefrontal grey matter than the controls in the right hemisphere. In the schizophrenia patients, grey matter volumes of the bilateral superior frontal gyrus, left middle frontal gyrus, bilateral inferior frontal gyrus and bilateral straight gyrus were smaller than those in the controls. The schizophrenia patients also had reduced grey matter volumes in the right superior frontal gyrus, bilateral middle frontal gyrus and right inferior frontal gyrus relative to the schizotypal patients. Compared with the controls, the schizotypal patients had larger volumes of the bilateral middle frontal gyrus and smaller volumes of the right straight gyrus. There were no significant between-group differences in volumes of the ventral medial prefrontal cortex or the orbitofrontal cortex. These findings suggest that volume reductions in the amygdala and hippocampus are the common morphological substrates for the schizophrenia spectrum, which presumably represent the vulnerability. Additional widespread involvement of the prefrontal cortex in schizophrenia may lead to the loss of inhibitory control in other brain regions and suggests (although it is not specifically be related to) its critical role in the manifestation of overt psychosis.

Volumetric analysis of sulci/gyri-defined in vivo frontal lobe regions in schizophrenia: Precentral gyrus, cingulate gyrus, and prefrontal region.

Methodological limitations in most previous magnetic resonance imaging (MRI)-based volumetric studies might have contributed to the inconsistent results regarding the frontal lobe regions of schizophrenia. Thus, applying the largest sample to date among those that have fully taken account of the intrinsic anatomical landmarks, this study aimed at clarifying the volumetric alterations of the frontal lobe and its subregions in schizophrenia. Participants comprised 59 patients with schizophrenia and 58 healthy controls. Measurements were performed on consecutive 1-mm-thick coronal slices reformatted from three-dimensional 1.5-T MR images. The whole frontal lobe was demarcated and then subdivided into the precentral gyrus (PCG), anterior cingulate, and posterior cingulate, and the remainder temporarily as the prefrontal region. Patients with schizophrenia had significant cortical volume reductions in the bilateral whole frontal lobe, prefrontal region, PCG, posterior cingulate, and right anterior cingulate. This study has confirmed that patients with schizophrenia do have cortical volume reductions in the whole frontal lobe and its subregions. Volume reduction in the PCG suggests that the primary motor cortex might contribute to the mechanisms of schizophrenia, considering its important role in the processing of multiple motor-related cognitive functioning suggested by the recent literature.

Relationship between exploratory eye movements and brain morphology in schizophrenia spectrum patients: voxel-based morphometry of three-dimensional magnetic resonance imaging.

The exploratory eye movements of schizophrenia patients and their relatives have been shown to differ from those of patients without schizophrenia and healthy controls. However the mechanism of exploratory eye movement disturbances in schizophrenia patients remains elusive. We investigated the relationship between the exploratory eye movements and brain morphology in 39 schizophrenia spectrum patients. Voxel-based morphometric analysis on three-dimensional magnetic resonance imaging was conducted by means of statistical parametric mapping 99. The decrease in the responsive search score, which is the total number of sections on which the eyes fixed in response to questioning in a comparison task, was significantly correlated with the decreased gray matter in the right frontal eye field (rFEF) including the right supplementary eye field (rSEF), right parietal eye field (rPEF), and right inferior frontal region. These results suggest that disturbance in exploratory eye movement in schizophrenia spectrum patients may be related to neural network dysfunction in FEF, SEF and PEF, which are the eye movement related areas, and in the inferior frontal region that may be related to information organization.

Volumetric MRI study of the short and long insular cortices in schizophrenia spectrum disorders.

We have previously reported volume reductions of the insular cortex in schizophrenia, but it is still not clear whether insular cortex volume loss preferentially involves the anterior (short insular cortex) or posterior (long insular cortex) portion. On the other hand, no volumetric studies of the brain have examined changes in insular cortex volume in subjects with schizotypal features. In this study, we separately investigated the volumes of the short and long insular cortex portions using magnetic resonance imaging in 37 schizotypal disorder patients (24 males, 13 females), 62 schizophrenia patients (32 males, 30 females), and 69 healthy controls (35 males, 34 females). While the volumes of the short and long insular cortex were significantly reduced in schizophrenia patients compared with schizotypal disorder patients and control subjects, there was no difference between schizotypal disorder patients and control subjects. These results suggest that the volume reduction of the insular cortex may be specific to overt schizophrenia without topographically specific localization.

Male-specific volume expansion of the human hippocampus during adolescence.

To clarify the developmental brain changes during adolescence, brain morphology was compared between healthy younger adolescent and elder adolescent subjects using both voxel-based morphometry (VBM) and volumetric region-of-interest (ROI) analysis of magnetic resonance imaging (MRI). High-resolution three-dimensional MRI scans were acquired in 23 (10 males and 13 females) younger adolescent subjects (13-14 years) and 30 (15 males and 15 females) elder adolescent subjects (19-21 years). Whole-brain analysis by VBM revealed that the elder adolescent subjects had significantly more gray matter in the left medial temporal regions than the younger adolescent subjects and significantly less gray matter in the left medial frontal region (Brodmann area 6). In the volumetric analysis, significantly less cerebral gray matter volume and significantly greater cerebral white matter volume were found in elder adolescents compared with younger adolescents. The volume of the hippocampus was significantly larger in male elder adolescents than in male younger adolescents. The volume of the parahippocampal gyrus did not differ between younger and elder adolescent subjects. These results suggest a robust maturational process ongoing in the human hippocampus during adolescence, especially in males. The possible relevance of these findings to progress in myelination and implications in psychiatric disorders were discussed.

Volume reduction of the amygdala in patients with schizophrenia: a magnetic resonance imaging study.

The amygdala is known to be involved in the pathology of schizophrenia. While only a limited number of studies in schizophrenia have measured the amygdala as a single structure. The aim of this study was to examine the hypothesis that patients with schizophrenia would show reduced volumes in the amygdala compared with normal controls. We investigated amygdala volume in 40 patients with schizophrenia (20 males, 20 females) and 40 age- and gender-matched normal controls using three-dimensional magnetic resonance imaging (MRI). Whole volumes of both the amygdala and the temporal lobe were measured on consecutive coronal 1-mm slices. The amygdala volume was significantly smaller in schizophrenia patients than in controls. Considering gender differences, male patients had significantly smaller volumes in the bilateral amygdala than male controls; female patients had a significantly reduced right amygdala compared with female controls. Furthermore, a significant left-smaller-than-right volumetric asymmetry of the amygdala was detected in male patients with schizophrenia. The results may be important for understanding the role of the amygdala in the pathophysiology of schizophrenia and the anatomical substrates of gender difference in the expressions of the illness.

Structural brain differences in patients with schizophrenia and schizotypal disorder demonstrated by voxel-based morphometry.

Brain abnormalities of schizophrenia probably consist of deviation related to the vulnerability and pathological changes in association with overt psychosis. We conducted a cross-sectional comparison in brain morphology between patients with overt schizophrenia and schizotypal disorder, a schizophrenia-spectrum disorder without florid psychotic episode. Voxelbased morphometry was applied to assess gray matter volume in 25 patients with schizophrenia, 25 patients with schizotypal disorder, and 50 healthy control subjects. In comparison with controls, schizophrenia patients showed gray matter reductions in the bilateral medial frontal, inferior frontal, medial temporal, and septal regions, and the left middle frontal, orbitofrontal, insula, and superior temporal regions, and an increased gray matter in the left basal ganglia. Schizotypal disorder patients showed reductions in the left inferior frontal, insula, superior temporal, and medial temporal regions. There was a significant reduction in the left orbitofrontal region of schizophrenia compared with schizotypal disorder. Gray matter reductions that are common to both patient groups such as those in the left medial temporal and inferior frontal regions may represent vulnerability to schizophrenia, and additional involvement of several frontal regions may be crucial to florid psychosis.

Bilateral volume reduction of the insular cortex in patients with schizophrenia: a volumetric MRI study.

The morphologic changes of the insular cortex have been described in schizophrenia, but with inconsistencies between reports. We investigated the insular cortex volume by magnetic resonance imaging in 59 schizophrenia patients (31 males, 28 females) and 62 age- and gender-matched healthy controls (31 males, 31 females). The insular cortex volume was measured on consecutive coronal 1-mm slices. Volumes of the left and right insular cortex were significantly reduced in schizophrenia patients compared with control subjects. There were no effects of gender on the insular cortex volume in the patient group or control subjects. Bilateral insular cortex volumes were correlated negatively with illness duration in the patient group. The findings of this study suggest that there is a possible progressive loss of the gray matter volume of the bilateral insular cortices subsequent to the onset of schizophrenia.

Lack of normal gender differences of the perigenual cingulate gyrus in schizophrenia spectrum disorders. A magnetic resonance imaging study.

We have previously reported a lack of normal gender differences of the perigenual cingulate gyrus in patients with schizophrenia. The purpose of this study was to examine the perigenual cingulate gyrus morphology in patients with schizotypal disorder. We investigated volume of the gray and white matter of the perigenual cingulate gyrus in 26 patients with schizotypal disorder (14 males, 12 females) in comparison with 61 age- and gender-matched healthy controls (30 males, 31 females) and 58 schizophrenia patients (31 males, 27 females) using magnetic resonance imaging. The volumetric measures of the perigenual cingulate gyrus were compared among the three groups that were entered into the same multiple analysis of variance model. The gray and white matter volume of the perigenual cingulate gyrus in the schizotypal patients did not differ significantly from the values in the healthy controls or the schizophrenia patients. Similar to schizophrenia, however, the schizotypal patients showed a lack of normal gender differences of the perigenual cingulate gray matter seen in the healthy controls (females > males). These results suggest that both schizotypal and schizophrenia patients may share the same disruption of the normal pattern of gender differences of the perigenual cingulate gyrus.

Multiple structural brain measures obtained by three-dimensional magnetic resonance imaging to distinguish between schizophrenia patients and normal subjects.

This study was designed to investigate the extent to which schizophrenia patients can be differentiated from normal subjects by structural brain measures. High-resolution magnetic resonance imaging scans were performed on 57 schizophrenia patients (30 males, 27 females) and 47 normal controls (25 males, 22 females). Significant enlargements of the left and right body of the lateral ventricle, the left and right sylvian fissure, and the third ventricle were observed in the male patients. Significant enlargements of the left inferior horn, and the left and right sylvian fissure, and a significant volume reduction of the right temporal lobe were observed in the female patients. Discriminant function analysis using brain anatomical measures as variables allowed correct classification of 80.0 percent of the male patients, 80.0 percent of the male controls, 77.8 percent of the female patients, and 86.4 percent of the female controls. These findings support the view that schizophrenia patients have structural deviations in multiple brain areas and that a combination of structural brain measures can distinguish between patients and controls.