T. Takahashi

Abnormal asymmetries in subcortical brain volume in schizophrenia

Subcortical structures, which include the basal ganglia and parts of the limbic system, have key roles in learning, motor control and emotion, but also contribute to higher-order executive functions. Prior studies have reported volumetric alterations in subcortical regions in schizophrenia. Reported results have sometimes been heterogeneous, and few large-scale investigations have been conducted. Moreover, few large-scale studies have assessed asymmetries of subcortical volumes in schizophrenia. Here, as a work completely independent of a study performed by the ENIGMA consortium, we conducted a large-scale multisite study of subcortical volumetric differences between patients with schizophrenia and controls. We also explored the laterality of subcortical regions to identify characteristic similarities and differences between them. T1-weighted images from 1680 healthy individuals and 884 patients with schizophrenia, obtained with 15 imaging protocols at 11 sites, were processed with FreeSurfer. Group differences were calculated for each protocol and meta-analyzed. Compared with controls, patients with schizophrenia demonstrated smaller bilateral hippocampus, amygdala, thalamus and accumbens volumes as well as intracranial volume, but larger bilateral caudate, putamen, pallidum and lateral ventricle volumes. We replicated the rank order of effect sizes for subcortical volumetric changes in schizophrenia reported by the ENIGMA consortium. Further, we revealed leftward asymmetry for thalamus, lateral ventricle, caudate and putamen volumes, and rightward asymmetry for amygdala and hippocampal volumes in both controls and patients with schizophrenia. Also, we demonstrated a schizophrenia-specific leftward asymmetry for pallidum volume. These findings suggest the possibility of aberrant laterality in neural pathways and connectivity patterns related to the pallidum in schizophrenia.

Anomalous Cerebral Asymmetry in Patients with Schizophrenia Demonstrated by Voxel-Based Morphometry

BACKGROUND Evaluating cerebral asymmetry in schizophrenia patients potentially leads to understanding the extent to which the disorder involves a neurodevelopmental failure. We sought to clarify in which brain regions of the patient the normal cerebral asymmetry is disrupted and the extent of disruption. METHODS Voxel-based morphometry to evaluate gray matter asymmetry was carried out with magnetic resonance images from a total of 120 right-handed subjects. They comprised four groups of 30 subjects (i.e., male schizophrenia, female schizophrenia, male control, and female control). To examine gray matter asymmetry we generated images of the lateralization index. RESULTS The analysis within each of four groups revealed a consistent pattern of gray matter asymmetry over all groups. However group comparison between all patients and all healthy subjects showed significant difference in the cerebral lateralization in the pars triangularis and planum temporale. Frequency distributions of the lateralization index showed a skew toward rightward asymmetry in the pars trianglaris and a reduction in leftward asymmetry in the planum temporale in patients relative to control subjects. CONCLUSIONS A disturbance of cerebral asymmetry in schizophrenia was suggested to be present in language-related regions, which might reflect a perturbation in the lateralization process underlying left cerebral dominance for language.

Morphological brain changes associated with Schneider's first-rank symptoms in schizophrenia: an MRI study

BACKGROUND Schneiders first-rank symptoms involve an alienated feature of the sense of ones own mental or physical activity. To clarify the brain morphological basis for the production of these symptoms, volumes of the frontal and medial temporal regions and their clinical correlates were examined in patients with schizophrenia. METHOD Twenty-two patients with schizophrenia and 44 age- and gender-matched healthy control subjects were included. All patients were in their psychotic episodes with definite Schneiderian symptoms, rated by using the Scale for Assessment of Positive Symptoms. Volumetric measurements of high-resolution magnetic resonance imaging were performed in the prefrontal area, cingulate gyrus, and precentral gyrus, and the medial temporal structures such as the amygdala, hippocampus, and parahippocampal gyrus. RESULTS Patients had significantly decreased volumes in the cingulate gray matter and the amygdala compared to controls. In the patient group, Schneiderian symptom severity showed significant inverse correlations with volumes of the right posterior cingulate gray matter and of the left anterior parahippocampal gyrus. CONCLUSIONS Schneiderian symptoms may be associated with morphological abnormalities in the limbic-paralimbic regions such as the cingulate gyrus and parahippocampal gyrus, which possibly serve the self-monitoring function and the coherent storage and reactivation of information.

High-resolution copy number variation analysis of schizophrenia in Japan

Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 × 10−9, 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e.g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P=0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.

Common variants at 1p36 are associated with superior frontal gyrus volume.

The superior frontal gyrus (SFG), an area of the brain frequently found to have reduced gray matter in patients with schizophrenia, is involved in self-awareness and emotion, which are impaired in schizophrenia. However, no genome-wide association studies of SFG volume have investigated in patients with schizophrenia. To identify single-nucleotide polymorphisms (SNPs) associated with SFG volumes, we demonstrated a genome-wide association study (GWAS) of gray matter volumes in the right or left SFG of 158 patients with schizophrenia and 378 healthy subjects. We attempted to bioinformatically ascertain the potential effects of the top hit polymorphism on the expression levels of genes at the genome-wide region. We found associations between five variants on 1p36.12 and the right SFG volume at a widely used benchmark for genome-wide significance (P<5.0 × 10−8). The strongest association was observed at rs4654899, an intronic SNP in the eukaryotic translation initiation factor 4 gamma, 3 (EIF4G3) gene on 1p36.12 (P=7.5 × 10−9). No SNP with genome-wide significance was found in the volume of the left SFG (P>5.0 × 10−8); however, the rs4654899 polymorphism was identified as the locus with the second strongest association with the volume of the left SFG (P=1.5 × 10−6). In silico analyses revealed a proxy SNP of rs4654899 had effect on gene expression of two genes, HP1BP3 lying 3′ to EIF4G3 (P=7.8 × 10−6) and CAPN14 at 2p (P=6.3 × 10−6), which are expressed in moderate-to-high levels throughout the adult human SFG. These results contribute to understand genetic architecture of a brain structure possibly linked to the pathophysiology of schizophrenia.

P-1313 - Altered brain activation during self-referential processing in schizophrenia: an fMRI study

Introduction Impaired self-awareness has been noted as a core feature of schizophrenia. Recent neuroimaging studies examining self-referential process in schizophrenia have yielded inconsistent results. We aimed to examine the self-referential neural network using the self- and other-evaluation tasks in schizophrenia. Methods Fifteen schizophrenia patients and fifteen age-, sex- and parental education-matched healthy subjects underwent functional magnetic resonance imaging. Subjects were required to make a decision whether the sentence described their own personal trait (self-evaluation) and that of their close friends (other-evaluation). Results Both patients and healthy groups showed significant activation in multiple brain regions including the medial- and lateral-prefrontal, temporal and parietal cortices during self- and other-evaluation tasks. The control subjects showed higher activations in left posterior cingulate and parahippocampal gyri during self-evaluation than other-evaluation, whereas there was no difference in activated regions between self- and other-conditions in the patients. As compared with the controls, the patients showed higher activations in the right superior frontal and right supramarginal gyri during self-evaluation. Conclusions These findings provide evidence for neural basis for deficits in self-awareness in schizophrenia and may underlie core clinical symptomatology of schizophrenia.

P02-336 Longitudinal voxel - based morphometry to evaluate progressive gray mater changes in first - episode schizophrenia

Background Although longitudinal magnetic resonance imaging (MRI) studies have shown that various brain regions undergo progressive tissue loss during the early phases of schizophrenia, regional pattern of these changes remain unclear. Methods Longitudinal MRI data were obtained from 18 (12 males and 6 females) patients with first-episode schizophrenia and 20 (11 males and 9 females) healthy controls and at baseline and follow-up with mean scan interval of 2.7 years. To compare gray matter changes over time between patients and controls were evaluated with voxel-based morphometry (VBM) using SPM8 following the longitudinal DARTEL protocol. Results In both groups of patient and control longitudinal gray mater reduction was observed in various brain regions including lateral and medial frontal regions and superior temporal region. Excessive decrease in gray matter was found in patients as compared to healthy controls in the left superior temporal region and right inferior frontal region. Discussion Our findings suggest that there are differing longitudinal gray matter changes in patients with schizophrenia during the early phases of the illness as compared to healthy individuals.

PW01-147 - Diminished limbic activation associated with face perception in patients with schizophrenia

Objective The authors evaluated cerebral blood flow response in schizophrenia patients during face perception to test the hypothesis of diminished limbic activation related to emotional relevance of facial stimuli. Method Thirteen patients with schizophrenia and 17 comparison subjects viewed facial displays of happiness, sadness, surprise, anger, fear, and disgust as well as neutral faces using the Japanese and Caucasian Facial Expressions of Emotion and Neutral Faces (Matsumoto and Ekman, 1988). Functional magnetic resonance imaging was used to measure blood-oxygen-level-dependent signal changes as the subjects alternated between tasks of discriminating sex with an interleaved reference condition. Results The groups did not differ in performance on the task. Healthy participants showed activation in the bilateral fusiform gyrus, medial temporal structures, occipital lobe, and inferior frontal cortex relative to the baseline condition. The increase was greater these regions in the right hemisphere than those in the left hemisphere. In the patients with schizophrenia, minimal focal response in the right fusiform gyrus, medial temporal structures, and occipital lobe was observed for the facial perception task relative to the baseline condition. Contrasting patients and comparison subjects revealed voxels in the left medial temporal structures, occipital lobe in which the healthy comparison subjects had significantly greater activation. Conclusions Impaired activation was seen in patients with schizophrenia for detection of facial attributes such as sex. Impairment in the medial temporal structure such as amygdale may lead to misunderstanding of social communication and may underlie difficulties in social adjustment experienced by people with schizophrenia.