Hiroaki Okubo

Structural alterations of the superior temporal gyrus in schizophrenia: Detailed subregional differences

BACKGROUND Reduced gray matter volumes in the superior temporal gyrus (STG) have been reported in patients with schizophrenia. Such volumetric abnormalities might denote alterations in cortical thickness, surface area, local gyrification or all of these factors. The STG can be anatomically divided into five subregions using automatic parcellation in FreeSurfer: lateral aspect of the STG, anterior transverse temporal gyrus of Heschl gyrus (HG), planum polare (PP) of the STG, planum temporale (PT) of the STG and transverse temporal sulcus. METHODS We acquired magnetic resonance imaging (MRI) 3T scans from 40 age- and sex-matched patients with schizophrenia and 40 healthy subjects, and the scans were automatically processed using FreeSurfer. General linear models were used to assess group differences in regional volumes and detailed thickness, surface area and local gyrification. RESULTS As expected, patients with schizophrenia had significantly smaller bilateral STG volumes than healthy subjects. Of the five subregions in the STG, patients with schizophrenia showed significantly and marginally reduced volumes in the lateral aspect of the STG and PT of the STG bilaterally compared with healthy subjects. The volumetric alteration in bilateral lateral STG was derived from both the cortical thickness and surface area but not local gyrification. There was no significant laterality of the alteration in the lateral STG between patients and controls and no correlation among the structures and clinical characteristics. CONCLUSIONS These findings suggest that of five anatomical subregions in the STG, the lateral STG is one of the most meaningful regions for brain pathophysiology in schizophrenia.

Specific gene expression patterns of 108 schizophrenia-associated loci in cortex

The latest genome-wide association study of schizophrenia identified 108 distinct genomic loci that contribute to schizophrenia. Brain development and function depend on the precise regulation of gene expression. The expression of many genes is differentially regulated across brain regions and developmental time points. We investigated the specific gene expression patterns arising from the 108 schizophrenia-associated loci using multiple publicly available databases and multiple regional brain datasets from developing and adult post-mortem human brains. The temporal-spatial expression analysis revealed that the genes in these loci were intensively enriched in the cortex during several developmental stages. These cortex-specific genes were particularly expressed in the fetal brain and adult neocortex.

Impact of Familial Loading on Prefrontal Activation in Major Psychiatric Disorders: A Near-Infrared Spectroscopy (NIRS) Study

Family history (FH) is predictive of the development of major psychiatric disorders (PSY). Familial psychiatric disorders are largely a consequence of genetic factors and typically exhibit more severe impairments. Decreased prefrontal activity during verbal fluency testing (VFT) may constitute an intermediate phenotype for PSY. We investigated whether familial PSY were associated with a greater severity of prefrontal dysfunction in accordance with genetic loading. We measured prefrontal activity during VFT using near-infrared spectroscopy (NIRS) in patients with schizophrenia (SCZ, n = 45), major depressive disorder (MDD, n = 26) or bipolar disorder (BIP, n = 22) and healthy controls (HC, n = 51). We compared prefrontal activity among patients with or without FH and HC. Patients in the SCZ, MDD and BIP patient groups had lower prefrontal activity than HC subjects. Patients with and without FH in all diagnostic groups had lower prefrontal activity than HC subjects. Moreover, SCZ patients with FH had lower prefrontal activity than SCZ patients without FH. When we included patients with SCZ, MDD or BIP in the group of patients with PSY, the effects of psychiatric FH on prefrontal activity were enhanced. These findings demonstrate the association of substantially more severe prefrontal dysfunction with higher genetic loading in major psychiatric disorders.

Schizophrenia risk variants in ITIH4 and CALN1 regulate gene expression in the dorsolateral prefrontal cortex.

On the basis of the findings from European GenomeWide Association Studies (GWAS) in the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC1) [9394 cases and 12 462 controls for GWAS and 8442 cases and 21 397 for replication (Ripke et al., 2011)] and the subsequent study (CLOZUK) [2640 cases and 2878 controls (Hamshere et al., 2013)], Li et al. (2015) have tried to replicate the associations of genetic variants including genome-wide significant variants and variants located in the predicted MIR137 target genes in the Han Chinese population (Li et al., 2015). They have found that two single-nucleotide polymorphisms (SNPs) in the interalpha-trypsin inhibitor heavy chain family, member 4 (ITIH4) (rs2239547) and the calneuron 1 (CALN1) (rs2944829) genes, were associated with risk for schizophrenia at genome-wide significant threshold in Chinese GWAS (3750 cases and 6468 controls) and/or the replication (3585 cases and 5496 controls) cohorts. They compared these SNP findings between PGC1/ PGC1+CLOZUK and their studies; however, they used rs12699131 (35.4 kb upstream from rs2944829, r= 0.79 in CEU 1000 Genomes Pilot 1) but not rs2944829 in only PGC1 GWAS sample for the comparison. Recently, the latest and largest GWAS, which combined all available schizophrenia samples in the PGC2 (34 241 cases, 45 604 controls and 1235 trios for GWAS and 1513 cases and 66 236 controls for replication), has been published (Ripke et al., 2014), and these two SNPs (rs2239547 and rs2944829) in the GWAS were available directly in the public database (https://www.med.unc.edu/pgc/downloads). Therefore, we combined the Chinese GWAS and the replication data with those of PGC2 using their odds ratios (OR) and SE derived from 95% confidence interval of OR. The meta-analysis still supported their findings at genome-wide significant level [rs2239547 (minor C-allele) OR= 0.93, P= 1.98× 10, rs2944829 (minor A-allele) OR= 0.94, P= 1.97× 10]. These findings suggest that these SNPs could contribute to risk for schizophrenia in both European and Asian populations.

Cognitive clustering in schizophrenia patients, their first-degree relatives and healthy subjects is associated with anterior cingulate cortex volume

Cognitive impairments are a core feature in schizophrenia patients (SCZ) and are also observed in first-degree relatives (FR) of SCZ. However, substantial variability in the impairments exists within and among SCZ, FR and healthy controls (HC). A cluster-analytic approach can group individuals based on profiles of traits and create more homogeneous groupings than predefined categories. Here, we investigated differences in the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery (six subscales) among SCZ, unaffected FR and HC. To identify three homogeneous and meaningful cognitive groups regardless of categorical diagnoses (SCZ, FR and HC), cognitive clustering was performed, and differences in the BACS subscales among the cognitive cluster groups were investigated. Finally, the effects of diagnosis and cognition on brain volumes were examined. As expected, there were significant differences in the five BACS subscales among the diagnostic groups. The cluster-analytic approach generated three meaningful subgroups: (i) neuropsychologically normal, (ii) intermediate impaired and (iii) widespread impaired. The cognitive subgroups were mainly affected by the clinical diagnosis, and significant differences in all BACS subscales among clusters were found. The effects of the diagnosis and cognitive clusters on brain volumes overlapped in the frontal, temporal and limbic regions. Frontal and temporal volumes were mainly affected by the diagnosis, whereas the anterior cingulate cortex (ACC) volumes were affected by the additive effects of diagnosis and cognition. Our findings demonstrate a cognitive continuum among SCZ, FR and HC and support the concept of cognitive impairment and the related ACC volumes as intermediate phenotypes in SCZ.

Smoking Rates and Number of Cigarettes Smoked per Day in Schizophrenia: A Large Cohort Meta-Analysis in a Japanese Population

Abstract Background Cigarette smoking is consistently more common among schizophrenia patients than the general population worldwide; however, the findings of studies in Japan are inconsistent. Recently, the smoking rate has gradually decreased among the general population. Methods We performed a meta-analysis of smoking status in a large Japanese cohort of (1) 1845 schizophrenia patients and 196845 general population and (2) 842 schizophrenia patients and 766 psychiatrically healthy controls from 12 studies over a 25-year period, including 301 patients and 131 controls from our study. Results In our case-control sample, schizophrenia patients had a significantly higher smoking rate than healthy controls (P=.031). The proportion of heavy smokers (P=.027) and the number of cigarettes smoked per day (P=8.20×10–3) were significantly higher among schizophrenia patients than healthy controls. For the smokers in the schizophrenia group, atypical antipsychotics dosage was positively correlated with cigarettes per day (P=1.00×10–3). A meta-analysis found that schizophrenia patients had a higher smoking rate than the general population for both men (OR=1.53, P=.035; schizophrenia patients, 52.9%; general population, 40.1%) and women (OR=2.40, P=1.08×10–5; schizophrenia patients, 24.4%; general population, 11.8%). In addition, male schizophrenia patients had a higher smoking rate than male healthy controls (OR=2.84, P=9.48×10–3; schizophrenia patients, 53.6%; healthy controls, 32.9%), but the difference was not significant for women (OR=1.36, P=.53; schizophrenia patients, 17.0%; healthy controls,14.1%). Among both males and females, schizophrenia patients had a higher smoking rate than both the general population (OR=1.88, P=2.60×10–5) and healthy controls (OR=2.05, P=.018). These rates were not affected by the patients’ recruitment year (P>.05). The cigarettes per day values of schizophrenia patients and the general population were 22.0 and 18.8, respectively. Conclusions Schizophrenia patients are approximately 2 times more likely to smoke than the general population and healthy controls based on data collected over a decade in Japan.

F73. COGNITIVE CLUSTERING IN SCHIZOPHRENIA PATIENTS, THEIR FIRST-DEGREE RELATIVES AND HEALTHY SUBJECTS IS ASSOCIATED WITH ANTERIOR CINGULATE CORTEX VOLUME

Abstract Background Cognitive impairments are a core feature in schizophrenia patients and are also observed in first-degree relatives of the schizophrenia patients. However, substantial variability in the impairments exists within and among schizophrenia patients, first-degree relatives and healthy controls. A cluster-analytic approach can group individuals based on profiles of traits and create more homogeneous groupings than predefined categories. Methods Here, we investigated differences in the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery (six subscales) among 81 schizophrenia patients, 20 unaffected first-degree relatives and 25 healthy controls. To identify three homogeneous and meaningful cognitive groups regardless of categorical diagnoses (schizophrenia patients, first-degree relatives and healthy controls), cognitive clustering was performed using a k-means clustering analysis approach, and differences in the BACS subscales (verbal memory, digit sequencing, token motor, verbal fluency, symbol coding and Tower of London) among the cognitive cluster groups were investigated. Finally, the effects of diagnosis and cognition on brain volumes were examined. Results As expected, there were significant differences in the five BACS subscales among the diagnostic groups (verbal memory, F2,123=20.6, P=1.90 × 10–8; digit sequencing, F2,123=8.0, P=5.65 × 10–4; token motor, F2,123=16.0, P=6.92 × 10–7; verbal fluency, F2,123=14.8, P=1.79 × 10–6 and symbol coding, F2,123=28.8, P=5.64 × 10–11). The cluster-analytic approach generated three meaningful subgroups: (i) neuropsychologically normal (Cluster 1, N=36), (ii) intermediate impaired (Cluster 2, N=60) and (iii) widespread impaired (Cluster 3, N=30). The cognitive subgroups were mainly affected by the clinical diagnosis (χ2=46.7, P=5.33 × 10-10), and significant differences in all BACS subscales among clusters were found (verbal memory, F2,123=64.1, P=8.49 × 10–20; digit sequencing, F2,123=35.7, P=5.89 × 10–13; token motor, F2,123=71.7, P=2.29 × 10–21; verbal fluency, F2,123=84.2, P=9.05 × 10–24; symbol coding, F2,123=115.6, P=5.70 × 10–29 and Tower of London, F2,123=6.9, P=1.43 × 10–3). The effects of the diagnosis (SCZ<FR<HC) and cognitive clusters (Clusters 3<2<1) on brain volumes overlapped in the frontal, temporal and limbic regions. Frontal and temporal volumes were mainly affected by the diagnosis, whereas the anterior cingulate cortex volumes were affected by the additive effects of diagnosis and cognition (FWE-corrected P<0.05, x, y, z=1.5, 40.5, 19.5, T=5.49). Discussion We investigated the cognitive heterogeneity and cognitive continuum among schizophrenia patients, first-degree relatives and healthy controls. The cognitive clustering approach without using clinical diagnoses successfully produced more homogeneous cognitive clusters: a neuropsychologically normal, an intermediately impaired and a globally impaired cognitive cluster. Clinical diagnoses (healthy controls, first-degree relatives and schizophrenia patients) were not evenly distributed into the three clusters; i.e., these clusters were mainly affected by clinical diagnoses. Both diagnoses and cognitive clusters were associated with decreased anterior cingulate cortex volumes. Our findings demonstrate a cognitive continuum among schizophrenia patients, first-degree relatives and healthy controls and support the hypothesis that cognitive impairments and the related anterior cingulate cortex volumes would be useful intermediate phenotypes in the pathophysiology of schizophrenia.

Meta-analysis of physical activity and effects of social function and quality of life on the physical activity in patients with schizophrenia

Schizophrenia patients have increased mortality and morbidity, mainly due to premature cardiovascular disease resulting from decreased physical activity (PA). However, which PA intensity is impaired in the patients and how factors such as social function and quality of life (QoL) are related to decreased PA is unknown. To assess PA, social function and QoL, the International Physical Activity Questionnaire (IPAQ), Social Functioning Scale (SFS) and Schizophrenia Quality of Life Scale (SQLS), respectively, were used in 109 schizophrenia patients and 69 healthy subjects. A meta-analysis comparing PA intensities (vigorous, moderate and light) assessed by the single PA measurement between schizophrenia patients and healthy subjects after including our case–control sample was performed. Furthermore, the effects of social function and QoL on each level of PA intensity were investigated in patients and controls. The meta-analysis in 212 schizophrenia patients and 132 healthy subjects revealed that patients showed lower total PA, particularly vigorous PA, than controls (I2 = 0, Hedges’ g = − 0.41, P = 2.80 × 10−4). The decreased total PA was correlated with impaired total SFS scores (β = 0.24, P = 2.86 × 10−3), withdrawal (β = 0.23, P = 3.74 × 10−3) and recreation (β = 0.23, P = 3.49 × 10−3) without significant heterogeneity between patients and controls. In contrast, the decreased total PA was affected by low independence–performance (β = 0.22, P = 0.034), employment/occupation (β = 0.27, P = 8.74 × 10−3), psychosocial (β = − 0.24, P = 0.021) and motivation/energy (β = − 0.26, P = 0.013), but only in patients. Similar findings were obtained for vigorous PA but not moderate or light PA. Our findings suggest that the impaired vigorous PA in schizophrenia patients may be mediated by schizophrenia-specific factors of social functioning and QoL. Understanding these factors has important implications for increasing PA participation in schizophrenia patients.