A Retrospective Study on the Relationship Between Cognitive Function and Social Function in Patients With Schizophrenia.

Background: Social dysfunction is associated with decreased activity, employment difficulties, and poor prognosis in patients with schizophrenia. Cognitive functions, such as attention and processing speed, have been implicated in the social functions of schizophrenia patients; however, the relationship between cognitive functions and social functions remains unclear. Thus, understanding the factors that influence social functioning can aid the development of therapeutic strategies for schizophrenia. Herein, we retrospectively analyzed factors that influence social functioning in patients with schizophrenia. Methods: Patient background, intelligence quotient (IQ) scores, Japanese version of the Brief Assessment of Cognition in Schizophrenia (BACS-J) scores, the dose of antipsychotic drugs, Positive and Negative Syndrome Scale (PANSS) scores, and the factors influencing each subscale of the Japanese version of the Social Functioning Scale (SFS-J) were evaluated using univariate and multivariate analyses. The Bonferroni correction was applied to evaluate the correlation between each factor in the univariate analysis. In multivariate analysis, independent variables were selected using a stepwise method. In each model, considering the sample size, the maximum number of variables extracted using the stepwise method was set to three. We then calculated the standard partial regression coefficient (standard ß) between the SFS-J subscale scores and each factor. Results: Data from 36 patients were analyzed. The average age, illness duration, and total length of hospitalization were 57.8 years, 34.8 years, and 196.7 months, respectively. Of the seven significant correlations with the SFS-J subscale in the univariate analysis, only three were significant in the multivariate analysis model. According to the multivariable model, BACS-J verbal fluency positively correlated with SFS-J withdrawal, interpersonal communication, and employment/occupation. Moreover, BACS-J token motor and educational history were positively correlated with SFS-J recreation and SFS-J employment/occupation, respectively. PANSS scores, IQ scores, and doses of antipsychotic drugs did not show clear associations with SFS-J scores. Conclusions: In conclusion, there were significant correlations between BACS-J subscale scores for cognitive functioning and SFS-J subscale scores for social functioning in patients with schizophrenia.

A case report of late-onset schizophrenia differentiated from a dementing disorder.

We report a case of late-onset schizophrenia that required differentiation from a dementing disorder. The patient was an 83-year-old woman who had experienced auditory hallucinations since she was 67 years old. The patient had slightly elevated total tau and slightly decreased amyloid ß1-42, cerebrospinal fluid biomarkers. This case was identified as late-onset schizophrenia. However, the results of cerebrospinal fluid biomarkers indicated that neurofibrillary tangles and neuronal death, which are characteristic of Alzheimer 's disease, may also have been present. Late-onset schizophrenia should be treated based on an appropriate differential diagnosis, including neuropathological consideration of dementing disorders.

Effects of genome-wide neuroticism-associated variants on five-factor model personality traits in schizophrenia.

Patients with schizophrenia (SCZ) have characteristic personality traits compared with healthy subjects. Genome-wide significant variants for neuroticism have been reported in healthy subjects. However, the associations of these genome-wide neuroticism-associated variants with five-factor personality traits in patients with SCZ are less clear. We investigated the influences of nine independent genome-wide significant variants for neuroticism on five-factor personality traits (neuroticism, extraversion, openness, agreeableness, and conscientiousness) assessed by the NEO Five-Factor Inventory (NEO-FFI) in 107 patients with SCZ and 119 healthy controls (HCs). As expected, patients with SCZ scored significantly higher for neuroticism and lower for extraversion, openness, agreeableness and conscientiousness than HCs (p < 0.05). Of nine neuroticism-associated variants, the T allele at rs4653663 related to lower neuroticism was only significantly associated with lower neuroticism in patients with SCZ (ß = -0.27, p = 3.88 × 10-3) and in combined subjects (ß = -0.15, p = 0.026). Furthermore, of other personality traits, the genetic variant was significantly associated with higher agreeableness in combined subjects (ß = 0.17, p = 9.41×10-3), higher conscientiousness in patients with SCZ (ß = 0.21, p = 0.031) and lower conscientiousness in HCs (ß = -0.20, p = 0.034), and nominally associated with higher extraversion in patients with SCZ (ß = 0.18, p = 0.056) and in combined subjects (ß = 0.13, p = 0.051). These outcomes were not affected by clinical variables. We suggest that genome-wide neuroticism-associated variant could be associated with neuroticism as well as other personality traits in schizophrenia.

Intelligence decline across major depressive disorder, bipolar disorder, and schizophrenia.

BACKGROUND: Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are associated with impaired intelligence that predicts poor functional outcomes. However, little is known regarding the extent and severity of intelligence decline, that is, decreased present intelligence quotient (IQ) relative to premorbid levels, across psychiatric disorders and which clinical characteristics affect the decline. METHODS: Premorbid IQ, present IQ, and intelligence decline were compared across patients with MDD (n = 45), BD (n = 30), and SCZ (n = 139), and healthy controls (HCs; n = 135). Furthermore, we investigated which factors contribute to the intelligence decline in each diagnostic group. RESULTS: Significant differences were observed in premorbid IQ, present IQ, and intelligence decline across the diagnostic groups. Patients with each psychiatric disorder displayed lower premorbid and present IQ and more intelligence decline than HCs. Patients with SCZ displayed lower premorbid and present IQ and more intelligence decline than patients with MDD and BD, while there were no significant differences between patients with MDD and BD. When patients with BD were divided based on bipolar I disorder (BD-I) and bipolar II disorder (BD-II), degrees of intelligence decline were similar between MDD and BD-II and between BD-I and SCZ. Lower educational attainment was correlated with a greater degree of intelligence decline in patients with SCZ and BD but not MDD. CONCLUSIONS: These findings confirm that although all psychiatric disorders display intelligence decline, the severity of intelligence decline differs across psychiatric disorders (SCZ, BD-I > BD-II, MDD > HCs). Higher educational attainment as cognitive reserve contributes to protection against intelligence decline in BD and SCZ.

Alterations in hippocampal subfield volumes among schizophrenia patients, their first-degree relatives and healthy subjects.

Reduced hippocampal volumes feature prominently in schizophrenia patients (SCZ). Although several studies have investigated hippocampal volume alterations between unaffected first-degree relatives (FR) of SCZ and healthy controls (HC), the results were inconsistent. Furthermore, it remains unclear whether FR have specific alterations in hippocampal subfield volumes. Three-Tesla T1-weighted MP-RAGE brain scans were collected from 347 subjects (138 SCZ, 47 FR and 162 HC) and processed using the hippocampal subfields algorithm in FreeSurfer v6.0. We investigated volumetric differences in the twelve hippocampal subfields bilaterally among SCZ, FR and HC. SCZ displayed bilateral reductions in whole hippocampal volume compared with FR and HC. The hippocampal volumes of FR did not differ from those of HC but exceeded those observed in SCZ. We found volumetric differences in specific hippocampal subfields, including the CA1, hippocampal fissure, presubiculum, molecular layer, fimbria and hippocampal-amygdala transitional area, among diagnostic groups. These alterations arose from differences in the hippocampal subfield volumes between SCZ and the other two diagnostic groups. However, right hippocampal fissure volumes linearly increased among the groups. In contrast, no significant volumetric differences were found in other hippocampal subfields between HC and FR. There were no significant intergroup differences in laterality in any hippocampal subfield volumes and no significant correlations between hippocampal subfield volumes and illness duration, psychiatric symptoms, antipsychotics or premorbid IQ in SCZ. Our findings suggest that volumetric alterations in hippocampal subfields (except the hippocampal fissure) in SCZ could be stable phenomena that are present at illness onset and minimally affected by antipsychotics.

Differences in executive function among patients with schizophrenia, their unaffected first-degree relatives and healthy participants.

BACKGROUND: Patients with schizophrenia (SCZ) display impaired executive functions compared with healthy controls (HCs). Furthermore, unaffected first-degree relatives (FRs) of patients with SCZ independently perform worse executive functions than do HCs. However, few studies have investigated the differences in executive functions assessed among patients with SCZ, FRs, and HCs, and the findings are inconsistent. METHODS: We investigated diagnostic differences in executive functions, namely, (i) numbers of categories achieved (CA), (ii) total errors (TE) and (iii) %perseverative errors of Nelson types (%PEN), using the Wisconsin card sorting test (WCST) among patients with SCZ (n=116), unaffected FRs (n=62) and HCs (n=146) at a single institute. Correlations between these executive functions and clinical variables were investigated. RESULTS: Significant differences existed in all executive functions among diagnostic groups (CA, F2,319=15.5, p=3.71×10-7; TE, F2,319=16.2, p=2.06×10-7; and %PEN, F2,319=21.3, p=2.15×10-9). Patients with SCZ had fewer CA and more TE and %PEN than those of HCs (CA, Cohen's d=-0.70, p=5.49×10-8; TE, d=0.70, p=5.62×10-8; and %PEN, d=0.82, p=2.85×10-10) and FRs (TE, d=0.46, p=3.73×10-3 and %PEN, d=0.38, p=0.017). Of the three executive functions, CA and %PEN of FRs were intermediately impaired between patients with SCZ and HCs (CA, d=-0.41, p=0.011 and %PEN, d=0.41, p=0.012). In contrast, no significant difference in TE existed between FRs and HCs (d=0.22, p=0.18). Although CA and TE were affected by the duration of illness (p<0.017), %PEN was not affected by any clinical variable in patients with SCZ (p>0.017). CONCLUSIONS: Executive function, particularly %PEN, could be a useful intermediate phenotype for understanding the genetic mechanisms implicated in SCZ pathophysiology.

The First Report of Macrolide-Resistant Bordetella pertussis Isolation in Japan.

We report the first detection of a macrolide-resistant Bordetella pertussis strain in Japan. The isolate was highly resistant to the macrolides (minimum inhibitory concentrations for erythromycin and clarithromycin: > 256 µg/ml, for azithromycin: 32 µg/ml) and A2047G mutation was identified in the 23S rRNA. The Multilocus Sequence Typing and Multilocus Variable Number of Tandem Repeat Analysis genotypes of this isolate were MT195 and ptxP1/ptxA1/prn1/fim3A/fhaB3, respectively, suggesting a relationship with the macrolide-resistant B. pertussis lineage currently found in China. This raises the possibility that macrolide-resistant B. pertussis has already fully spread in Japan. For a better control of B. pertussis infections, the surveillance for macrolide-resistant B. pertussis is essential in not only Japan, but also other Asian countries.

Genetic correlations between subcortical brain volumes and psychiatric disorders.

Psychiatric disorders as well as subcortical brain volumes are highly heritable. Large-scale genome-wide association studies (GWASs) for these traits have been performed. We investigated the genetic correlations between five psychiatric disorders and the seven subcortical brain volumes and the intracranial volume from large-scale GWASs by linkage disequilibrium score regression. We revealed weak overlaps between the genetic variants associated with psychiatric disorders and subcortical brain and intracranial volumes, such as in schizophrenia and the hippocampus and bipolar disorder and the accumbens. We confirmed shared aetiology and polygenic architecture across the psychiatric disorders and the specific subcortical brain and intracranial volume.

Polygenetic Risk Scores for Major Psychiatric Disorders Among Schizophrenia Patients, Their First-Degree Relatives, and Healthy Participants.

BACKGROUND: The genetic etiology of schizophrenia (SCZ) overlaps with that of other major psychiatric disorders in samples of European ancestry. The present study investigated transethnic polygenetic features shared between Japanese SCZ or their unaffected first-degree relatives and European patients with major psychiatric disorders by conducting polygenic risk score (PRS) analyses. METHODS: To calculate PRSs for 5 psychiatric disorders (SCZ, bipolar disorder [BIP], major depressive disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder) and PRSs differentiating SCZ from BIP, we utilized large-scale European genome-wide association study (GWAS) datasets as discovery samples. PRSs derived from these GWASs were calculated for 335 Japanese target participants [SCZ patients, FRs, and healthy controls (HCs)]. We took these PRSs based on GWASs of European psychiatric disorders and investigated their effect on risk in Japanese SCZ patients and unaffected first-degree relatives. RESULTS: The PRSs obtained from European SCZ and BIP patients were higher in Japanese SCZ patients than in HCs. Furthermore, PRSs differentiating SCZ patients from European BIP patients were higher in Japanese SCZ patients than in HCs. Interestingly, PRSs related to European autism spectrum disorder were lower in Japanese first-degree relatives than in HCs or SCZ patients. The PRSs of autism spectrum disorder were positively correlated with a young onset age of SCZ. CONCLUSIONS: These findings suggest that polygenic factors related to European SCZ and BIP and the polygenic components differentiating SCZ from BIP can transethnically contribute to SCZ risk in Japanese people. Furthermore, we suggest that reduced levels of an ASD-related genetic factor in unaffected first-degree relatives may help protect against SCZ development.

Altered neural basis of self-reflective processing in schizophrenia: An fMRI study.

BACKGROUND: Impaired self-awareness has often been described in schizophrenia. Recent neuroimaging studies examining the self-reflection processes in schizophrenia have produced inconsistent results. METHOD: We examined the self-reflective neural network using self- and other-evaluation tasks in schizophrenia. Fifteen schizophrenia patients and fifteen age- and sex-matched healthy subjects underwent functional magnetic resonance imaging. Subjects were required to decide whether the sentence described their own personal trait (self-evaluation) and that of their close friends (other-evaluation). RESULTS: Unlike normal control subjects, the schizophrenia patients did not have greater activation of the left posterior cingulate gyrus and hippocampus during self-evaluation than during other-evaluation. On the other hand, the schizophrenia patients had higher activation of the right superior frontal and right supramarginal gyri during self-evaluation than control subjects. Only the patient group exhibited hyperactivation in the left hippocampus and right external capsule associated with the other-evaluation task. CONCLUSIONS: These findings provide evidence for an altered neural basis of self-reflective processing, which may underlie the self-awareness deficits in schizophrenia.

Intelligence decline between present and premorbid IQ in schizophrenia: Schizophrenia Non-Affected Relative Project (SNARP).

Schizophrenia patients (SCZ) display widespread cognitive deficits that are strongly associated with functional outcomes. Cognitive impairments occur along a genetic continuum among SCZ, their unaffected first-degree relatives (FRs) and healthy controls (HCs). Although SCZ impairs the premorbid intelligence quotient (IQ) and causes a subsequent intelligence decline (ID), a decrease in present IQ from the premorbid level, it remains unclear when during the illness course these impairments develop. Differences in premorbid and present IQ and ID were investigated among 125 SCZ, 61 FRs and 107 HCs, using analysis of covariance and a paired t-test. Furthermore, these subjects were classified into preserved and deteriorated IQ groups based on the degree of ID, and we investigated which factors contribute to this classification. We found significant differences in premorbid and present IQ among the diagnostic groups. Compared with HCs, SCZ and FRs displayed lower premorbid and present IQ. There was no significant difference in premorbid IQ between SCZ and FRs, but SCZ had a significantly lower present IQ than FRs. Only SCZ showed a significant ID. As most FRs and HCs did not display an ID, there were fewer subjects with deteriorated IQ among FRs and HCs than among SCZ. Subjects with preserved IQ showed higher educational attainment than those with deteriorated IQ among SCZ and FRs. These findings suggest that the impairment of premorbid IQ and the ID in SCZ become evident before and around the time of onset, respectively, and different pathophysiological mechanisms might be related to these impairments.

Open-label study of cognitive behavioural therapy for individuals with at-risk mental state: Feasibility in the Japanese clinical setting.

AIM: To date, most cognitive behavioural therapy (CBT) trials for individuals with at-risk metal state (ARMS) have been conducted in few Western countries and its feasibility in other regions, including Japan, has not been established. METHODS: We designed an open-label pilot study. Fourteen ARMS participants received CBT over 6 months and were followed-up for 6 months. RESULTS: Thirteen individuals completed the CBT intervention and assessments. The mean total score on the Positive and Negative Syndrome Scale improved from 60.2 to 46.0 after the intervention (Cohen's d = 1.1). The effects were maintained at the follow-up assessment. One participant transitioned to psychosis after the CBT intervention, and was the only patient who received antipsychotics. CONCLUSIONS: We confirmed the feasibility of the provision of CBT for ARMS in Japan. Since overprescription of antipsychotics is a matter of great concern in Japan, CBT could be a valuable alternative treatment strategy.

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 (ß = 0.24, P = 2.86 × 10-3), withdrawal (ß = 0.23, P = 3.74 × 10-3) and recreation (ß = 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 (ß = 0.22, P = 0.034), employment/occupation (ß = 0.27, P = 8.74 × 10-3), psychosocial (ß = - 0.24, P = 0.021) and motivation/energy (ß = - 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.

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

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.

Genome-Wide Variants Shared Between Smoking Quantity and Schizophrenia on 15q25 Are Associated With CHRNA5 Expression in the Brain.

Cigarette smokers with schizophrenia consume more cigarettes than smokers in the general population. Schizophrenia and smoking quantity may have shared genetic liability. Genome-wide association studies (GWASs) of schizophrenia and smoking quantity have highlighted a biological pleiotropy in which a robust 15q25 locus affects both traits. To identify the genetic variants shared between these traits on 15q25, we used summary statistics from large-scale GWAS meta-analyses of schizophrenia in the Psychiatric Genomics Consortium 2 and smoking quantity assessed by cigarettes smoked per day in the Tobacco and Genetics Consortium. To evaluate the regulatory potential of the shared genetic variants, expression quantitative trait loci analysis in 10 postmortem brain regions was performed using the BRAINEAC dataset in 134 neuropathologically normal individuals. Twenty-two genetic variants on 15q25 were associated with both smoking quantity and schizophrenia at the genome-wide significance level (P < 5.00 × 10-8). Major alleles of all variants were associated with higher smoking quantity and risk of schizophrenia. These genetic variants were associated with PSMA4, CHRNA3, and CHRNB4 expression in specific brain regions (lowest P = 4.81 × 10-4) and with CHRNA5 expression in multiple brain regions (lowest P = 8.70 × 10-6). Risk-associated major alleles of these variants were commonly associated with higher expression in several brain regions, excluding the medulla, at the transcript level. In addition, the risk-associated major allele at rs637137 was associated with higher CHRNA5 expression at the specific exon level in multiple brain regions (lowest P = 2.37 × 10-5). Our findings suggest that genome-wide variants shared between smoking quantity and schizophrenia contribute to a common pathophysiology underlying these traits involving altered CHRNA5 expression in the brain.

Cerebellar activation during a motor task in conversion disorder with motor paralysis: A case report and fMRI study.

BACKGROUND: Motor conversion disorders are characterized by movement symptoms without a neurological cause. A psychogenic etiology is presumed for these disorders, but little is known about their underlying neural mechanisms. Functional magnetic resonance imaging (fMRI) has been utilized to understand the mechanisms associated with unexplained motor symptoms. Here, we used fMRI to investigate the cerebral response to motor stimulation in a patient with conversion disorder with motor paralysis to determine the underlying neural mechanisms of this disorder. METHODS: Brain activation induced by movements of the bilateral ankle joints (repeated plantar flexion and dorsiflexion) was recorded using fMRI in a patient with conversion disorder with unexplained motor paralysis. We acquired 2 types of imaging data: (i) data obtained while motor paralysis remained present and (ii) data obtained after motor paralysis had completely improved. We used a within-subject fMRI block design to compare the patient's brain activities during the motor task and at rest. RESULTS: Cerebral motor areas were significantly activated during the motor task relative to at rest, both when motor paralysis remained present and when paralysis had improved (FWE-corrected P < .05), although there was greater activation in motor areas when motor paralysis had improved than when motor paralysis remained. Notably, activation in the cerebellum posterior lobe during the motor task when motor paralysis remained (FWE-corrected P < .05) disappeared after motor paralysis had completely improved. CONCLUSIONS: The cerebellum is a region that is closely associated with voluntary motion. We suggest that complementary abnormal function in the cerebellum might be associated with the neural basis of conversion disorder with motor paralysis.

Educational benefits for nurses and nursing students of the dementia supporter training program in Japan.

In Japan, which is thought to be a rapidly growing super-aging society, a national campaign named "the Dementia Supporter Caravan" has been deployed. The aim of this study was to assess the educational benefits of the dementia supporter training program for nurses and nursing students. We conducted dementia supporter training, and measured knowledge and attitudes regarding people with dementia as educational benefits pre- and post-training. Data sets of 134 nursing students and 63 nurses were analyzed. The results indicated that the two groups gained knowledge, understanding, and the confidence to care for people with dementia after attending the dementia supporter training program. Moreover, the two groups derived different benefits from the program. Nursing students gained substantial knowledge and learnt the importance of early detection and treatment, to levels similar to those of nurses prior to training. The training program reduced the difficulties of nurses to interact with and care for people with dementia. We can conclude that the dementia supporter training program has considerable educational benefits for nurses and nursing students.

Inhibition of GluR Current in Microvilli of Sensory Neurons via Na+-Microdomain Coupling Among GluR, HCN Channel, and Na+/K+ Pump.

Glutamatergic dendritic EPSPs evoked in cortical pyramidal neurons are depressed by activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels expressed in dendritic spines. This depression has been attributed to shunting effects of HCN current (Ih) on input resistance or Ih deactivation. Primary sensory neurons in the rat mesencephalic trigeminal nucleus (MTN) have the somata covered by spine-like microvilli that express HCN channels. In rat MTN neurons, we demonstrated that Ih enhancement apparently diminished the glutamate receptor (GluR) current (IGluR) evoked by puff application of glutamate/AMPA and enhanced a transient outward current following IGluR (OT-IGluR). This suggests that some outward current opposes inward IGluR. The IGluR inhibition displayed a U-shaped voltage-dependence with a minimal inhibition around the resting membrane potential, suggesting that simple shunting effects or deactivation of Ih cannot explain the U-shaped voltage-dependence. Confocal imaging of Na+ revealed that GluR activation caused an accumulation of Na+ in the microvilli, which can cause a negative shift of the reversal potential for Ih (Eh). Taken together, it was suggested that IGluR evoked in MTN neurons is opposed by a transient decrease or increase in standing inward or outward Ih, respectively, both of which can be caused by negative shifts of Eh, as consistent with the U-shaped voltage-dependence of the IGluR inhibition and the OT-IGluR generation. An electron-microscopic immunohistochemical study revealed the colocalization of HCN channels and glutamatergic synapses in microvilli of MTN neurons, which would provide a morphological basis for the functional interaction between HCN and GluR channels. Mathematical modeling eliminated the possibilities of the involvements of Ih deactivation and/or shunting effect and supported the negative shift of Eh which causes the U-shaped voltage-dependent inhibition of IGluR.

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.