Longitudinal reduction in brain volume in patients with schizophrenia and its association with cognitive function.

Establishing a brain biomarker for schizophrenia is strongly desirable not only to support diagnosis by psychiatrists but also to help track the progressive changes in the brain over the course of the illness. A brain morphological signature of schizophrenia was reported in a recent study and is defined by clusters of brain regions with reduced volume in schizophrenia patients compared to healthy individuals. This signature was proven to be effective at differentiating patients with schizophrenia from healthy individuals, suggesting that it is a good candidate brain biomarker of schizophrenia. However, the longitudinal characteristics of this signature have remained unclear. In this study, we examined whether these changes occurred over time and whether they were associated with clinical outcomes. We found a significant change in the brain morphological signature in schizophrenia patients with more brain volume loss than the natural, age-related reduction in healthy individuals, suggesting that this change can capture a progressive morphological change in the brain. We further found a significant association between changes in the brain morphological signature and changes in the full-scale intelligence quotient (IQ). The patients with IQ improvement showed preserved brain morphological signatures, whereas the patients without IQ improvement showed progressive changes in the brain morphological signature, suggesting a link between potential recovery of intellectual abilities and the speed of brain pathology progression. We conclude that the brain morphological signature is a brain biomarker that can be used to evaluate progressive changes in the brain that are associated with cognitive impairment due to schizophrenia.

Visual salience is affected in participants with schizophrenia during free-viewing.

Abnormalities in visual exploration affect the daily lives of patients with schizophrenia. For example, scanpath length during free-viewing is shorter in schizophrenia. However, its origin and its relevance to symptoms are unknown. Here we investigate the possibility that abnormalities in eye movements result from abnormalities in visual or visuo-cognitive processing. More specifically, we examined whether such abnormalities reflect visual salience in schizophrenia. Eye movements of 82 patients and 252 healthy individuals viewing natural and/or complex images were examined using saliency maps for static images to determine the contributions of low-level visual features to salience-guided eye movements. The results showed that the mean value for orientation salience at the gazes of the participants with schizophrenia were higher than that of the healthy control subjects. Further analyses revealed that orientation salience defined by the L + M channel of the DKL color space is specifically affected in schizophrenia, suggesting abnormalities in the magnocellular visual pathway. By looking into the computational stages of the visual salience, we found that the difference between schizophrenia and healthy control emerges at the earlier stage, suggesting functional decline in early visual processing. These results suggest that visual salience is affected in schizophrenia, thereby expanding the concept of the aberrant salience hypothesis of psychosis to the visual domain.

Better adherence to guidelines among psychiatrists providing pharmacological therapy is associated with longer work hours in patients with schizophrenia.

Schizophrenia is a psychiatric disorder that is associated with various social dysfunctions, including shorter work hours. To measure the degree to which psychiatrists adhere to guidelines for pharmacological therapy of schizophrenia, we recently developed the individual fitness score (IFS) for adherence among psychiatrists in each patient. However, it remains unclear whether better adherence among psychiatrists is associated with higher patients' social functional outcomes, such as work hours. In this study, we examined the relationship between adherence to guidelines among psychiatrists and work hours in patients with schizophrenia. To evaluate the association between adherence to guidelines for pharmacological therapy among psychiatrists for treating schizophrenia and work hours, we used the IFS and social activity assessment, respectively, in 286 patients with schizophrenia. The correlation between IFS values and work hours was investigated in the patients. The adherence among psychiatrists to guidelines was significantly and positively correlated with work hours in patients with schizophrenia (rho = 0.18, p = 2.15 × 10-3). When we divided the patients into treatment-resistant schizophrenia (TRS) and nontreatment-resistant schizophrenia (non-TRS) groups, most patients with TRS (n = 40) had shorter work hours (0-15 h/week). Even after excluding patients with TRS, the positive correlation between adherence to guidelines among psychiatrists and work hours in patients with non-TRS (n = 246) was still significant (rho = 0.19, p = 3.32 × 10-3). We found that work hours were longer in patients who received the guideline-recommended pharmacotherapy. Our findings suggest that widespread education and training for psychiatrists may be necessary to improve functional outcomes in patients with schizophrenia.

Cerebral cortical structural alteration patterns across four major psychiatric disorders in 5549 individuals.

According to the operational diagnostic criteria, psychiatric disorders such as schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and autism spectrum disorder (ASD) are classified based on symptoms. While its cluster of symptoms defines each of these psychiatric disorders, there is also an overlap in symptoms between the disorders. We hypothesized that there are also similarities and differences in cortical structural neuroimaging features among these psychiatric disorders. T1-weighted magnetic resonance imaging scans were performed for 5,549 subjects recruited from 14 sites. Effect sizes were determined using a linear regression model within each protocol, and these effect sizes were meta-analyzed. The similarity of the differences in cortical thickness and surface area of each disorder group was calculated using cosine similarity, which was calculated from the effect sizes of each cortical regions. The thinnest cortex was found in SZ, followed by BD and MDD. The cosine similarity values between disorders were 0.943 for SZ and BD, 0.959 for SZ and MDD, and 0.943 for BD and MDD, which indicated that a common pattern of cortical thickness alterations was found among SZ, BD, and MDD. Additionally, a generally smaller cortical surface area was found in SZ and MDD than in BD, and the effect was larger in SZ. The cosine similarity values between disorders were 0.945 for SZ and MDD, 0.867 for SZ and ASD, and 0.811 for MDD and ASD, which indicated a common pattern of cortical surface area alterations among SZ, MDD, and ASD. Patterns of alterations in cortical thickness and surface area were revealed in the four major psychiatric disorders. To our knowledge, this is the first report of a cross-disorder analysis conducted on four major psychiatric disorders. Cross-disorder brain imaging research can help to advance our understanding of the pathogenesis of psychiatric disorders and common symptoms.

Subcortical volumetric alterations in four major psychiatric disorders: a mega-analysis study of 5604 subjects and a volumetric data-driven approach for classification.

Differential diagnosis is sometimes difficult in practical psychiatric settings, in terms of using the current diagnostic system based on presenting symptoms and signs. The creation of a novel diagnostic system using objective biomarkers is expected to take place. Neuroimaging studies and others reported that subcortical brain structures are the hubs for various psycho-behavioral functions, while there are so far no neuroimaging data-driven clinical criteria overcoming limitations of the current diagnostic system, which would reflect cognitive/social functioning. Prior to the main analysis, we conducted a large-scale multisite study of subcortical volumetric and lateralization alterations in schizophrenia, bipolar disorder, major depressive disorder, and autism spectrum disorder using T1-weighted images of 5604 subjects (3078 controls and 2526 patients). We demonstrated larger lateral ventricles volume in schizophrenia, bipolar disorder, and major depressive disorder, smaller hippocampus volume in schizophrenia and bipolar disorder, and schizophrenia-specific smaller amygdala, thalamus, and accumbens volumes and larger caudate, putamen, and pallidum volumes. In addition, we observed a leftward alteration of lateralization for pallidum volume specifically in schizophrenia. Moreover, as our main objective, we clustered the 5,604 subjects based on subcortical volumes, and explored whether data-driven clustering results can explain cognitive/social functioning in the subcohorts. We showed a four-biotype classification, namely extremely (Brain Biotype [BB] 1) and moderately smaller limbic regions (BB2), larger basal ganglia (BB3), and normal volumes (BB4), being associated with cognitive/social functioning. Specifically, BB1 and BB2-3 were associated with severe and mild cognitive/social impairment, respectively, while BB4 was characterized by normal cognitive/social functioning. Our results may lead to the future creation of novel biological data-driven psychiatric diagnostic criteria, which may be expected to be useful for prediction or therapeutic selection.

Longitudinal characteristics of insight and clinical factors in patients with schizophrenia.

AIMS: Schizophrenia is a psychiatric disorder presenting a lack of insight. Although insight changes over time, longitudinal studies of insight in schizophrenia are scarce. Furthermore, most previous studies on insight and intelligence have not measured full-scale IQ and have not been able to examine the relationship between detailed dimensions of cognitive function and insight. In this study, we assessed insight at two time points and assessed dimensions of cognitive function. METHODS: A total of 163 patients with schizophrenia participated in the study. We evaluated insight at two time points to understand the patterns of change and examined the association between insight and clinical variables. Additionally, we examined the relationship between the dimensions of cognitive function and insight. RESULTS: The patients were divided into three groups based on their change in insight over time: stable at a low level of insight (poor insight), stable at a high level of insight (good insight), and changed in insight over time (unstable insight). Those in the poor insight group had lower general intelligence scores than those in the good insight and unstable insight groups. Regarding cognitive function, verbal comprehension was associated with the level of insight at baseline and follow-up. Regarding psychiatric symptoms, the poor insight group exhibited more severe symptoms than the other two groups, especially regarding positive symptoms. CONCLUSIONS: Our classification of patients based on changes in insight revealed that poor insight patients had impaired cognitive function, especially verbal comprehension, and more severe positive symptoms than good insight or unstable insight patients.

Relationships Between Adherence to Guideline Recommendations for Pharmacological Therapy Among Clinicians and Psychotic Symptoms in Patients With Schizophrenia.

BACKGROUND: Clinician adherence to guideline recommendations in the pharmacological therapy of schizophrenia is important for favorable patient outcomes. To evaluate whether prescriptions followed the guidelines for pharmacological therapy of schizophrenia, we recently developed a summary indicator of multiple quality indicators: the individual fitness score (IFS). It is unclear whether adherence to the guidelines is related to patient outcomes. Here, we investigated correlations between the IFS values and psychotic symptoms in patients with schizophrenia. METHODS: We assessed whether patients' current prescriptions adhered to the guideline recommendations using the IFS in 47 patients with treatment-resistant schizophrenia (TRS) and 353 patients with non-TRS (total n = 400), respectively. We investigated correlations between the IFS and total scores and scores on the 5 subscales of the Positive and Negative Syndrome Scale (PANSS). Furthermore, we explored correlations between over 2-year longitudinal changes in IFS values and changes in psychotic symptoms in some patients (n = 77). RESULTS: We found significant negative correlation between the IFS and PANSS total score in all patients with schizophrenia (ß = -0.18, P = 9.80 × 10-5). The IFS was significantly and nominally negatively correlated with the PANSS total score in patients with non-TRS (Spearman's rho = -0.15, P = 4.40 × 10-3) and patients with TRS (rho = -0.37, P = .011), respectively. The IFS was also significantly and nominally negatively correlated with several factors, such as the negative and depressed factors, in patients with non-TRS and patients with TRS, respectively (P < .05). Furthermore, the change in IFS values was marginally negatively correlated with the changes in PANSS total scores and scores on the positive and depressed factors (P < .05). CONCLUSIONS: These findings suggest that efforts to improve clinician adherence to guideline recommendations for pharmacological therapy of schizophrenia, as assessed by the IFS, may lead to better outcomes in patients with schizophrenia.

Discrimination in the clinical diagnosis between patients with schizophrenia and healthy controls using eye movement and cognitive functions.

AIM: Eye movements and cognitive functions are significantly impaired in patients with schizophrenia. The authors aimed to develop promising clinical diagnostic markers that fit practical digital health applications in psychiatry using eye movement and cognitive function data from 1254 healthy individuals and 336 patients with schizophrenia. METHODS: Multivariate analyses using logistic regression were performed to confirm net performance of eye movements and cognitive functions scored using the Wechsler Adult Intelligence Scale, Third Edition, and Wechsler Memory Scale-Revised. The authors then examined the discrimination performance of pairs containing an eye movement and a cognitive function measure to search the pairs that would be effective in practical application for the discrimination according to the diagnostic criterion between the groups. RESULTS: Multivariate analyses confirmed that eye movements and cognitive functions were effective modalities for discriminating between patients with schizophrenia and healthy controls. The discriminant analyses of the pairs demonstrated that seven eye movement measures and seven scores from cognitive function tests showed high discrimination performance when paired with one measure from the other modality. Moreover, seven pairs of digit-symbol coding or symbol-search and eye movement measures had high and robust discrimination performance. CONCLUSION: Seven pairs of an eye movement and a cognitive function measure were effective, robust, and less time-consuming in assisting with clinical diagnosis by categorizing healthy individuals or patients with schizophrenia. These findings may help develop an objective auxiliary diagnosis method working even on portable devices, which facilitates the consistency of diagnosis, earlier intervention, and shared decision-making.

Association Study Between White Matter Microstructure and Intelligence Decline in Schizophrenia.

Patients with schizophrenia can exhibit intelligence decline, which is an important element of cognitive impairment. Previous magnetic resonance imaging (MRI) studies have demonstrated that patients with schizophrenia have altered gray matter structures and functional connectivity associated with intelligence decline defined by a difference between premorbid and current intelligence quotients (IQs). However, it has remained unclear whether white matter microstructures are related to intelligence decline. In the present study, the indices of diffusion tensor imaging (DTI) obtained from 138 patients with schizophrenia and 554 healthy controls were analyzed. The patients were classified into three subgroups based on intelligence decline: deteriorated (94 patients), preserved (42 patients), and compromised IQ (2 patients) groups. Given that the DTI of each subject was acquired using either one of two different MRI scanners, we analyzed DTI indices separately for each scanner group. In the comparison between the deteriorated IQ group and the healthy controls, differences in some DTI indices were noted in three regions of interest irrespective of the MRI scanners, whereas differences in only one region of interest were noted between the preserved IQ group and the healthy controls. However, the comparisons between the deteriorated and preserved IQ groups did not show any reproducible differences. Together with the previous findings, it is thought that gray matter structures and functional connectivity are more promising as markers of intelligence decline in schizophrenia than white matter microstructures.

Transdiagnostic comparisons of intellectual abilities and work outcome in patients with mental disorders: multicentre study.

BACKGROUND: Cognitive impairment is common in people with mental disorders, leading to transdiagnostic classification based on cognitive characteristics. However, few studies have used this approach for intellectual abilities and functional outcomes. AIMS: The present study aimed to classify people with mental disorders based on intellectual abilities and functional outcomes in a data-driven manner. METHOD: Seven hundred and forty-nine patients diagnosed with schizophrenia, bipolar disorder, major depression disorder or autism spectrum disorder and 1030 healthy control subjects were recruited from facilities in various regions of Japan. Two independent k-means cluster analyses were performed. First, intelligence variables (current estimated IQ, premorbid IQ, and IQ discrepancy) were included. Second, number of work hours per week was included instead of premorbid IQ. RESULTS: Four clusters were identified in the two analyses. These clusters were specifically characterised in terms of IQ discrepancy in the first cluster analysis, whereas the work variable was the most salient feature in the second cluster analysis. Distributions of clinical diagnoses in the two cluster analyses showed that all diagnoses were unevenly represented across the clusters. CONCLUSIONS: Intellectual abilities and work outcomes are effective classifiers in transdiagnostic approaches. The results of our study also suggest the importance of diagnosis-specific strategies to support functional recovery in people with mental disorders.

Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder.

BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.

Relationship between autistic traits and social functioning in healthy individuals.

AIM: Social functioning is influenced by various factors. Autistic traits could be one of the factors that affect social functioning. METHODS: In the present study, the relationship between autistic traits and social functioning among 755 healthy individuals was analyzed. Autistic traits were assessed with the autism-spectrum quotient. Social functioning was assessed by the social functioning scale and the social activity assessment. RESULTS: The Autism-Spectrum Quotient total score was significantly negatively correlated with the social functioning scale total and all subscales of the social functioning scale. All subscales of the Autism-Spectrum Quotient except attention to detail were significantly negatively correlated with the social functioning scale total score. However, the Autism-Spectrum Quotient was not correlated with the social activity assessment, which indicates labor functioning. CONCLUSION: Autistic traits of healthy individuals had a negative impact on situations in real life through social functioning for daily life-sustaining. The effect was not enough to affect labor functioning as indicated by working hours in healthy individuals. These findings should also be examined in individuals with autism spectrum disorder in future studies.

Neurocognitive features, personality traits, and social function in patients with schizophrenia with a history of violence.

Recent literature examining associations between cognitive function, clinical features, and violence in patients with schizophrenia has been growing; however, the results are inconsistent. Reports on social function and personality are limited. These studies are yet to be reflected in risk assessment tools and management plans. The aim of this study is to provide a resource for risk assessment and intervention studies by conducting multifaceted well-established assessments in a large population. Data from 355 patients with schizophrenia (112 patients with a history of violence; 243 patients without a history of violence) and 1265 healthy subjects were extracted from a large database of individuals with mental disorders in a general psychiatric population in Japan. The associations between violence in patients with schizophrenia and intellectual function, cognitive function (memory function, executive function, attentional function, verbal learning, processing speed, social cognition), clinical variables, personality traits, social function, and quality of life (QOL) were analyzed. Compared with healthy subjects, the schizophrenia group had broadly impaired cognitive function and social cognition, and their personality traits showed similar differences as those reported previously. Patients with schizophrenia with a history of violence showed significantly more impaired visual memory function (P = 1.9 × 10-5, Cohen's d = 0.34), longer hospitalization (P = 5.9 × 10-4, Cohen's d = 0.38), more severe excited factor on Positive and Negative Syndrome Scale (P = 1.6 × 10-4, Cohen's d = 0.47), higher self-transcendence personality construct on the Temperament and Character Inventory (P = 1.8 × 10-4, Cohen's d = 0.46), and shorter total working hours per week (P = 4.8 × 10-4, Cohen's d = 0.53) than those with schizophrenia without a history of violence. New findings, including impaired visual memory, a high self-transcendence personality trait, and shorter total working hours, could be focused on in future interventional research.

Methylation Analysis in Monozygotic Twins With Treatment-Resistant Schizophrenia and Discordant Responses to Clozapine.

Schizophrenia is a mental illness that involves both genetic and environmental factors. Clozapine, an atypical antipsychotic, is a well-established therapy for treatment-resistant schizophrenia. In this study, we focused on a set of monozygotic twins with treatment-resistant schizophrenia in which one twin effectively responded to clozapine treatment and the other did not. Our previous study generated neurons from induced pluripotent stem (iPS) cells derived from these patients and compared the transcriptome profiles between mock- and clozapine-treated neurons. In this study, we performed genome-wide DNA methylation profiling to investigate the mechanisms underlying gene expression changes. First, we extracted the differentially methylated sites from each twin based on statistical analysis. Then, we combined the DNA methylation profiling with transcriptome profiling from our previous RNA-seq data. Among the genes with altered methylation and expression, we found the different proportions of the genes related to neuronal and synaptic functions between the clozapine responder and non-responder (35.7 and 6.7%, respectively). This trend was observed even when the basal differences between the responder and non-responder was excluded. These results suggest that effective clozapine action may correct the abnormalities of neuronal and synapse functions in schizophrenia via changes in methylation.

Multiple alterations in glutamatergic transmission and dopamine D2 receptor splicing in induced pluripotent stem cell-derived neurons from patients with familial schizophrenia.

An increasing body of evidence suggests that impaired synapse development and function are associated with schizophrenia; however, the underlying molecular pathophysiological mechanism of the disease remains largely unclear. We conducted a family-based study combined with molecular and cellular analysis using induced pluripotent stem cell (iPSC) technology. We generated iPSCs from patients with familial schizophrenia, differentiated these cells into neurons, and investigated the molecular and cellular phenotypes of the patient's neurons. We identified multiple altered synaptic functions, including increased glutamatergic synaptic transmission, higher synaptic density, and altered splicing of dopamine D2 receptor mRNA in iPSC-derived neurons from patients. We also identified patients' specific genetic mutations using whole-exome sequencing. Our findings support the notion that altered synaptic function may underlie the molecular and cellular pathophysiology of schizophrenia, and that multiple genetic factors cooperatively contribute to the development of schizophrenia.

Eye Movement Abnormalities in Major Depressive Disorder.

Background: Despite their high lifetime prevalence, major depressive disorder (MDD) is often difficult to diagnose, and there is a need for useful biomarkers for the diagnosis of MDD. Eye movements are considered a non-invasive potential biomarker for the diagnosis of psychiatric disorders such as schizophrenia. However, eye movement deficits in MDD remain unclear. Thus, we evaluated detailed eye movement measurements to validate its usefulness as a biomarker in MDD. Methods: Eye movements were recorded from 37 patients with MDD and 400 healthy controls (HCs) using the same system at five University hospitals. We administered free-viewing, fixation stability, and smooth pursuit tests, and obtained 35 eye movement measurements. We performed analyses of covariance with group as an independent variable and age as a covariate. In 4 out of 35 measurements with significant group-by-age interactions, we evaluated aging effects. Discriminant analysis and receiver operating characteristic (ROC) analysis were conducted. Results: In the free-viewing test, scanpath length was significantly shorter in MDD (p = 4.2 × 10-3). In the smooth pursuit test, duration of saccades was significantly shorter and peak saccade velocity was significantly lower in MDD (p = 3.7 × 10-3, p = 3.9 × 10-3, respectively). In the fixation stability test, there were no significant group differences. There were significant group differences in the older cohort, but not in the younger cohort, for the number of fixations, duration of fixation, number of saccades, and fixation density in the free-viewing test. A discriminant analysis using scanpath length in the free-viewing test and peak saccade velocity in the smooth pursuit showed MDD could be distinguished from HCs with 72.1% accuracy. In the ROC analysis, the area under the curve was 0.76 (standard error = 0.05, p = 1.2 × 10-7, 95% confidence interval = 0.67-0.85). Conclusion: These results suggest that detailed eye movement tests can assist in differentiating MDD from HCs, especially in older subjects.

Serum levels of glial cell line-derived neurotrophic factor as a biomarker for mood disorders and lithium response.

Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the pathophysiology of neuropsychiatric disorders. We examined serum GDNF levels in bipolar disorder (BD) patients and major depressive disorder (MDD) patients and their association with response to lithium therapy. We used a multicenter (six sites), exploratory, cross-sectional case-control design and recruited 448 subjects: 143 BD patients, 116 MDD patients, and 158 healthy controls (HCs). We evaluated the patients' clinical severity using the Clinical Global Impression (CGI), and responses to lithium therapy using the Alda scale. The serum GDNF levels were significantly decreased in the BD and MDD groups compared to the HCs, with no significant difference between the BD and MDD groups. After adjustment, the serum GDNF levels in the BD and MDD patients in remission or depressive states were decreased compared to the HC values. Lower serum GDNF levels in BD patients were associated with higher CGI and Alda scores (i.e., severe illness and good response to lithium therapy, respectively). Our findings suggest that the serum GDNF level may be a biomarker for both BD and MDD in remission or depressive states. The serum GDNF level may be associated with the lithium response of BD patients.

Effects of age and sex on eye movement characteristics.

Abnormal eye movements are often associated with psychiatric disorders. Eye movements are sensorimotor functions of the brain, and aging and sex would affect their characteristics. A precise understanding of normal eye movements is required to distinguish disease-related abnormalities from natural differences associated with aging or sex. To date, there is no multicohort study examining age-related dependency and sex effects of eye movements in healthy, normal individuals using large samples to ensure the robustness and reproducibility of the results. In this study, we aimed to provide findings showing the impact of age and sex on eye movement measures. The present study used eye movement measures of more than seven hundred healthy individuals from three large independent cohorts. We herein evaluated eye movement measures quantified by using a set of standard eye movement tests that have been utilized for the examination of patients with schizophrenia. We assessed the statistical significance of the effects of age and sex and its reproducibility across cohorts. We found that 4-18 out of 35 eye movement measures were significantly correlated with age, depending on the cohort, and that 10 of those, which are related to the fixation and motor control of smooth pursuit and saccades, showed high reproducibility. On the other hand, the effects of sex, if any, were less reproducible. The present results suggest that we should take age into account when we evaluate abnormalities in eye movements.

Impaired inhibition of return during free-viewing behaviour in patients with schizophrenia.

Schizophrenia affects various aspects of cognitive and behavioural functioning. Eye movement abnormalities are commonly observed in patients with schizophrenia (SZs). Here we examined whether such abnormalities reflect an anomaly in inhibition of return (IOR), the mechanism that inhibits orienting to previously fixated or attended locations. We analyzed spatiotemporal patterns of eye movement during free-viewing of visual images including natural scenes, geometrical patterns, and pseudorandom noise in SZs and healthy control participants (HCs). SZs made saccades to previously fixated locations more frequently than HCs. The time lapse from the preceding saccade was longer for return saccades than for forward saccades in both SZs and HCs, but the difference was smaller in SZs. SZs explored a smaller area than HCs. Generalized linear mixed-effect model analysis indicated that the frequent return saccades served to confine SZs' visual exploration to localized regions. The higher probability of return saccades in SZs was related to cognitive decline after disease onset but not to the dose of prescribed antipsychotics. We conclude that SZs exhibited attenuated IOR under free-viewing conditions, which led to restricted scene scanning. IOR attenuation will be a useful clue for detecting impairment in attention/orienting control and accompanying cognitive decline in schizophrenia.