Tablet-Based Cognitive and Eye Movement Measures as Accessible Tools for Schizophrenia Assessment: Multisite Usability Study.

BACKGROUND: Schizophrenia is a complex mental disorder characterized by significant cognitive and neurobiological alterations. Impairments in cognitive function and eye movement have been known to be promising biomarkers for schizophrenia. However, cognitive assessment methods require specialized expertise. To date, data on simplified measurement tools for assessing both cognitive function and eye movement in patients with schizophrenia are lacking. OBJECTIVE: This study aims to assess the efficacy of a novel tablet-based platform combining cognitive and eye movement measures for classifying schizophrenia. METHODS: Forty-four patients with schizophrenia, 67 healthy controls, and 41 patients with other psychiatric diagnoses participated in this study from 10 sites across Japan. A free-viewing eye movement task and 2 cognitive assessment tools (Codebreaker task from the THINC-integrated tool and the CognitiveFunctionTest app) were used for conducting assessments in a 12.9-inch iPad Pro. We performed comparative group and logistic regression analyses for evaluating the diagnostic efficacy of the 3 measures of interest. RESULTS: Cognitive and eye movement measures differed significantly between patients with schizophrenia and healthy controls (all 3 measures; P<.001). The Codebreaker task showed the highest classification effectiveness in distinguishing schizophrenia with an area under the receiver operating characteristic curve of 0.90. Combining cognitive and eye movement measures further improved accuracy with a maximum area under the receiver operating characteristic curve of 0.94. Cognitive measures were more effective in differentiating patients with schizophrenia from healthy controls, whereas eye movement measures better differentiated schizophrenia from other psychiatric conditions. CONCLUSIONS: This multisite study demonstrates the feasibility and effectiveness of a tablet-based app for assessing cognitive functioning and eye movements in patients with schizophrenia. Our results suggest the potential of tablet-based assessments of cognitive function and eye movement as simple and accessible evaluation tools, which may be useful for future clinical implementation.

The evaluation study for social cognition measures in Japan: Psychometric properties, relationships with social function, and recommendations.

AIM: Patients with schizophrenia can have significant subjective difficulties in social cognition, but few undergo testing or treatment for social cognition. The Social Cognition Psychometric Evaluation (SCOPE) study recommends six social cognitive measures; however, the reliability and validity of these measures in different cultural and linguistic areas has not been adequately examined. We examined the psychometric properties of nine social cognitive measures and the relationship to social function, with the aim of determining the level of recommendation for social cognitive measures in clinical practice in Japan. METHODS: For our test battery, an expert panel previously selected nine measures: the Bell Lysaker Emotion Recognition Task (BLERT); Facial Emotion Selection Test (FEST); Hinting Task (Hinting); Metaphor and Sarcasm Scenario Test (MSST); Intentionality Bias Task (IBT); Ambiguous Intentions and Hostility Questionnaire (AIHQ); Social Attribution Task-Multiple Choice (SAT-MC); SAT-MCII; and Biological Motion (BM) task. In total, 121 outpatients with schizophrenia and 70 healthy controls were included in the analysis, and the results were provided to an expert panel to determine the recommendations for each measure. The quantitative psychological indices of each measure were evaluated for practicality, tolerability, test-retest reliability, correlation with social function, and the incremental validity of social function. RESULTS: Hinting and FEST received the highest recommendations for use in screening, severity assessment, and longitudinal assessment, followed by BLERT, MSST AIHQ, SAT-MC, and SAT-MCII, with IBT and BM receiving the lowest recommendations. CONCLUSION: This study provides a uniform assessment tool that can be used in future international clinical trials for social cognitive impairment.

Feasibility of a wrist-worn wearable device for estimating mental health status in patients with mental illness.

Object: Real-world data from wearable devices has the potential to understand mental health status in everyday life. We aimed to investigate the feasibility of estimating mental health status using a wrist-worn wearable device (Fitbit Sense) that measures movement using a 3D accelerometer and optical pulse photoplethysmography (PPG). Methods: Participants were 110 patients with mental illnesses from different diagnostic groups. The study was undertaken between 1 October 2020 and 31 March 2021. Participants wore a Fitbit Sense on their wrist and also completed the State-Trait Anxiety Inventory (STAI), Positive and Negative Affect Schedule (PANAS), and EuroQol 5 dimensions 5-level (EQ-5D-5L) during the study period. To determine heart rate (HR) variability (HRV), we calculated the sdnn (standard deviation of the normal-to-normal interval), coefficient of variation of R-R intervals, and mean HR separately for each sleep stage and the daytime. The association between mental health status and HR and HRV was analyzed. Results: The following significant correlations were found in the wake after sleep onset stage within 3 days of mental health status assessment: sdnn, HR and STAI scores, HR and PANAS scores, HR and EQ-5D-5L scores. The association between mental health status and HR and HRV was stronger the closer the temporal distance between mental health status assessment and HR measurement. Conclusion: A wrist-worn wearable device that measures PPG signals was feasible for use with patients with mental illness. Resting state HR and HRV could be used as an objective assessment of mental health status within a few days of measurement.

Assessment of electroencephalography modification by antipsychotic drugs in patients with schizophrenia spectrum disorders using frontier orbital theory: A preliminary study.

AIM: Schizophrenia is characterized by an abnormality in electroencephalography (EEG), which can be affected by antipsychotic drugs. Recently, the mechanism underlying these EEG alterations in schizophrenia patients was reframed from the perspective of redox abnormalities. The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) can be calculated using a computational method and may be useful for evaluating the antioxidant/prooxidant effect of antipsychotic drugs. Thus, we examined the association between the effects of antipsychotic monotherapy on quantitative EEG and HOMO/LUMO energy. METHODS: We used medical report data including EEG results of psychiatric patients admitted to Hokkaido University Hospital. We extracted the EEG records of patients diagnosed with a schizophrenia spectrum disorder undergoing antipsychotic monotherapy during the natural course of treatment (n = 37). We evaluated the HOMO/LUMO energy of all antipsychotic drugs using computational methods. Multiple regression analyses were used to examine the relationship between the HOMO/LUMO energy of all antipsychotic drugs and spectral band power in all patients. Statistical significance was set at p < 6.25 × 10-4 adjusted with Bonferroni correction. RESULTS: We showed that the HOMO energy of all antipsychotic drugs had weak positive correlations with delta- and gamma-band power (e.g., standardized ß = 0.617 for delta in the F3 channel, p = 6.6 × 10-5 ; standardized ß = 0.563 for gamma in the O1 channel, p = 5.0 × 10-4 ). CONCLUSION: Although there may be unexpected bias and confounding factors, our findings suggest that the effect of antipsychotic drugs on EEG may be related to their antioxidant actions.

Hyperthymic temperament predicts neural responsiveness for monetary reward.

BACKGROUND: Hyperthymic temperament is cheerful action orientation, and is suggested to have a protective effect on depressive symptoms. Responsiveness for reward, which is diminished in depressive patients, is suggested to be related to hyperthymic temperament. Moreover, neural hypoactivation in the reward system in depressive patients is well known. However, only a few previous studies have investigated the neurobiological substrate of hyperthymic temperament. We investigated the relationship between hyperthymic temperament and responsiveness to monetary rewards at the neural level. METHODS: Healthy participants performed a modified version of the monetary incentive delay task in a functional magnetic resonance imaging scanner. We explored the brain regions where neural responsiveness for monetary reward was predicted by hyperthymic temperament. RESULTS: Brain areas in the reward system were widely activated for reward anticipation. Activation in the left thalamus and left putamen was positively predicted by hyperthymic temperament. Conversely, activation in the ventral striatum and right insula was not modulated by hyperthymic temperament. No region activated for reward outcome was not modulated by hyperthymic temperament. LIMITATIONS: Behavioral responsiveness to reward was not predicted by hyperthymic temperament or neural activity. Moreover, we did not correct P values for multiple regression analysis, considering that this was an exploratory study. CONCLUSIONS: We found a neurobiological foundation for the protective aspect of hyperthymic temperament against depression in the reward system. Our findings suggest that the hyperthymic temperament may modulate attentional or motor responses or optimal selection of behavior based on reward, rather than value representation.

Hyperthymic temperament predicts neural responsiveness for nonmonetary reward.

Aim: Hyperthymic temperament is a cheerful action orientation that is suggested to have a protective effect on depressive symptoms. We recently reported that hyperthymic temperament can positively predict activation of reward-related brain areas in anticipation of monetary rewards, which could serve as a biomarker of hyperthymic temperament. However, the relationship between hyperthymic temperament and neural responsiveness to nonmonetary rewards (i.e., feedback indicating success in a task) remains unclear. Methods: Healthy participants performed a modified monetary incentive delay task inside a functional magnetic resonance imaging scanner. To examine the effect of nonmonetary positive feedback, the participants performed feedback and no-feedback trials. We explored brain regions whose neural responsiveness to nonmonetary rewards was predicted by hyperthymic temperament. Results: There was premotor area activation in anticipation of a nonmonetary reward, which was negatively predicted by hyperthymic temperament. Moreover, brain areas located mainly in the primary somatosensory area and somatosensory association area were activated by performance feedback, which was positively predicted by hyperthymic temperament. Conclusion: We found that hyperthymic temperament is related to neural responsiveness to both monetary and nonmonetary rewards. This may be related to the process of affective regulation in the somatosensory area.

Approach to impaired corollary discharge in patients with schizophrenia: An analysis of self-induced somatosensory evoked potentials and fields.

Background: Difficulty in distinguishing between self-generated actions and those generated by others is a core feature of schizophrenia. This is thought to be underpinned by the failure of corollary discharge. However, few studies have investigated these events using somatosensory evoked potentials (SEPs) and somatosensory evoked magnetic fields (SEFs). Methods: The study included 15 right-handed patients with schizophrenia and 16 healthy controls. SEP and SEF were elicited by electrical stimuli to the left median nerve at intervals of 1-3 s. In the external condition, stimuli were externally induced by a machine. In the self-condition, stimuli were induced by tapping the participants' own right index finger. Peak amplitude at C4' in SEP and root mean square in 10 channels on the right primary somatosensory area in SEF were analyzed. Results: Although there was a significant main effect of condition at N20m, and a significant main effect of condition and group at P30m, no significant interactions of condition and group were found in either N20m or P30m. The post-hoc Wilcoxon signed-rank test revealed that the peak value of P30m in the external condition was significantly higher than that in the self-condition in the healthy control group only. In addition, there was a significant positive correlation between the peak value of P30m in the self-condition and a positive symptom score. Conclusion: In the current study, we did not find abnormalities of corollary discharge in primary sensory areas in patients with schizophrenia. Further investigations with more cases may reveal the possibility of corollary discharge disturbance in the primary sensory cortex.

Subjects with bipolar disorder showed different reward system activation than subjects with major depressive disorder in the monetary incentive delay task.

BACKGROUND: Differentiating between bipolar disorder (BD) and major depressive disorder (MDD) during the depressive episode is an important clinical challenge. Reward system abnormalities have received much attention as one of the biological underpinnings of BD and MDD, but few studies have directly compared these abnormalities in remitted and depressed states. METHODS: This was a functional MRI study using the Monetary Incentive Delay task in 65 patients (BD [n = 33], MDD [n = 32]) and 33 healthy controls (HC). Regions of interest (ROI) analysis with 21 ROIs related to reward anticipation and 17 ROIs related to gain outcome were implemented, as well as whole-brain analysis. The difference in the dimensional effect of depression on brain activation was also examined. RESULTS: Relative to the HC group, BD patients showed significantly decreased activation during reward anticipation in the anterior cingulate cortex, anterior insula (AI), and putamen, and MDD patients showed significantly decreased activation in the AI and brainstem. The dimensional effect of depression severity showed a trend-level difference between BD and MDD in the right brainstem and left AI. CONCLUSIONS: The current study showed a possible differential effect of depression on the reward system between MDD and BD. Further studies on reward systems might offer reliable markers to distinguish between MDD and BD patients in the depressive phase.

A Brief, Individualized Exercise Program at Intensities Below the Ventilatory Threshold Exerts Therapeutic Effects for Depression: A Pilot Study.

Due to the fact that existing pharmacological treatments for depression are not ideal, effort has been devoted to the development of complementary, alternative therapies such as physical exercise. The antidepressant effect of exercise is well documented. However, current recommendations and prescriptions of exercise may be too demanding for depressed patients, as some complain about the design of exercise programs and depression is associated with reduced motivation and capacity to exercise. Therefore, appropriately designed, patient-friendly exercise programs may prove critical for the long-term maintenance and therapeutic effects of exercise. In this pilot study, we developed an exercise program based on patients' individual level of ventilatory threshold (VT), a submaximal index of aerobic capacity measured by Cardiopulmonary Exercise Testing (CPX). Compared to traditional measures, CPX provides more trustable indices of aerobic capacity and more homogenous exercise prescriptions. The main episode of the program consisted of 15-25 min of cycling twice a week at an intensity that approached but never went higher than subjects' VT (considered low to moderate in intensity). We found that in patients diagnosed with major depressive disorder or persistent depressive disorder (n = 8), the program resulted in a significant reduction in depressive symptoms at week 8, which was maintained at week 16. Meanwhile, patients' social functioning, quality of life, and cognitive functions improved. Although we used a single arm, non-randomized design, our results suggest that even a brief, low to moderate intensity exercise program may exert therapeutic effects for depression and CPX may be a useful tool for exercise prescriptions.

Plasma fatty acid-binding protein 7 concentration correlates with depression/anxiety, cognition, and positive symptom in patients with schizophrenia.

Because of the involvement of the brain in the pathophysiology of psychiatric disorders, obtaining information on the biochemical features that directly contribute to symptoms is challenging. The present study aimed to assess fatty acid-binding protein 7 (FABP7) expressed specifically in the brain and detectable in the peripheral blood and to investigate the correlation between blood FABP7 concentration and symptoms. We recruited 30, 29, and 35 patients with schizophrenia, bipolar disorder, and depression and evaluated using the Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale (YMRS), and Hamilton Depression Rating Scale (HAMD-21), respectively. Plasma FABP7 concentrations correlated with PANSS scores (R2 = 0.3305, p < 0.001) but not with other scales. In the analysis of the relationship between five dimensions of schizophrenia symptoms derived from the PANSS 5-factor model and measured plasma FABP7 concentrations, severities of depression/anxiety, cognition, and positive symptom were significantly correlated with plasma FABP7 concentrations. Further molecular investigation of the functional and kinetic analyses of FABP7 is necessary to understand the relationship of this protein with schizophrenia pathology. Nevertheless, the present study suggests that FABP7 can be a biological indicator reflecting the pathogenesis of schizophrenia and has potential applications as a biomarker for diagnosis and symptom assessment.

Study Protocol: The Evaluation Study for Social Cognition Measures in Japan (ESCoM).

In schizophrenia, social cognitive impairment is considered one of the greatest obstacles to social participation. Although numerous measures have been developed to assess social cognition, only a limited number of them have become available in Japan. We are therefore planning this evaluation study for social cognition measures in Japan (ESCoM) to confirm their psychometric characteristics and to promote research focused on social cognition. Participants in the cross-sectional observational study will be 140 patients with schizophrenia recruited from three Japanese facilities and 70 healthy individuals. In our primary analysis, we will calculate several psychometric indicators with a focus on whether they can independently predict social functioning. In secondary analyses, we will assess the reliability and validity of the Japanese translations of each measure and conduct an exploratory investigation of patient background, psychiatric symptoms, defeatist performance belief, and gut microbiota as determinants of social cognition. The protocol for this study is registered in UMIN-CTR, unique ID UMIN000043777.

Quantitative Resting State Electroencephalography in Patients with Schizophrenia Spectrum Disorders Treated with Strict Monotherapy Using Atypical Antipsychotics.

OBJECTIVE: The effect of antipsychotic drugs on quantitative electroencephalography (EEG) has been mainly examined by the administration of a single test dose or among patients using combinations of other psychotropic drugs. We therefore investigated the effects of strict monotherapy with antipsychotic drugs on quantitative EEG among schizophrenia patients. METHODS: Data from 2,364 medical reports with EEG results from psychiatric patients admitted to the Hokkaido University Hospital were used. We extracted EEG records of patients who were diagnosed with schizophrenia spectrum disorders and who were either undergoing strict antipsychotic monotherapy or were completely free of psychotropic drugs. The spectral power was compared between drug-free patients and patients using antipsychotic drugs. We also performed multiple regression analysis to evaluate the relationship between spectral power and the chlorpromazine equivalent daily dose of antipsychotics in all the patients. RESULTS: We included 31 monotherapy and 20 drug-free patients. Compared with drug-free patients, patients receiving antipsychotic drugs demonstrated significant increases in theta, alpha and beta power. When patients taking different types of antipsychotics were compared with drug-free patients, we found no significant change in any spectrum power for the aripiprazole or blonanserin groups. Patients taking risperidone demonstrated significant increases in alpha and beta power. Patients taking clozapine and olanzapine demonstrated significant slow wave increases. Multiple regression analysis revealed that the chlorpromazine equivalent dose was positively associated with theta power. CONCLUSION: Use of any antipsychotic drug by patients was associated with a dose-dependent increase in theta power. However, each type of antipsychotic demonstrated different spectral power changes.

Evaluation of Social Cognition Measures for Japanese Patients with Schizophrenia Using an Expert Panel and Modified Delphi Method.

Social cognition is strongly linked to social functioning outcomes, making it a promising treatment target. Because social cognition measures tend to be sensitive to linguistic and cultural differences, existing measures should be evaluated based on their relevance for Japanese populations. We aimed to establish an expert consensus on the use of social cognition measures in Japanese populations to provide grounds for clinical use and future treatment development. We assembled a panel of experts in the fields of schizophrenia, social psychology, social neuroscience, and developmental disorders. The panel engaged in a modified Delphi process to (1) affirm expert consensus on the definition of social cognition and its constituent domains, (2) determine criteria to evaluate measures, and (3) identify measures appropriate for Japanese patients with a view toward future quantitative research. Through two online voting rounds and two online video conferences, the panel agreed upon a definition and four-domain framework for social cognition consistent with recent literature. Evaluation criteria for measures included feasibility and tolerability, reliability, clinical effectiveness, validity, and international comparability. The panel finally identified nine promising measures, including one task originally developed in Japan. In conclusion, we established an expert consensus on key discussion points in social cognition and arrived at an expert-selected set of measures. We hope that this work facilitates the use of these measures in Japanese clinical scenarios. We plan to further examine these measures in a psychometric evaluation study.

Associations between cognitive impairment and illness awareness in fully remitted bipolar outpatients.

The euthymic state of bipolar disorder is often characterized by impaired cognitive function. In this investigation, we hypothesized that subjective cognitive function is impaired and illness awareness is inadequate and we further explored the associations among cognitive complaints, objective cognitive functions, and current illness awareness in Japanese patients. Twenty-seven patients in remission and 27 healthy subjects were recruited in this study. The Japanese version of the Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA) and Scale to Assess Unawareness in Mental Disorders (Japanese, SUMD-J) were used to assess each patient. All patients underwent neuropsychological tests for the assessment of objective cognitive functions. Only SUMD2.C (current awareness of the effects of medication) was significantly correlated with COBRA, and the objective cognitive assessments, Word Fluency Test and Stroop Test Reaction Time, represented significant correlations with SUMD1.C (current awareness of mental illness). In remitted bipolar outpatients, both the objective and subjective cognitive functions were found to be associated with illness awareness. However, subjective and objective cognitive functions differed in the related illness awareness subscales in fully remitted bipolar outpatients.

Impact of a Rice-Centered Diet on the Quality of Sleep in Association with Reduced Oxidative Stress: A Randomized, Open, Parallel-Group Clinical Trial.

Previously, we found that a Japanese diet was associated with psychological status, and a combination of rice and miso was related to mental and physical health. We hypothesized that the intake of a rice-based diet affected mental and physical health and aimed to investigate the consequences of a dietary intervention with rice. We conducted a randomized, open-label, parallel-group clinical trial that included 60 participants, who were randomly assigned to receive either rice-based meals or meals with other cereals for three daily meals over 2 months. The participants were surveyed for psychological status and biochemical changes. Sleep quality index scores showed significant improvement after the rice-based intervention. Additionally, blood oxidative stress levels were reduced in the rice-diet group compared with the no-rice-diet group. Although the molecular mechanisms should be investigated in detail, our findings suggest that controlling oxidative stress through the intake of a rice-centered diet may be key to improving sleep quality.

Associations between cognitive impairment and P300 mean amplitudes in individuals with bipolar disorder in remission.

Cognitive functions are often affected during the euthymic state of bipolar disorder (BD). In this study, we investigated the associations among cognitive complaints, objective cognitive functions, and the mean amplitudes of the P300 event-related potential (ERP) wave in individuals with BD. The study population comprised 33 individuals with BD who were in remission and was conducted at Hokkaido University Hospital, Sapporo, Japan. Cognitive complaints were assessed using the Japanese version of the tool named "cognitive complaints in bipolar disorder rating assessment (COBRA)", whereas objective cognitive functions were measured by neuropsychological tests. P300 mean amplitudes were investigated during two- and three-stimulus oddball tasks and showed significant correlations with neuropsychological test scores at all electrode locations, confirming that ERPs and objective cognitive tests that assessed attention and memory function tend to coincide; however, neither P300 amplitudes nor neuropsychological test scores were correlated with COBRA scores. ERPs most likely represent the neurophysiological basis for objective rather than subjective cognitive function in euthymic individuals. Thus, our results suggest that objective cognitive function is related more to P300 mean amplitude scores than subjective cognitive function in individuals with BD.

Effects of Palmaria palmata on lipid metabolism and glycemic control in participants with hypercholesterolemia in a randomized double-blind placebo-controlled trial.

BACKGROUND: Red algae have been reported to improve lipid and glucose metabolism in rats. We investigated the effects of Palmaria palmata (P. palmata), a red alga from northern Japan, on lipid metabolism and glycemic control in participants with hypercholesterolemia. METHODS: We conducted an 8-week, randomized, double-blind, placebo-controlled, and parallel-group comparison trial. The study enrolled Japanese participants with a serum low-density protein cholesterol (LDL-C) ≥120 mg/dL. The participants were randomly assigned to take either capsules containing P. palmata (2 g/day) or placebo capsules. The primary endpoint was the change in LDL-C from baseline to week 8 and the secondary endpoints were the changes in other lipid parameters and glycemic control. RESULTS: Of the 104 participants completed the study protocol. There were no significant differences in change in LDL-C, body mass index, waist circumference, or glycemic control between the two groups. However, serum triglyceride showed significantly greater improvement in women in the P. palmata group (-9.0 [-25.0, +5.0]) vs. those in the placebo group (-1.0 [-11.0, +19.0]; p = .03). CONCLUSIONS: The present study did not show that P. palmata had significant effect on serum LDL-C nor glycemic control, but hypertriglyceridemia could be ameliorated by administration of P. palmata in women.

Pilot Validation Study of the Japanese Translation of the Brief Negative Symptoms Scale (BNSS).

PURPOSE: The brief negative symptoms scale (BNSS) is a concise instrument used to assess negative symptoms of subjects with schizophrenia covering five domains of negative symptoms and is suitable for use in clinical, experimental, and epidemiological settings. The original and translated version of BNSS has thus far been shown to have adequate psychometric properties. This study aimed to examine internal consistency, inter-rater and test-retest reliability, discriminant and convergent validity, and factor structure of the Japanese version of BNSS. PATIENTS AND METHODS: The assessment was performed by 11 raters using interview videos of nine subjects. Reliability was calculated with Cronbach's alpha for internal consistency and intra class correlation coefficient (ICC) for inter-rater reliability. Pearson's correlation coefficients were calculated to estimate the test-retest reliability. In addition to BNSS, Scale for assessment of negative symptoms (SANS) and scale for assessment of positive symptoms (SAPS) was obtained to assess the convergent and discriminant validity. Factor structure was assessed using principle factor analysis. RESULTS: The Japanese BNSS showed excellent internal consistency (Cronbach's alpha=0.95), inter-rater reliability (intra class correlation coefficient=0.97), and test-retest reliability (r=0.94, p<0.001). The convergent validity shown by correlation with SANS total score (r=0.87, p<0.001) and discriminant validity shown by correlation with SAPS total score (r=0.17, p=-0.68) were also good. Principal factor analysis revealed a two-factor structure of BNSS, although the loading of each item differed from that in the literature. CONCLUSION: Our pilot study demonstrated that Japanese BNSS had good psychometric properties which were achieved with relatively brief training. Further studies with more subjects and raters with various backgrounds recruited from multiple sites are warranted.