Preliminary observations on the associations between sensory processing abnormalities and event-related potentials in adults with autism spectrum disorder.

Aim: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is thought to involve a variety of neurophysiological characteristics. Event-related potentials (ERPs) reflect cognitive functions in the brain's cognitive processing. In this study, we investigated differences in P300 and N100 of ERPs between ASD and typically developing groups and focused on the relationship between the components of ERPs and measures of autistic traits and sensory processing characteristics. Methods: ERPs were measured in 96 subjects in the ASD group and 62 subjects in the age- and sex-adjusted typically developing group. Correlations between each component and the scores of the Autism-Spectrum Quotient Japanese version (AQ-J) and the Adolescent and Adult Sensory Profile (AASP) were also evaluated. Results: The ASD group showed a significant decrease in the amplitude of N100 at C3. Furthermore, a negative correlation was found between lower amplitude at C3 of N100 and low registered sensory scores in both groups. Conclusion: Our findings imply that the N100 amplitude at C3 could be a potential indicator for examining the neurophysiological traits of ASD; however, these results should be interpreted with caution due to their preliminary nature. These tentative insights into sensory processing anomalies may be discernible in specific subsets of the ASD population, providing a foundation for future investigative pathways.

DPP8 Selective Inhibitor Tominostat as a Novel and Broad-Spectrum Anticancer Agent against Hematological Malignancies.

DPP8/9 inhibition induces either pyroptotic or apoptotic cell death in hematological malignancies. We previously reported that treatment with the DPP8/9 inhibitor 1G244 resulted in apoptotic cell death in myeloma, and our current study further evaluates the mechanism of action of 1G244 in different blood cancer cell lines. Specifically, 1G244 inhibited DPP9 to induce GSDMD-mediated-pyroptosis at low concentrations and inhibited DPP8 to cause caspase-3-mediated-apoptosis at high concentrations. HCK expression is necessary to induce susceptibility to pyroptosis but does not participate in the induction of apoptosis. To further characterize this DPP8-dependent broad-spectrum apoptosis induction effect, we evaluated the potential antineoplastic role for an analog of 1G244 with higher DPP8 selectivity, tominostat (also known as 12 m). In vitro studies demonstrated that the cytotoxic effect of 1G244 at high concentrations was enhanced in tominostat. Meanwhile, in vivo work showed tominostat exhibited antitumor activity that was more effective on a cell line sensitive to 1G244, and at higher doses, it was also effective on a cell line resistant to 1G244. Importantly, the weight loss morbidity associated with increasing doses of 1G244 was not observed with tominostat. These results suggest the possible development of novel drugs with antineoplastic activity against selected hematological malignancies by refining and increasing the DPP8 selectivity of tominostat.

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.

Automatic evaluation-feedback system for automated social skills training.

Social skills training (SST), which is a rehabilitation program for improving daily interpersonal communication, has been used for more than 40 years. Although such training's demand is increasing, its accessibility is limited due to the lack of experienced trainers. To tackle this issue, automated SST systems have been studied for years. An evaluation-feedback pipeline of social skills is a crucial component of an SST system. Unfortunately, research that considers both the evaluation and feedback parts of automation remains insufficient. In this paper, we collected and analyzed the characteristics of a human-human SST dataset that consisted of 19 healthy controls, 15 schizophreniacs, 16 autism spectrum disorder (ASD) participants, and 276 sessions with score labels of six clinical measures. From our analysis of this dataset, we developed an automated SST evaluation-feedback system under the supervision of professional, experienced SST trainers. We identified their preferred or most acceptable feedback methods by running a user-study on the following conditions: with/without recorded video of the role-plays of users and different amounts of positive and corrective feedback. We confirmed a reasonable performance of our social-skill-score estimation models as our system's evaluation part with a maximum Spearman's correlation coefficient of 0.68. For the feedback part, our user-study concluded that people understood more about what aspects they need to improve by watching recorded videos of their own performance. In terms of the amount of feedback, participants most preferred a 2-positive/1-corrective format. Since the average amount of feedback preferred by the participants nearly equaled that from experienced trainers in human-human SSTs, our result suggests the practical future possibilities of an automated evaluation-feedback system that complements SSTs done by professional trainers.

The Validation of Automated Social Skills Training in Members of the General Population Over 4 Weeks: Comparative Study.

BACKGROUND: Social skills training by human trainers is a well-established method of teaching appropriate social and communication skills and strengthening social self-efficacy. Specifically, human social skills training is a fundamental approach to teaching and learning the rules of social interaction. However, it is cost-ineffective and offers low accessibility, since the number of professional trainers is limited. A conversational agent is a system that can communicate with a human being in a natural language. We proposed to overcome the limitations of current social skills training with conversational agents. Our system is capable of speech recognition, response selection, and speech synthesis and can also generate nonverbal behaviors. We developed a system that incorporated automated social skills training that completely adheres to the training model of Bellack et al through a conversational agent. OBJECTIVE: This study aimed to validate the training effect of a conversational agent-based social skills training system in members of the general population during a 4-week training session. We compare 2 groups (with and without training) and hypothesize that the trained group's social skills will improve. Furthermore, this study sought to clarify the effect size for future larger-scale evaluations, including a much larger group of different social pathological phenomena. METHODS: For the experiment, 26 healthy Japanese participants were separated into 2 groups, where we hypothesized that group 1 (system trained) will make greater improvement than group 2 (nontrained). System training was done as a 4-week intervention where the participants visit the examination room every week. Each training session included social skills training with a conversational agent for 3 basic skills. We evaluated the training effect using questionnaires in pre- and posttraining evaluations. In addition to the questionnaires, we conducted a performance test that required the social cognition and expression of participants in new role-play scenarios. Blind ratings by third-party trainers were made by watching recorded role-play videos. A nonparametric Wilcoxson Rank Sum test was performed for each variable. Improvement between pre- and posttraining evaluations was used to compare the 2 groups. Moreover, we compared the statistical significance from the questionnaires and ratings between the 2 groups. RESULTS: Of the 26 recruited participants, 18 completed this experiment: 9 in group 1 and 9 in group 2. Those in group 1 achieved significant improvement in generalized self-efficacy (P=.02; effect size r=0.53). We also found a significant decrease in state anxiety presence (P=.04; r=0.49), measured by the State-Trait Anxiety Inventory (STAI). For ratings by third-party trainers, speech clarity was significantly strengthened in group 1 (P=.03; r=0.30). CONCLUSIONS: Our findings reveal the usefulness of the automated social skills training after a 4-week training period. This study confirms a large effect size between groups on generalized self-efficacy, state anxiety presence, and speech clarity.

Eye-movement analysis on facial expression for identifying children and adults with neurodevelopmental disorders.

Experienced psychiatrists identify people with autism spectrum disorder (ASD) and schizophrenia (Sz) through interviews based on diagnostic criteria, their responses, and various neuropsychological tests. To improve the clinical diagnosis of neurodevelopmental disorders such as ASD and Sz, the discovery of disorder-specific biomarkers and behavioral indicators with sufficient sensitivity is important. In recent years, studies have been conducted using machine learning to make more accurate predictions. Among various indicators, eye movement, which can be easily obtained, has attracted much attention and various studies have been conducted for ASD and Sz. Eye movement specificity during facial expression recognition has been studied extensively in the past, but modeling taking into account differences in specificity among facial expressions has not been conducted. In this paper, we propose a method to detect ASD or Sz from eye movement during the Facial Emotion Identification Test (FEIT) while considering differences in eye movement due to the facial expressions presented. We also confirm that weighting using the differences improves classification accuracy. Our data set sample consisted of 15 adults with ASD and Sz, 16 controls, and 15 children with ASD and 17 controls. Random forest was used to weight each test and classify the participants as control, ASD, or Sz. The most successful approach used heat maps and convolutional neural networks (CNN) for eye retention. This method classified Sz in adults with 64.5% accuracy, ASD in adults with up to 71.0% accuracy, and ASD in children with 66.7% accuracy. Classifying of ASD result was significantly different (p<.05) by the binomial test with chance rate. The results show a 10% and 16.7% improvement in accuracy, respectively, compared to a model that does not take facial expressions into account. In ASD, this indicates that modeling is effective, which weights the output of each image.

Analysis of Feedback Contents and Estimation of Subjective Scores in Social Skills Training.

This paper introduces our analysis results on the feedback contents of Social Skills Training and the consequences of automated score estimation of users' social skills with computational multimodal features. Although previous work showed the possibility of a computerized SST system as a clinical tool, its feedback strategies have not been well-investigated. We focused on the feedback content given by experienced SST trainers in human-human SST sessions to overcome this limitation. We analyzed the points mentioned by experienced SST trainers to determine where they focused during social skills evaluation. We calculated multimodal computational features from video and audio recordings inspired by the results and trained machine learning models for social skills evaluation using these features as input. We trained social skill score prediction models with the highest scores of 0.53 for correlation coefficient and 0.26 for R2. Clinical relevance- We described our automated social skills evaluation method with machine learning models toward a computerized SST system, which can be an additional option to boost the effect of SST by experienced trainers in the future.

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.

Evaluating Guanfacine Hydrochloride in the Treatment of Attention Deficit Hyperactivity Disorder (ADHD) in Adult Patients: Design, Development and Place in Therapy.

Attention-deficit/hyperactivity disorder (ADHD) is characterized by age-inappropriate and impairing levels of inattention, hyperactivity, or impulsivity, or a combination of these characteristics. It is estimated to affect around 4% of adults worldwide. In the past few decades, prescriptions for ADHD drugs (psychostimulants and non-psychostimulants) have increased significantly. However, the efficacy and safety of adult ADHD medications remains controversial. Guanfacine extended-release (GXR) is a non-psychostimulant ADHD drug that is a selective α2A-adrenergic receptor agonist, first approved for treatment of adult ADHD in Japan in June 2019. Our aim was to provide an overview of GXR pharmacology and review the studies on efficacy and safety that have been conducted in adults with ADHD. The beneficial actions of guanfacine are thought to be attributed to the strengthening of prefrontal cortical network connections, which regulate attention, emotion, and behavior via the activity at post-synaptic α2A receptors. Current evidence of GXR efficacy and safety suggests that GXR is an effective monotherapy treatment option for adults with ADHD.

A Randomized Controlled Trial Evaluating the Effectiveness of a Short Video-Based Educational Program for Improving Mental Health Literacy Among Schoolteachers.

Background: Mental illness-related stigma represents a barrier to seeking and receiving appropriate mental health care. Mental health literacy (MHL) can improve mental health knowledge, decrease stigmatizing attitudes, and enhance help-seeking behavior. Starting from 2022, mental illness-related education is due to be introduced in high schools in Japan. For this current situation, we conducted a parallel group, randomized controlled trial to examine the effectiveness of MHL educational program for teachers. Methods: The educational program described in this study comprised a 50-min video lesson designed to improve teachers' MHL. All participants were schoolteachers and were assigned either to an educational group or a waitlist control group. The assessment was conducted for both groups twice: first at baseline and then at 1-h post-intervention. The outcome measures for this trial were changes in knowledge, attitudes, and intended behaviors. Results: The educational group showed a greater improvement in knowledge regarding mental health than did the control group. The program was not effective for decreasing stigma toward mental illness. However, the educational group showed an increased intention to assist students with depression. Limitations: No long-term follow-up was implemented, which means the persistence of the educational program's effect could not be determined. Further, we could not report whether the program induced a change in teachers' behaviors regarding providing support for their students. Conclusions: The short video-based MHL educational program could improve schoolteachers' MHL and increase their intention to assist students. These findings can help in the development of similar educational programs in countries/regions experiencing similar issues regarding mental health.

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.

Analyzing Self-Efficacy and Summary Feedback in Automated Social Skills Training.

Goal: Although automated social skills training has been proposed to enhance human social skills, the following two aspects have not been adequately explored: what types of feedback are effective from virtual agents and the extent to which such systems enhance users' social self-efficacy. Methods: We developed an automated social skills trainer+ that follows human-based social skills training processes and implemented two types of feedback: 1) a summary of the displayed feedback and 2) feedback based on the results of their previous training. Using our developed system, we measured social self-efficacy, feedback evaluations, and the third-party ratings of participants between pre- and post-training as well as their social responsiveness scales. Results: Self-efficacy is significantly correlated to the social responsiveness scale (r = -0.72) and can be improved with our system (mean improvement of 0.68, p < 0.05). The participants highly rated the feedback that was compared to their past training (14 out of 16, p < 0.05) more than the cases without it and the displayed summary feedback (11 out of 16, p = 0.21) more than the verbal comments. Conclusions: Our system effectively summarized user feedback in terms of user self-efficacy and third-party ratings.

Associations of childhood experiences with event-related potentials in adults with autism spectrum disorder.

Childhood maltreatment is defined as experiencing of physical, emotional and sexual abuse and neglect in childhood. Maltreatment in childhood leads to substantial psychosocial problems later in life in the general population. Individuals with autism spectrum disorder (ASD) have a higher risk of experiencing stressful and traumatic events, such as maltreatment, during childhood. Although childhood maltreatment reportedly leads to psychosocial problems in adults with ASD, the biological associations between childhood experiences and brain function in this population remain understudied. Here, we evaluated the relationships between childhood experiences and event-related potential (ERP) components during the auditory odd-ball task in adults with ASD (N = 21) and typically developed (TD) individuals (N = 22). We found that the higher the severity of sexual abuse, the larger the amplitude of P300 at Fz, Cz, C3, and C4 in individuals with ASD. Conversely, the severity of child maltreatment was associated with P300 latency at Cz and C3 in TD individuals. Moreover, full IQ was significantly associated with the MMN amplitude at Fz, Cz, C3, and C4 in TD individuals. These findings provide the first evidence that ERPs could be used to study the impacts childhood experiences on the brain of individuals with ASD and that childhood sexual abuse has salient impacts on brain function in this population.

Delayed prefrontal hemodynamic response associated with suicide risk in autism spectrum disorder.

Adults diagnosed with Autism spectrum disorder (ASD) are at high risk of experiencing suicidality compared with other clinical groups. Recently, near-infrared spectroscopy (NIRS) studies have investigated the association between frontotemporal functional abnormalities and suicidality in patients with mood disorders. However, whether these prefrontal hemodynamic responses are associated with suicide vulnerability in individuals with ASD remains unclear. Here, we used 24-channel NIRS to examine the characteristics of prefrontal hemodynamic responses during a verbal fluency task in 20 adults with ASD and in age-, sex-, and intelligence quotient-matched healthy controls. In addition, we used Spearman's correlation analysis to identify the relationship between the time-course of prefrontal hemodynamic activation and the current suicide risk in patients with ASD. We found no significant differences between the verbal fluency task-induced prefrontal hemodynamic responses in the ASD vs. control group. However, we found a significant positive correlation between the current suicide risk score and the time-course of prefrontal hemodynamic activation in the ASD group. Thus, the 24-channel NIRS system appears to be useful in assessing suicide risk in individuals with ASD.

Influence of Self-Esteem and Psychiatric Diagnosis on Health-Related Quality of Life in Children and Adolescents with School Refusal Behavior.

BACKGROUND: School refusal behavior (SRB), which is the refusal to attend or remain in school, has been associated with emotional, psychological, and other behavioral problems, as well as a lower health-related quality of life (HRQOL). However, the effects of self-esteem and a psychiatric diagnosis in students with SRB on HRQOL are not yet known. Understanding these relationships could help to develop more effective therapeutic interventions. METHODS: A total of 175 young people (aged 8-18 years old) who visited our medical centers and outpatient clinics participated in the study. This comprised the SRB group (n = 70) and an age- and sex-matched control group (n = 105). Information about any psychiatric diagnosis was collected from medical records, HRQOL was measured using the J-KIDSCREEN-52, SRB was assessed using the School Refusal Assessment Scale-Revised for Japanese Attendance at School, self-esteem was measured using the Rosenberg Self-Esteem Scale, children's mental health status was measured using the Strengths and Difficulties Questionnaire, and social support was measured using the Oslo 3-item Social Support Scale. We performed between-group comparisons and multiple regression analysis. RESULTS: The SRB had a significantly lower HRQOL than the control group in several of the KIDSCREEN-52 dimensions. In the SRB group, 35.7% had chronic disease and 35.7% of their parents had health problems and were receiving treatment. The multiple regression analysis revealed that, within the SRB group, a psychiatric diagnosis was associated with a lower HRQOL. However, this was not the case for a diagnosis of autistic spectrum disorder. Self-esteem positively affected HRQOL in six dimensions of the KIDSCREEN-52 within the SRB group. CONCLUSION: Our results could inform the development of support strategies for young people with SRB. Namely, support that enhances self-esteem could be used to increase HRQOL in young people with SRB. Furthermore, the presence of psychiatric disorders should be assessed as early as possible.

Reduced prefrontal hemodynamic response in pediatric autism spectrum disorder measured with near-infrared spectroscopy.

BACKGROUND: Functional neuroimaging studies suggest that prefrontal cortex dysfunction is present in people with autism spectrum disorder (ASD). Near-infrared spectroscopy is a noninvasive optical tool for examining oxygenation and hemodynamic changes in the cerebral cortex by measuring changes in oxygenated hemoglobin. METHODS: Twelve drug-naïve male participants, aged 7-15 years and diagnosed with ASD according to DSM-5 criteria, and 12 age- and intelligence quotient (IQ)-matched healthy control males participated in the present study after giving informed consent. Relative concentrations of oxyhemoglobin were measured with frontal probes every 0.1 s during the Stroop color-word task, using 24-channel near-infrared spectroscopy. RESULTS: Oxyhemoglobin changes during the Stroop color-word task in the ASD group were significantly smaller than those in the control group at channels 12 and 13, located over the dorsolateral prefrontal cortex (FDR-corrected P: 0.0021-0.0063). CONCLUSION: The results suggest that male children with ASD have reduced prefrontal hemodynamic responses, measured with near-infrared spectroscopy.

Guanfacine monotherapy for ADHD/ASD comorbid with Tourette syndrome: a case report.

BACKGROUND: Patients with attention deficit/hyperactivity disorder (ADHD) often experience comorbid conditions, such as autism spectrum disorder (ASD) and Tourette syndrome (TS). Although pharmacotherapies are effective for treating ADHD, they are likely to elicit a variety of adverse effects. It is, thus, important to select an effective and well-tolerated pharmacotherapeutic treatment for patients with ADHD/ASD comorbid with TS. CASE PRESENTATION: We report the case of a 10-year-old boy with ADHD/ASD comorbid with TS who was treated with guanfacine (GUAN). He experienced several side effects of atomoxetine (ATX) and methylphenidate (MPH) before being treated with GUAN. In the presented case, symptoms of ADHD as well as tic symptoms were improved by treatment with GUAN. CONCLUSION: GUAN might be effective and well tolerated in the treatment of patients with ADHD/ASD comorbid with TS who experience side effects of ATX and MPH.

How does Hsp90 function in RNAi-dependent heterochromatin assembly?

Heat-shock protein 90 (Hsp90) was recently identified as a silencing factor required for RNA interference (RNAi)-dependent heterochromatin assembly in the fission yeast Schizosaccharomyces pombe. As Hsp90 is known to contribute to the formation of small RNA-containing effector complexes, it would be expected that Hsp90 is also involved in the RNAi pathway in fission yeast. However, upon investigation, we found it very difficult to determine how Hsp90 modulates RNAi-dependent heterochromatin assembly in the cell. A lack of detectable small interfering RNAs in hsp90 mutant cells prevented us from examining the role of Hsp90 in the siRNA loading in the cell. In addition, deletion of genes encoding co-chaperones for Hsp90 appears not to affect RNAi-dependent pericentromeric silencing. One possible approach for elucidating the role of Hsp90 in RNAi-dependent heterochromatin assembly is the use of forward genetic screens to identify novel factors linking Hsp90 with other known RNAi factors. Here, we discuss the benefits of conducting further screenings and present some technical hints to help identify new factors.