Electrode montage for transcranial direct current stimulation governs its effect on symptoms and functionality in schizophrenia.

Backgrounds: Patients with schizophrenia suffer from cognitive impairment that worsens real-world functional outcomes. We previously reported that multi-session transcranial direct current stimulation (tDCS) delivered to the left dorsolateral prefrontal cortex (DLPFC) improved daily living skills, while stimulation on the left superior temporal sulcus (STS) enhanced performance on a test of social cognition in these patients. To examine the region-dependent influence of tDCS on daily-living skills, neurocognition, and psychotic symptoms, this study compared effects of anodal stimulation targeting either of these two brain areas in patients with schizophrenia. Methods: Data were collected from open-label, single-arm trials with anodal electrodes placed over the left DLPFC (N = 28) or STS (N = 15). Daily-living skills, neurocognition, and psychotic symptoms were measured with the UCSD performance-based skills assessment-brief (UPSA-B), Brief Assessment of Cognition in Schizophrenia (BACS), and Positive and Negative Syndrome Scale (PANSS), respectively. After baseline evaluation, tDCS (2 mA × 20 min) were delivered two times per day for 5 consecutive days. One month after the final stimulation, clinical assessments were repeated. Results: Performance on the UPSA-B was significantly improved in patients who received anodal tDCS at the left DLPFC (d = 0.70, p < 0.001), while this effect was absent in patients with anodal electrodes placed on the left STS (d = 0.02, p = 0.939). Significant improvement was also observed for scores on the BACS with anodal tDCS delivered to the DLPFC (d = 0.49, p < 0.001); however, such neurocognitive enhancement was absent when the STS was stimulated (d = 0.05, p = 0.646). Both methods of anodal stimulation showed a significant improvement of General Psychopathology scores on the PANSS (DLPFC, d = 0.50, p = 0.027; STS, d = 0.44, p = 0.001). Conclusion: These results indicate the importance of selecting brain regions as a target for tDCS according to clinical features of individual patients. Anodal stimulation of the left DLPFC may be advantageous in improving higher level functional outcomes in patients with schizophrenia. Trial registration: These studies were registered within the University hospital Medical Information Network Clinical Trials Registry [(24), UMIN000015953], and the Japan Registry of Clinical Trials [(28), jRCTs032180026].

Transcranial Direct Current Stimulation on the Left Superior Temporal Sulcus Improves Social Cognition in Schizophrenia: An Open-Label Study.

Background: Patients with schizophrenia show impairments of social cognition, which cause poor real-world functional outcomes. Transcranial direct current stimulation (tDCS) delivered to frontal brain areas has been shown to partially alleviate disturbances of social cognition. In this study, we aimed to determine whether multisession tDCS targeting the superior temporal sulcus (STS), a brain region closely related to social cognition, would improve social cognitive performance in patients with schizophrenia. Methods: This was an open-label, single-arm trial to investigate the benefits and safety of multisession tDCS over the left STS. Fifteen patients received tDCS (2 mA × 20 min) two times per day for 5 consecutive days. Anodal and cathodal electrodes were placed over the left STS and right supraorbital regions, respectively. Assessments with the Social Cognition Screening Questionnaire (SCSQ), the Hinting Task (HT), the Brief Assessment of Cognition in Schizophrenia (BACS), and the Positive and Negative Syndrome Scale (PANSS) were conducted at baseline and 1 month after the final stimulation. Results: Significant improvements were found on theory of mind, as measured using the SCSQ (d = 0.53) and the HT (d = 0.49). These changes on social cognition were not correlated with those of neurocognition, as measured using the BACS or psychotic symptoms, as measured using the PANSS. There were no adverse events of serious/moderate levels attributable to tDCS. Conclusion: These results suggest that administration of multisession tDCS with anode stimulation targeting the left STS provides a novel strategy to improve functional outcomes in patients with schizophrenia. Ethics Statement: The National Center of Neurology and Psychiatry Clinical Research Review Board (CRB3180006) approved this study. Trial Registration: This study was registered within the Japan Registry of Clinical Trials (jRCTs032180026).

Emotional and behavioral problems in Japanese preschool children with subthreshold autistic traits: findings from a community-based sample.

BACKGROUND: Recently, there has been a growing recognition that autistic traits exist along a continuum beyond diagnostic categories and that even subclinical symptoms may be associated with an increased risk for the psychosocial well-being and mental health of children. However, as yet, there has been little research on whether preschool children with autism spectrum disorder (ASD) symptoms, who do not meet the diagnostic criteria for ASD, are more likely to experience difficulties. To address this deficit this study examined whether young children with subthreshold autistic traits have an increased risk for emotional/behavioral difficulties. METHODS: Data were analyzed from 1057 Japanese preschool children aged 5-years old collected during the first wave of the Tama Children's Survey (TCS) cohort study. Parent-reported autistic traits were assessed with the Social Responsiveness Scale (SRS), while they provided information on their child's emotional/behavioral problems using the Strengths and Difficulties Questionnaire (SDQ). Logistic regression analysis was used to examine associations. RESULTS: Preschool children with mild-to-moderate autistic traits, corresponding to subclinical autism were significantly more likely to score above the clinical thresholds for emotional/behavioral problems compared to children with fewer autistic traits. Follow-up diagnostic assessments and analyses of 72 children from the cohort confirmed these findings and showed that these children with subthreshold autistic traits also had a significantly lower intelligence quotient (IQ) as measured by the Wechsler Preschool and Primary Scale of Intelligence (WPPSI). CONCLUSIONS: Although subthreshold autistic traits are difficult to define due to the sometimes vague border between typical and atypical development, there may be a large number of preschool children with subthreshold autistic traits, who may have an increased risk for a variety of different emotional/behavioral difficulties as well as lower cognitive functioning.

Efficacy and Safety of Multi-Session Transcranial Direct Current Stimulation on Social Cognition in Schizophrenia: A Study Protocol for an Open-Label, Single-Arm Trial.

BACKGROUNDS: Social cognition is defined as the mental operations underlying social behavior. Patients with schizophrenia elicit impairments of social cognition, which is linked to poor real-world functional outcomes. In a previous study, transcranial direct current stimulation (tDCS) improved emotional recognition, a domain of social cognition, in patients with schizophrenia. However, since social cognition was only minimally improved by tDCS when administered on frontal brain areas, investigations on the effect of tDCS on other cortical sites more directly related to social cognition are needed. Therefore, we present a study protocol to determine whether multi-session tDCS on superior temporal sulcus (STS) would improve social cognition deficits of schizophrenia. METHODS: This is an open-label, single-arm trial, whose objective is to investigate the efficacy and safety of multi-session tDCS over the left STS to improve social cognition in patients with schizophrenia. The primary outcome measure will be the Social Cognition Screening Questionnaire. Neurocognition, functional capacity, and psychotic symptoms will also be evaluated by the Brief Assessment of Cognition in Schizophrenia, UCSD Performance-Based Skills Assessment-Brief, and Positive and Negative Syndrome Scale, respectively. Data will be collected at baseline, and 4 weeks after the end of intervention. If social cognition is improved in patients with schizophrenia by tDCS based on this protocol, we may plan randomized controlled trial.

Facilitative Effects of Transcranial Direct Current Stimulation on Semantic Memory Examined by Text-Mining Analysis in Patients With Schizophrenia.

Background: Beneficial effects of transcranial direct current stimulation (tDCS) are relevant to cognition and functional capacity, in addition to psychiatric symptoms in patients with schizophrenia. However, whether tDCS would improve higher-order cognition, e.g., semantic memory organization, has remained unclear. Recently, text-mining analyses have been shown to reveal semantic memory. The purpose of the current study was to determine whether tDCS would improve semantic memory, as evaluated by text-mining analyses of category fluency data, in patients with schizophrenia. Methods: Twenty-eight patients entered the study. Cognitive assessment including the category fluency task was conducted at baseline (before tDCS treatment) and 1 month after t administration of tDCS (2 mA × 20 min, twice per day) for 5 days, according to our previous study. The category fluency data were also obtained from 335 healthy control subjects. The verbal outputs (i.e., animal names) from the category fluency task were submitted to singular valued decomposition (SVD) analysis. Semantic memory structures were estimated by calculating inter-item cosines (i.e., similarities) among animal names frequently produced in the category fluency task. Data were analyzed longitudinally and cross-sectionally to compare the semantic structure within the patient group (i.e., baseline vs. follow-up) and between groups (patients vs. healthy controls). In the former, semantic associations for frequent items were compared in the form of cosine profiles, while in the latter, the difference in the magnitude of the correlations for inter-item cosines between healthy controls and patients (baseline, follow-up) was examined. Results: Cosine profiles in the patient group became more cluster-based (i.e., pet, carnivores, and herbivores) at follow-up compared to those at baseline, yielding higher cosines within subcategories. The correlational coefficient of inter-item cosines between healthy controls and patients was significantly greater at follow-up compared to baseline; semantic associations in patients approached the normality status after multi-session tDCS. Conclusions: To our knowledge, this is the first study to demonstrate the facilitative effect of tDCS on semantic memory organization in patients with schizophrenia. Text-mining analysis was indicated to effectively evaluate semantic memory structures in patients with psychiatric disorders.

Social Cognition Deficits as a Target of Early Intervention for Psychoses: A Systematic Review.

Backgrounds: Social cognition deficits are a core feature of schizophrenia and deteriorate functionality of patients. However, evidence is sparse for the treatment effect on social cognition impairments in the early stage of psychosis. Here, we provide a systematic review of the literature on social cognitive impairment in early psychosis in relation to its intervention. Methods: A literature search was conducted on English articles identified by Web of Science and PubMed databases, according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Results: Five papers met the inclusion criteria. Results from two studies of cognitive training and one study of modafinil indicate positive results regarding social cognition outcomes in patients with early psychosis. On the other hand, two studies with oxytocin and modafinil did not suggest such effects. Conclusions: Further research is warranted to explore the benefit of early intervention into disturbances of social cognition in psychoses.

Electrophysiological Evidence in Schizophrenia in Relation to Treatment Response.

Several domains of cognitive function, e.g., verbal memory, information processing, fluency, attention, and executive function are impaired in patients with schizophrenia. Cognitive impairments in schizophrenia have attracted interests as a treatment target, because they are considered to greatly affect functional outcome. Electrophysiological markers, including electroencephalogram (EEG), particularly, event-related potentials, have contributed to psychiatric research and clinical practice. In this review, we provide a summary of studies relating electrophysiological findings to cognitive performance in schizophrenia. Electrophysiological indices may provide an objective marker of cognitive processes, contributing to the development of effective interventions to improve cognitive and social outcomes. Further efforts to understand biological mechanisms of cognitive disturbances, and develop effective therapeutics are warranted.

The effect of transcranial direct current stimulation on psychotic symptoms of schizophrenia is associated with oxy-hemoglobin concentrations in the brain as measured by near-infrared spectroscopy: A pilot study.

Transcranial direct current stimulation (tDCS) has been shown to be effective in treating some of the symptoms of schizophrenia. In the current study, we sought to determine whether oxy-hemoglobin ([oxy-Hb]), measured by near-infrared spectroscopy (NIRS), is associated with effects of transcranial direct current stimulation (tDCS) on psychotic symptoms of schizophrenia. Twenty-six patients underwent tDCS (2 mA × 20 min) two times per day for five consecutive days. The anodal electrode was placed over the left dorsolateral prefrontal cortex while the cathodal electrode was placed over the right supraorbital region. One month after the last administration of tDCS, positive, but not negative symptoms, evaluated by the Positive and Negative Syndrome Scale (PANSS), were significantly improved. At baseline, regional [oxy-Hb] concentrations in the brain were measured by a 52-channel NIRS instrument. Significant negative correlation was demonstrated between [oxy-Hb] concentrations of left temporoparietal regions throughout verbal fluency tasks vs. changes of PANSS Positive and Negative subscale scores. This is the first study to demonstrate the correlation between the response of neural activity to cognitive tasks at baseline and the ability of tDCS to improve positive and negative psychotic symptoms. Our observations suggest that NIRS provides a marker to predict the response to treatment with tDCS in schizophrenia.

Electrophysiological Markers of Motivation in Psychosis.

Motivation is associated with electrophysiological markers, such as awake state delta oscillation and frontal alpha asymmetry, as well as event-related potentials, such as error-related negativity, feedback-related negativity, and prepulse inhibition. These indicators provide an objective measure of motivational deficits in psychiatric conditions, and response to treatment. Also, these modalities of brain activities are drawing attention as a target of neurofeedback training. The aim of this article is to provide a brief overview on electrophysiological findings relevant to the understanding of the mechanisms underlying impaired motivation in psychiatric disorders and clinical practice.

Effect of Transcranial Direct Current Stimulation on Functional Capacity in Schizophrenia: A Study Protocol for a Randomized Controlled Trial.

Schizophrenia patients elicit a wide range of psychopathology, including psychotic symptoms, mood symptoms, and cognitive impairment. Functional capacity is defined as the ability to perform everyday living skills, which is linked to cognition and real-world functional outcome. In a previous open trial, we demonstrated that transcranial direct current stimulation (tDCS), one of the neuromodulation methods, improved cognition and functional capacity in 28 patients with schizophrenia. However, since it was a pilot study, a controlled trial is needed. Therefore, we present a study protocol for a randomized controlled trial designed to evaluate the effect of tDCS on functional capacity in patients with schizophrenia. This is a two-arm, parallel-design, randomized controlled trial, in which patients and assessors will be blinded. Patients meeting DSM-5 criteria for schizophrenia will be enrolled and randomized to receive either active or sham stimulation (with 10 sessions in five consecutive days). Functional capacity will be evaluated by the UCSD Performance-based Skills Assessment-Brief as primary outcome. Cognition, as measured by the Brief Assessment of Cognition in Schizophrenia, and psychotic symptoms, as measured by the Positive and Negative Syndrome Scale, will also be evaluated. Data will be collected at baseline, immediately after the last stimulation, and 1 and 2 months thereafter. If active stimulation elicits greater effects compared with those of sham stimulation, it may add to the efforts to improve functional outcomes by neuromodulation in patients with schizophrenia. TRIAL REGISTRATION: UMIN000028224; https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000032305.

Possible Facilitative Effects of Repeated Anodal Transcranial Direct Current Stimulation on Functional Outcome 1 Month Later in Schizophrenia: An Open Trial.

Recent research on neuromodulation techniques, such as transcranial direct current stimulation (tDCS), for the treatment of schizophrenia has mainly focused on psychotic symptoms. We aimed to determine whether repetitive tDCS is efficacious in improving determinants of outcome, such as cognitive function, daily living skills, and depressive mood in patients with schizophrenia. Twenty-eight patients underwent tDCS (2 mA × 20 min) two times per day for 5 consecutive days. The anodal electrode was placed over the left dorsolateral prefrontal cortex while the cathodal electrode was placed over the right supraorbital region. One month after the last stimulation, there was a significant improvement on cognitive function, measured by the brief assessment of cognition in schizophrenia (d = 0.49). Significant effects were also shown on daily living skills (functional capacity), measured by the UCSD performance-based skills assessment-brief (d = 0.70). Depressive symptoms, measured by the Calgary depression rating scale, as well as psychotic symptoms measured by on the positive and negative syndrome scale positive and general psychopathology subscales also responded to the treatment (d = 0.38, d = 0.48, and d = 0.50, respectively). This is the first study to suggest that tDCS with the anodal electrode on the left prefrontal cortex improves functional capacity and depressive symptoms in patients with schizophrenia. These results may add to the concept that tDCS provides a strategy to enhance functional outcomes in patients with schizophrenia. TRIAL REGISTRATION: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000018556, UMIN000015953.

Verbal Memory Impairment in Patients with Subsyndromal Bipolar Disorder.

BACKGROUNDS: Several domains of cognitive function, including learning memory and executive function, are impaired in mood disorders. Also, the relationship between disturbances of these two cognitive domains has been suggested. In line with the recent initiative to establish a standard measure of cognitive decline in bipolar disorder, the present study was conducted to (1) test the criterion-related validity and test-retest reliability of the California Verbal Learning Test (CVLT)-II Japanese version, and (2) determine if type of word learning tasks (i.e., with or without a category structure) affects severity of verbal memory deficits in patients with subsyndromal bipolar disorder. METHODS: Thirty-six patients with bipolar disorder with mild symptoms and 42 healthy volunteers participated in the study. We first compared effect sizes for memory deficits in patients among the CVLT-II, Brief Assessment of Cognition in Schizophrenia (BACS), and Hopkins Verbal Memory Tests-Revised (HVLT-R). We next evaluated the correlations between scores of the CVLT-II vs. those of the BACS and HVLT-R. Bipolar patients were re-assessed with the same (standard) or alternate forms of the CVLT-II and HVLT-R 1 month later. RESULTS: Scores on the CVLT-II 1-5 Free Recall and Long-delay Free Recall, as well as the HVLT-R Immediate Recall, but not the BACS List Learning were significantly lower for patients compared to control subjects. The effect sizes for cognitive decline due to the illness were comparable when measured by the CVLT-II and HVLT-R, ranging from 0.5 to 0.6. CVLT-II scores were significantly correlated with those of the HVLT-R and BACS. Test-retest reliability of the CVLT-II was acceptable, and no significant practice effect was observed when the alternate form was used. There was no consistent relationship between mood symptoms and performance on the CVLT-II. CONCLUSION: These results suggest the CVLT-II Japanese version is able to discriminate between bipolar disorder patients and healthy controls with good sensitivity and validity. Data in this study also indicate that the degree of verbal memory deficits in bipolar disorder may be influenced by memory organizational strategy.