The two-back task leads to activity in the left dorsolateral prefrontal cortex in schizophrenia patients with predominant negative symptoms: a fNIRS study and its implication for tDCS.

Transcranial direct current stimulation (tDCS) over left dorsolateral prefrontal cortex (DLPFC) has shown some potential as an adjunctive intervention for ameliorating negative symptoms of schizophrenia, but its efficacy requires optimization. Recently, 'functional targeting' of stimulation holds promise for advancing tDCS efficacy by coupling tDCS with a cognitive task where the target brain regions are activated by that task and further specifically polarized by tDCS.The study used 48-channel functional near infra-red spectroscopy (fNIRS) aiming to determine a cognitive task that can effectively induce a cortical activation of the left DLPFC in schizophrenia patients with predominant negative symptoms before running a tDCS trial. Sixty schizophrenia patients with predominant negative symptoms completed measures of clinical and psychosocial functioning characteristics and assessments across cognitive domains. Hemodynamic changes during n-back working memory tasks with different cognitive loads (1-back and 2-back) and verbal fluency test (VFT) were measured using fNIRS. For n-back tasks, greater signal changes were found when the task required elevated cognitive load. One sample t-test revealed that only 2-back task elicited significant activation in left DLPFC (t = 4.23, FDR-corrected p = 0.0007). During VFT, patients failed to show significant task-related activity in left DLPFC (one sample t-test, t = -0.25, FDR-corrected p > 0.05). Our study implies that 2-back task can effectively activate left DLPFC in schizophrenia patients with predominant negative symptoms. This neurophysiologically-validated task is considered highly potential to be executed in conjunction with high-definition tDCS for "functional targeting" of the left DLPFC to treat negative symptoms in a double-blind randomized sham-control trial, registered on ClinicalTrials.gov Registry (ID: NCT05582980).

Effects of online high-definition transcranial direct current stimulation over left dorsolateral prefrontal cortex on predominant negative symptoms and EEG functional connectivity in patients with schizophrenia: a randomized, double-blind, controlled trial.

AIMS: Schizophrenia, a debilitating mental disorder, is characterized by persistent negative symptoms such as avolition and anhedonia. Currently, there are no effective treatments available for these symptoms. Thus, our study aims to assess the efficacy of online high-definition transcranial direct current stimulation (online HD-tDCS) in addressing the negative symptoms of schizophrenia, utilizing a double-blind, randomized, sham-controlled trial design. METHODS: Fifty-nine patients with schizophrenia were randomized to receive either active HD-tDCS or sham stimulation, targeting the left dorsolateral prefrontal cortex. Outcomes were measured by changes in the Positive and Negative Syndrome Scale Factor Score for Negative Symptom (PANSS-FSNS). Exact low-resolution electromagnetic tomography was used to assess the functional connectivity. RESULTS: All 59 participants, including 50.84% females with an average age of 43.36 years, completed the trial. In the intention-to-treat analysis, patients receiving active HD-tDCS showed greater improvement in PANSS-FSNS scores compared to those receiving the sham procedure. The differences were 2.34 (95% confidence interval [CI], 1.28-3.40), 4.28 (95% CI, 2.93-5.62), and 4.91 (95% CI, 3.29-6.52) after the intervention, as well as at 1-week and 1-month follow-ups, respectively. A tingling sensation on the scalp was more common in the active group (63.3%) compared to the sham group (10.3%). Additionally, HD-tDCS was associated with a decrease in delta-band connectivity within the default mode network. CONCLUSIONS: High-definition transcranial direct current stimulation was effective and safe in ameliorating negative symptoms in patients with schizophrenia when combined with online functional targeting.

Identification of Schizophrenia Susceptibility Loci in the Urban Taiwanese Population.

Background and Objectives: Genomic studies have identified several SNP loci associated with schizophrenia in East Asian populations. Environmental factors, particularly urbanization, play a significant role in schizophrenia development. This study aimed to identify schizophrenia susceptibility loci and characterize their biological functions and molecular pathways in Taiwanese urban Han individuals. Materials and Methods: Participants with schizophrenia were recruited from the Taiwan Precision Medicine Initiative at Tri-Service General Hospital. Genotype-phenotype association analysis was performed, with significant variants annotated and analyzed for functional relevance. Results: A total of 137 schizophrenia patients and 26,129 controls were enrolled. Ten significant variants (p < 1 × 10-5) and 15 expressed genes were identified, including rs1010840 (SOWAHC and RGPD6), rs11083963 (TRPM4), rs11619878 (LINC00355 and LINC01052), rs117010638 (AGBL1 and MIR548AP), rs1170702 (LINC01680 and LINC01720), rs12028521 (KAZN and PRDM2), rs12859097 (DMD), rs1556812 (ATP11A), rs78144262 (LINC00977), and rs9997349 (ENPEP). These variants and associated genes are involved in immune response, blood pressure regulation, muscle function, and the cytoskeleton. Conclusions: Identified variants and associated genes suggest a potential genetic predisposition to schizophrenia in the Taiwanese urban Han population, highlighting the importance of potential comorbidities, considering population-specific genetic and environmental interactions.

Resting-State EEG Connectivity at High-Frequency Bands and Attentional Performance Dysfunction in Stabilized Schizophrenia Patients.

Background and Objectives: Attentional dysfunction has long been viewed as one of the fundamental underlying cognitive deficits in schizophrenia. There is an urgent need to understand its neural underpinning and develop effective treatments. In the process of attention, neural oscillation has a central role in filtering information and allocating resources to either stimulus-driven or goal-relevant objects. Here, we asked if resting-state EEG connectivity correlated with attentional performance in schizophrenia patients. Materials and Methods: Resting-state EEG recordings were obtained from 72 stabilized patients with schizophrenia. Lagged phase synchronization (LPS) was used to measure whole-brain source-based functional connectivity between 84 intra-cortical current sources determined by eLORETA (exact low-resolution brain electromagnetic tomography) for five frequencies. The Conners' Continuous Performance Test-II (CPT-II) was administered for evaluating attentional performance. Linear regression with a non-parametric permutation randomization procedure was used to examine the correlations between the whole-brain functional connectivity and the CPT-II measures. Results: Greater beta-band right hemispheric fusiform gyrus (FG)-lingual gyrus (LG) functional connectivity predicted higher CPT-II variability scores (r = 0.44, p < 0.05, corrected), accounting for 19.5% of variance in the CPT-II VAR score. Greater gamma-band right hemispheric functional connectivity between the cuneus (Cu) and transverse temporal gyrus (TTG) and between Cu and the superior temporal gyrus (STG) predicted higher CPT-II hit reaction time (HRT) scores (both r = 0.50, p < 0.05, corrected), accounting for 24.6% and 25.1% of variance in the CPT-II HRT score, respectively. Greater gamma-band right hemispheric Cu-TTG functional connectivity predicted higher CPT-II HRT standard error (HRTSE) scores (r = 0.54, p < 0.05, corrected), accounting for 28.7% of variance in the CPT-II HRTSE score. Conclusions: Our study indicated that increased right hemispheric resting-state EEG functional connectivity at high frequencies was correlated with poorer focused attention in schizophrenia patients. If replicated, novel approaches to modulate these networks may yield selective, potent interventions for improving attention deficits in schizophrenia.

The Effects of Bi-Anodal tDCS Over the Prefrontal Cortex Regions With Extracephalic Reference Placement on Insight Levels and Cardio-Respiratory and Autonomic Functions in Schizophrenia Patients and Exploratory Biomarker Analyses for Treatment Response.

BACKGROUND: We previously showed the efficacy of bi-anodal transcranial direct current stimulation (tDCS) over the prefrontal cortex (PFC) regions with extracephalic reference placement in improving negative symptoms in schizophrenia. In this ancillary investigation, the effects of this intervention on insight levels, other clinical outcomes, and cardio-respiratory and autonomic functions were examined and the potential of biomarkers for treatment response was explored. METHODS: Schizophrenia patients were randomly allocated to receive 10 sessions of bi-anodal tDCS over the PFC regions with extracephalic reference placement (2 mA, 20 minutes, twice daily for 5 weeks) or sham stimulation. We examined, in 60 patients at baseline, immediately after stimulation and at follow-up visits, the insight levels, other clinical outcomes, blood pressure, respiratory rate, heart rate, and heart rate variability. RESULTS: Insight levels as assessed by the abbreviated version of the Scale to Assess Unawareness in Mental Disorder in schizophrenia awareness of the disease, positive and negative symptoms dimensions, and beliefs about medication compliance as assessed by Medication Adherence Rating Scale were significantly enhanced by active stimulation relative to sham. No effects were observed on cognitive insight, other clinical outcomes, or cardio-respiratory and autonomic functions. Heart rate variability indices as biomarkers were not associated with the clinical response to the intervention. CONCLUSIONS: Our results provide evidence for bi-anodal tDCS over the PFC regions with extracephalic reference placement in heightening the levels of insight into the disease and symptoms, as well as beliefs about medication compliance in schizophrenia, without impacting other clinical outcomes and cardio-respiratory/autonomic functions.

Eating disorders and the risk of esophageal and stomach cancers-A nationwide, population-based cohort study in Taiwan.

BACKGROUND: Previous studies have shown elevated cancer risk in anorexia nervosa but the literature on other eating disorders (EDs) is scarce. This study aimed to investigate the association between all EDs and esophageal, stomach, and other cancers. METHODS: We used a retrospective cohort design, based on a two-million randomized longitudinal health insurance dataset, a sub-dataset of Taiwan's National Health Insurance Research Database. From all the potential participants aged 20 years or more, a total of 6,628 participants were enrolled, including 1,657 patients with EDs, with sex-, age-, and indexed date-matched (1:3) 4,971 controls. Each participant was individually tracked from 2000 to 2015 to identify incident cases of cancers, including esophageal cancer (EC), stomach cancer (SC), and all other cancers (AOC). The multivariate Cox proportional hazards model was employed to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between EDs and cancer. RESULTS: Of the total 6,628 enrollees, 222 in 1,657 individuals with EDs and 810 in the 4,971 non-ED control individuals developed cancer (1,262.40 vs. 1,472.15 per 100,000 person-years), and the Kaplan-Meier survival analysis was not statistically significant (log-rank, p = .324). However, after adjusting for covariates, the risk of EC and SC among the individuals with an ED was significantly higher, with adjusted HRs of 5.32 (95% CI: 1.07-26.49, p < .001) and 4.61 (95% CI: 1.91-11.14, p < .001), respectively. EDs were not associated with other cancers. CONCLUSIONS: This study provides evidence for the association between EDs and the risk for EC and SC. Further research on mechanisms and prevention is therefore needed.

Attenuated vagally-mediated heart rate variability at rest and in response to postural maneuvers in patients with generalized anxiety disorder.

BACKGROUND: Altered heart rate variability (HRV), an index of autonomic nervous system function, has been reported in generalized anxiety disorder (GAD), but the results have been mixed. Thus, the present study, using a large sample size and better methodology, aims to examine whether GAD is associated with impaired HRV, both at rest and in response to posture challenges. METHODS: In total, 1832 participants were recruited in this study, consisting of 682 patients with GAD (including 326 drug- and comorbidity-free GAD patients) and 1150 healthy controls. Short-term HRV was measured during the supine-standing-supine test (5-min per position). Propensity score matching (PSM), a relatively novel method, was used to control for potential confounders. RESULTS: After PSM algorithm, drug- and comorbidity-free GAD patients had reductions in resting (baseline) high-frequency power (HF), an index for parasympathetic modulation, and increases in the low-frequency/HF ratio (LF/HF), an index for sympathovagal balance as compared to matched controls. Furthermore, the responses of HF and LF/HF to posture changes were all attenuated when compared with matched controls. Effect sizes, given by Cohen's d, for resting HF and HF reactivity were 0.42 and 0.36-0.42, respectively. CONCLUSIONS: GAD is associated with altered sympathovagal balance, characterized by attenuation in both resting vagal modulation and vagal reactivity, with an almost medium effect size (Cohen's d ≈ 0.4), regardless of medication use or comorbidity status.

Sex-specific pathways among tri-allelic serotonin transporter polymorphism, trait neuroticism and generalized anxiety disorder.

Background: Neuroticism personality trait is recognized as an important endophenotypic predictor of generalized anxiety disorder (GAD). Furthermore, endophenotype-based pathway approaches have recently been shown to have greater advantages for gene-finding strategies than traditional case-control studies. In the present study, in addition to conventional case-control methods, we used pathway analyses to test whether the tri-allelic serotonin transporter promoter polymorphism (combining 5-HTTLPR and rs25531) is associated with risk of GAD through its effects on trait neuroticism. Methods: We included 2236 Han Chinese adults in this study, including 736 patients with GAD and 1500 healthy participants. We genotyped the 5-HTTLPR and rs25531 polymorphisms using the polymerase chain reaction restriction fragment length polymorphism method. We used the Neuroticism scale of the Maudsley Personality Inventory (MPI) short version (MPI-Neuroticism) to measure participants' tendency toward neuroticism. Results: Using endophenotype-based path analyses, we found significant indirect effects of the tri-allelic genotype on risk of GAD, mediated by MPI-Neuroticism in both men and women. Compared to women carrying the S'S' genotype, women carrying the L' allele had higher levels of MPI-Neuroticism, which in turn were associated with higher risk of GAD. Men, however, showed the opposite pattern. Using traditional case-control comparisons, we observed that the effect of tri-allelic genotype on GAD was significant, but only in women. Limitations: Participants were restricted to Han Chinese, and we used only 1 questionnaire to assess neuroticism. Conclusion: These findings are the first to show that the triallelic 5-HTTLPR polymorphism is associated with elevated risk of GAD, and that this effect is mediated via increased trait neuroticism, a sex-dependent risk pathway.

Psychiatric Disorders After Traumatic Brain Injury: A Nationwide Population-Based Cohort Study and the Effects of Rehabilitation Therapies.

OBJECTIVE: To investigate the risk of psychiatric disorders after traumatic brain injury (TBI), and to clarify whether the post-TBI rehabilitation was associated with a lower risk of developing psychiatric disorders. DESIGN: A register-based, retrospective cohort design. SETTING: Using data from the National Health Insurance Research Database of Taiwan, we established an exposed cohort with TBI and a nonexposed group without TBI matched by age and year of diagnosis between 2000 and 2015. PARTICIPANTS: This study included 231,894 patients with TBI and 695,682 patients without TBI (N=927,576). INTERVENTIONS: Rehabilitation therapies in TBI patients. MAIN OUTCOME MEASURES: A multivariable Cox proportional hazards regression model was used to compare the risk of developing psychiatric disorders. RESULTS: The incidence rate of psychiatric disorders was higher in the TBI group than the control group. Compared with the control group, the risk of psychiatric disorders in the TBI group was twofold (hazard ratio [HR]=2.072; 95% confidence interval [95% CI], 1.955-2.189; P<.001). Among the participants with TBI, 49,270 (21.25%) had received rehabilitation therapy and had a lower risk of psychiatric disorders (HR=0.691; 95% CI, 0.679-0.703; P<.001). In the subgroup analysis, the medium- to high-level intensity rehabilitation therapy was associated with lower risks of psychiatric disorder (HR=0.712 and 0.568, respectively), but there was no significant finding in the low-intensity group. CONCLUSIONS: We found that TBI was associated with a high risk for developing psychiatric disorders, and that the post-TBI rehabilitation significantly reduced the risk of psychiatric disorders in a dose-dependent manner.

Stimulants associated with reduced risk of hospitalization for motor vehicle accident injury in patients with obstructive sleep apnea-a nationwide cohort study.

BACKGROUND: The risk of injury directly related to hospitalization for motor vehicle accidents (MVAs) in the obstructive sleep apnea (OSA) patients has not been thoroughly understood. Our study aimed to examine the association between the OSA and the hospitalization for an MVA injury. METHODS: This retrospective cohort study used Taiwan's National Health Insurance Research Database (NHIRD) between 2000 and 2015. The OSA patients aged ≥20 years by age, sex, and index-year matched by non-OSA controls were enrolled (1:3). We used the Cox proportional regression model to evaluate the association between the OSA and the hospitalization for an MVA injury. RESULTS: The incidence rate of hospitalization for an MVA injury was higher in the OSA cohort (N = 3025) when compared with the non-OSA controls (N = 9075), as 575.3 and 372.0 per 100,000 person-years, respectively (p < 0.001). The Kaplan-Meier analysis showed that the OSA cohort had a significantly higher incidence of hospitalization for the MVA injury (log-rank test, p < 0.001). After adjusting for the covariates, the risk of hospitalization for the MVA injury among the OSA was significantly higher (hazard ratio [HR] =2.18; 95% confidence interval [CI] = 1.79-2.64; p < 0.001). Stimulants usage was associated with a nearly 20% decrease in the risk of an overall hospitalization for an MVA injury in the OSA patients. CONCLUSIONS: This study provides evidence that patients with OSA are at a two-fold higher risk of developing hospitalization for an MVA injury, and the usage of modafinil and methylphenidate was associated with a lower risk of an overall hospitalization for the MVA injury.

Pinworm infections associated with risk of psychiatric disorders-A nationwide cohort study in Taiwan: Pinworm infections and psychiatric disorders.

AIM: This study aimed to investigate the association between males with pinworm infections and the risk of developing psychiatric disorders. METHOD: A total of 2044 enrolled patients, with 511 pinworm subjects and 1533 unexposed subjects (1:3) matched for sex, age and index year, from Taiwan's Longitudinal Health Insurance Database (LHID) from 2000 to 2015, selected from the National Health Insurance Research Database (NHIRD). After adjusting for confounding factors, the Cox regression model was used to compare the risk of developing psychiatric disorders during the 15 years of follow-up. RESULTS: Of all the enrollees, 24 in the pinworm cohort and 18 in the unexposed cohort (343.10 vs 84.96 per 100,000 person-year) developed psychiatric disorders. The Cox regression model revealed that, after adjusting for sex, age, monthly income, urbanization level, geographic region, and comorbidities, the adjusted HR was 4.581 (95% CI: 2.214-9.480, p < .001, p < .001). Pinworm infections were associated with the increased risk in anxiety disorders, depressive disorders, and sleep disorders, respectively. CONCLUSION: Patients who suffered from pinworm infections have a higher risk of developing psychiatric disorders, and this finding should be considered as a timely reminder for the clinicians to provide much more attention for these patients because of their mental health issues.

The Effects of Add-on Fronto-Temporal Transcranial Direct Current Stimulation (tDCS) on Auditory Verbal Hallucinations, Other Psychopathological Symptoms, and Insight in Schizophrenia: A Randomized, Double-Blind, Sham-Controlled Trial.

Background: The efficacy of fronto-temporal transcranial direct current stimulation in treating auditory verbal hallucinations and other psychopathological symptoms of schizophrenia patients has been examined in a small number of clinical trials with limited sample sizes, but the results are mixed. Fronto-temporal transcranial direct current stimulation has also been demonstrated to enhance patients' insight into their mental illness in an open-label pilot study. The current investigation aimed to investigate the therapeutic effects of fronto-temporal transcranial direct current stimulation on the severity of auditory verbal hallucinations, other schizophrenia symptoms, and insight in a large double blind, randomized, sham-controlled trial. Methods: Sixty patients with medication-refractory auditory verbal hallucinations were randomized over 2 conditions: transcranial direct current stimulation with 2-mA, twice-daily sessions for 5 consecutive days, with anodal stimulation to the left prefrontal cortex and cathodal stimulation to the left temporo-parietal junction, and sham treatment. Results: Fronto-temporal transcranial direct current stimulation failed to cause significant changes in the severity of auditory verbal hallucinations and other schizophrenia symptoms. The levels of insight into illness (effect size=0.511, P<.001) and positive symptoms (effect size=0.781, P<.001) were largely promoted by 5 days of transcranial direct current stimulation relative to sham treatment. The beneficial effects on the 2 insight dimensions remained 1 month after transcranial direct current stimulation. Conclusions: Fronto-temporal transcranial direct current stimulation is not more effective for auditory verbal hallucinations and other schizophrenia symptoms than sham treatment. But the results of transcranial direct current stimulation-associated improvement in awareness of illness and positive symptoms show promise and provide a new direction for future research into insight promotion interventions in schizophrenia.

The impact of cognitive insight, self-stigma, and medication compliance on the quality of life in patients with schizophrenia.

Impaired quality of life (QoL) is a common and clinically relevant feature of schizophrenia. In the present study, we attempted to formulate a model of QoL in the chronic stage of schizophrenia by including key variables-namely cognitive insight, self-stigma, insight into treatment, and medication compliance-that were proposed as its significant predictors in previous studies. We employed structural equation modeling (SEM) to simultaneously test the associations between these variables. A total of 170 community-dwelling patients with schizophrenia participated in this study. Cognitive insight, self-stigma, insight into treatment, medication compliance, and QoL were assessed through self-reporting. Symptoms were rated by interviewers. The influences of cognitive insight, stigma, insight into treatment, and medication compliance on QoL were supported using SEM. Our findings indicated that cognitive insight had a significant, positive, and direct effect on both self-stigma and insight into treatment; in contrast, it had a negative and direct effect on medication compliance. Notably, no evidence indicated a direct effect of cognitive insight on QoL. Thus, individuals with high cognitive insight reported low QoL because of stigma, low medication compliance, and their increased insight into treatment. In contrast, cognitive insight might indirectly ameliorate QoL mediated by the effect of insight into treatment on medication compliance. The findings provide additional support of the links between cognitive and clinical insight, self-stigma, medication compliance, and QoL in those with schizophrenia and suggest the need for screening and intervention services appropriate for this high-risk population.

Stigma Resistance in Stable Schizophrenia: The Relative Contributions of Stereotype Endorsement, Self-Reflection, Self-Esteem, and Coping Styles.

OBJECTIVE: Stigma resistance (SR) has recently emerged as a prominent aspect of research on recovery from schizophrenia, partly because studies have suggested that the development of stigma-resisting beliefs may help individuals lead a fulfilling life and recover from their mental illness. The present study assessed the relationship between personal SR ability and prediction variables such as self-stigma, self-esteem, self-reflection, coping styles, and psychotic symptomatology. METHOD: We performed an exploratory cross-sectional study of 170 community-dwelling patients with schizophrenia. Self-stigma, self-esteem, self-reflection, coping skills, and SR were assessed through self-report. Psychotic symptom severity was rated by the interviewers. Factors showing significant association in univariate analyses were included in a stepwise backward regression model. RESULTS: Stepwise regressions revealed that acceptance of stereotypes of mental illness, self-esteem, self-reflection, and only 2 adaptive coping strategies (positive reinterpretation and religious coping) were significant predictors of SR. The prediction model accounted for 27.1% of the variance in the SR subscale score in our sample. CONCLUSIONS: Greater reflective capacity, greater self-esteem, greater preferences for positive reinterpretation and religious coping, and fewer endorsements of the stereotypes of mental illness may be key factors that relate to higher levels of SR. These factors are potentially modifiable in tailored interventions, and such modification may produce considerable improvements in the SR of the investigated population. This study has implications for psychosocial rehabilitation and emerging views of recovery from mental illness.

Are Chronic Periodontitis and Gingivitis Associated with Dementia? A Nationwide, Retrospective, Matched-Cohort Study in Taiwan.

BACKGROUND: Chronic periodontitis and gingivitis are associated with various diseases; however, their impact on dementia is yet to be elucidated. This study is aimed at investigating the association between chronic periodontitis and gingivitis, and the risk of developing dementia. METHODS: A total of 2,207 patients, with newly diagnosed chronic periodontitis and gingivitis between January 1, 2000 and December 31, 2000, were selected from the National Health Insurance Research Database of Taiwan, along with 6,621 controls matched for sex and age. After adjusting for confounding factors, Cox proportional hazards analysis was used to compare the risk of developing dementia during the 10-year follow-up period. RESULTS: Of the study subjects, 25 (1.13%) developed dementia compared to 61 (0.92%) in the control group. Cox proportional hazards regression analysis revealed that the study subjects were more likely to develop dementia (hazard ratio (HR) 2.085, 95% CI 1.552-4.156, p < 0.001). After adjusting for sex, age, monthly income, urbanization level, geographic region, and comorbidities, the HR for dementia was 2.54 (95% CI 1.297-3.352, p = 0.002). CONCLUSIONS: Patients with chronic periodontitis and gingivitis have a higher risk of developing dementia. However, further studies on other large or national data sets are required to support the current findings.