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.

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.

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.

Correlation between health-related quality of life in the physical domain and heart rate variability in asymptomatic adults.

BACKGROUND: Reduced health-related quality of life in the physical domain (HRQOLphysical) has been reported to increase risks for cardiovascular disease (CVD); however, the mechanism underlying this phenomenon is still unclear. The autonomic nervous system (ANS) that connects the body and mind is a biologically plausible candidate to investigate this mechanism. The aim of our study is to examine whether the HRQOLphysical independently contributes to heart rate variability (HRV), which reflects ANS activity. METHODS: We recruited 329 physically and mentally healthy adults. All participants completed Beck Anxiety Inventory, Beck Depression Inventory and World Health Organization Questionnaire on Quality of Life: Short Form-Taiwanese version (WHOQOL-BREF). They were divided into groups of individuals having high or low scores of HRQOLphysical as discriminated by the quartile value of WHOQOL-BREF. We obtained the time and frequency-domain indices of HRV, namely variance (total HRV), the low-frequency power (LF; 0.05-0.15 Hz), which may reflect baroreflex function, the high-frequency power (HF; 0.15-0.40 Hz), which reflects cardiac parasympathetic activity, and the LF/HF ratio. RESULTS: There was an independent contribution of HRQOLphysical to explaining the variance in HRV after excluding potential confounding factors (gender, age, physical activity, alcohol use, depression and anxiety). Compared with the participants with high levels of HRQOLphysical, those with low levels of HRQOLphysical displayed significant reductions in variance and LF. CONCLUSIONS: This study highlights the independent role of low HRQOLphysical in contributing to the reduced HRV in healthy adults and points to a potential underlying mechanism for HRQOLphysical to confer increased risks for CVD.

Dopamine transporter gene may be associated with bipolar disorder and its personality traits.

Dopamine transporter and its genetic factors have been suggested to play a critical role in the development of bipolar disorder (BPD). However, the importance of the dopamine transporter gene (DAT1) in the pathogenesis of BPD remains unclear. The aims of this study were to assess 18 polymorphisms of the DAT1 gene to determine whether this gene is associated with BPD and whether it influences personality traits of patients with BPD. DAT1 polymorphisms were analyzed in 492 BPD (374 BPDI and 118 BPDII) patients and 436 controls. All participants were screened using the same assessment tool, and all met the criteria for BPD. The Tridimensional Personality Questionnaire was used to assess personality traits in both patients and controls. Several polymorphisms had a weak association with BPD, including rs2550948, rs2652511, and rs2975226 in allele distribution analysis (P < 0.05). Furthermore, the promoter G-A-C-G haplotype (rs6350-rs2975226-rs2652511-rs6413429) was over-represented in the BPD patients compared to the controls (P = 0.007). In personality assessment, the BPDII patients had the highest harm avoidance score, followed by the BPDI patients and controls (P = 3.7 × 10(-32)). In addition, a significant association between rs40184 and harm avoidance was found in the patients with BPD. The DAT1 promoter may be associated with vulnerabilities in BPD. The BPD patients had a higher rate of harm avoidance personality traits than the controls, and DAT1 variants may influence personality traits in patients with BPD.

Sex-specific association between nerve growth factor polymorphism and cardiac vagal modulation.

OBJECTIVE: Substantial research has shown that anxiety disorders are associated with decreased cardiac vagal tone, which is a known risk factor for cardiac vulnerability. A functional nerve growth factor (NGF) polymorphism (rs6330, c.104C > T, p.Ala35Val) has been associated with anxiety such that in males but not females, T-allele carriers exhibit higher levels of trait anxiety. Here we investigate whether the nonsynonymous NGF variant has an effect on cardiac autonomic control. METHODS: From 705 adults initially screened for medical and psychiatric illnesses, a final cohort of 580 healthy Han Chinese (352 men, 228 women; mean [standard deviation] age = 34.46 [8.45] years) was included in the NGF genotyping (C/C: 428% [73.8%] and T-allele carriers: 152% [26.2%]). Short-term heart rate variability was used to assess cardiac autonomic function. RESULTS: There were significant genotype-by-sex interaction effects (p < .05) on high-frequency power (HF) and root mean square of successive heartbeat interval differences (RMSSD), both indices of cardiac vagal control. Even after adjusting for possible confounders, men with any T allele showed lower HF and RMSSD compared with men with the C/C genotype. Women, however, showed an opposite but nonsignificant pattern. CONCLUSIONS: The studied NGF polymorphism modulates autonomic outflow to the heart in a sex-dependent manner. The findings support the view that male T-allele carriers are at increased susceptibility for anxiety by association with low vagal activity and suggest a potential sex-specific genetic link between the highly comorbid anxiety disorders and cardiovascular diseases.

Heart rate variability in unmedicated patients with bipolar disorder in the manic phase.

AIMS: Decreased heart rate variability (HRV) has been proposed in bipolar disorder. To date, there has been no adequate study that has investigated resting HRV in unmedicated patients with bipolar disorder in the manic state. METHODS: To examine whether bipolar mania is associated with decreased HRV, 61 unmedicated patients with bipolar mania and 183 healthy volunteers aged 20-65 years were recruited for this case-control analysis. The Young Mania Rating Scale (YMRS), Clinical Global Impression-Severity, Hamilton Depression Rating Scale (HAM-D), and Hamilton Anxiety Rating Scale (HAM-A) were used for the clinical ratings. Cardiac autonomic function was evaluated by measuring HRV parameters and the frequency-domain indices of HRV were obtained. RESULTS: Patients with bipolar mania exhibited significantly lower mean RR interval, variance, low-frequency (LF)-HRV, and high-frequency (HF)-HRV but higher LF/HF compared to controls. Decreased HRV (variance) was associated with the YMRS total scores. Both the YMRS total scores and the Clinical Global Impression-Severity scores were positively correlated with the LH/HF ratio and inversely correlated with the HF-HRV. There was no significant correlation between the HAM-D/HAM-A scores and any HRV parameter. CONCLUSIONS: Bipolar mania is associated with cardiac autonomic dysregulation, highlighting the importance of assessing HRV in manic patients. Further studies examining the influence of anti-manic psychotropic drugs on cardiac autonomic regulation in bipolar mania are needed.

Cardiac autonomic dysregulation in acute schizophrenia.

OBJECTIVE: Altered cardiac autonomic function has been proposed in schizophrenia, but the results are mixed. Therefore, analyses with larger sample sizes and better methodology are needed. METHODS: To examine whether acute schizophrenia is associated with cardiac autonomic dysfunction, 314 unmedicated patients with acute schizophrenia and 409 healthy volunteers, aged 18-65 years, were recruited for a case-control analysis. The severity of schizophrenia symptoms was assessed with the Positive and Negative Syndrome Scale. Cardiac autonomic function was evaluated by measuring heart rate variability (HRV) parameters during the supine-standing-supine test. Frequency-domain indices of HRV were obtained. RESULTS: Unmedicated patients with acute schizophrenia consistently exhibited reduced mean RR interval and HRV levels in a supine rest and standing position compared with healthy volunteers. The severity of psychopathology, in particular positive symptoms, was negatively correlated with cardiac vagal control. CONCLUSION: These data suggest that acute schizophrenia is accompanied by cardiac autonomic dysregulation. In view of the higher risk for cardiac complications in these patients, one might also consider the antipsychotic treatment in favour of improving cardiac autonomic modulation. Further studies using larger patient groups and controlled therapeutics may better understand the influence of antipsychotic treatment on cardiac autonomic regulation in schizophrenia.

High-Frequency Transcranial Random Noise Stimulation over the Left Prefrontal Cortex Increases Resting-State EEG Frontal Alpha Asymmetry in Patients with Schizophrenia.

Reduced left-lateralized electroencephalographic (EEG) frontal alpha asymmetry (FAA), a biomarker for the imbalance of interhemispheric frontal activity and motivational disturbances, represents a neuropathological attribute of negative symptoms of schizophrenia. Unidirectional high-frequency transcranial random noise stimulation (hf-tRNS) can increase the excitability of the cortex beneath the stimulating electrode. Yet, it is unclear if hf-tRNS can modulate electroencephalographic FAA in patients with schizophrenia. We performed a randomized, double-blind, sham-controlled clinical trial to contrast hf-tRNS and sham stimulation for treating negative symptoms in 35 schizophrenia patients. We used electroencephalography to investigate if 10 sessions of hf-tRNS delivered twice-a-day for five consecutive weekdays would modulate electroencephalographic FAA in schizophrenia. EEG data were collected and FAA was expressed as the differences between common-log-transformed absolute power values of frontal right and left hemisphere electrodes in the alpha frequency range (8-12.5 Hz). We found that hf-tRNS significantly increased FAA during the first session of stimulation (p = 0.009) and at the 1-week follow-up (p = 0.004) relative to sham stimulation. However, FAA failed to predict and surrogate the improvement in the severity of negative symptoms with hf-tRNS intervention. Together, our findings suggest that modulating electroencephalographic frontal alpha asymmetry by using unidirectional hf-tRNS may play a key role in reducing negative symptoms in patients with schizophrenia.

Adjunct high-frequency transcranial random noise stimulation over the lateral prefrontal cortex improves negative symptoms of schizophrenia: A randomized, double-blind, sham-controlled pilot study.

High-frequency transcranial random noise stimulation (hf-tRNS) is a non-invasive neuromodulatory technique capable of increasing human cortex excitability. There were only published case reports on the use of hf-tRNS targeting the lateral prefrontal cortex in treating negative symptoms of schizophrenia, thus necessitating systematic investigation. We designed a randomized, double-blind, sham-controlled trial in a cohort of stabilized schizophrenia patients to examine the efficacy of add-on hf-tRNS (100-640 Hz; 2 mA; 20 min) using a high definition 4 × 1 electrode montage (anode AF3, cathodes AF4, F2, F6, and FC4) in treating negative symptoms (ClinicalTrials.gov ID: NCT04038788). Participants received either active hf-tRNS or sham twice daily for 5 consecutive weekdays. Primary outcome measure was the change over time in the Positive and Negative Syndrome Scale Factor Score for Negative Symptoms (PANSS-FSNS), which was measured at baseline, after 10-session stimulation, and at one-week and one-month follow-ups. Among 36 randomized patients, 35 (97.2%) completed the trial. Intention-to-treat analysis showed a significantly greater decrease in PANSS-FSNS score after active (-17.11%) than after sham stimulation (-1.68%), with a large effect size (Cohen's d = 2.16, p < 0.001). The beneficial effect lasted for up to one month. In secondary-outcome analyses, the authors observed improvements with hf-tRNS of disorganization symptoms, unawareness of negative symptoms, subjective response to taking antipsychotics, and antipsychotic-induced extrapyramidal symptoms. No effects were observed on the neurocognitive performance and other outcome measures. Overall, hf-tRNS was safe and efficacious in improving negative symptoms. Our promising findings should be confirmed in a larger sample of patients with predominant negative symptoms.

Efficacy and neurophysiological predictors of treatment response of adjunct bifrontal transcranial direct current stimulation (tDCS) in treating unipolar and bipolar depression.

BACKGROUND: Although add-on transcranial direct current stimulation (tDCS) is a promising intervention for treating unipolar (UD) and bipolar depression (BD), its moderate antidepressant efficacy urges research into biomarkers for predicting therapeutic response and achieving highly targeted applications. METHODS: This open-label trial enrolled UD (N=58) and BD (N=22) patients who had failed 1 or more trials of adequate pharmacologic interventions (ClinicalTrials.gov ID: NCT03287037). Bifrontal tDCS (anode/cathode: F3/F4) was applied using a 2 mA current for 20 min, twice daily, for 5 consecutive weekdays. Depression was measured with Hamilton Depression Rating Scale-17 (HAMD) at baseline, after 10-session stimulation, 1- and 4-week follow-ups. Heart rate (HR) and heart rate variability (HRV) was measured at baseline, during the initial 5 min of the 1st session, after 10-session stimulation, 1- and 4-week follow-ups. Cognitive performance and other outcomes were also assessed. RESULTS: Bifrontal tDCS rapidly and equally improved depression in both groups. The effects persisted until the end of the trial. Both groups had similar improvements in cognitive performance, anxiety, and psychosocial functioning. Compared with baseline, increased vagally-mediated HRV was observed one month after tDCS for both groups. A positive correlation was found between HR deceleration within the 1st session and treatment response after 10-session tDCS only among UD patients, explaining 20% of the variance. CONCLUSION: tDCS as an adjunct therapy is effective for both UD and BD. Data suggest that the greater the increase in parasympathetic signaling during the 1st session, the better the clinical response after 10-session tDCS for UD patients.

Online Left-Hemispheric In-Phase Frontoparietal Theta tACS for the Treatment of Negative Symptoms of Schizophrenia.

Negative symptoms represent an unmet need for schizophrenia treatment. The effect of theta frequency transcranial alternating current stimulation (theta-tACS) applied during working memory (WM) tasks on negative symptoms has not been demonstrated as of yet. We conducted a randomized, double-blind, sham-controlled trial of 36 stabilized schizophrenia patients, randomized to receive either twice daily, 6 Hz 2 mA, 20 min sessions of in-phase frontoparietal tACS or sham for five consecutive weekdays. Participants were concurrently engaged in WM tasks during stimulation. The primary outcome measure was the change over time in the Positive and Negative Syndrome Scale (PANSS) negative subscale score measured from baseline through to the 1-month follow-up. Secondary outcome measures were other symptom clusters, neurocognitive performance, and relevant outcomes. The intention-to-treat analysis demonstrated greater reductions in PANSS negative subscale scores at the end of stimulation in the active (-13.84%) than the sham (-3.78%) condition, with a large effect size (Cohen's d = 0.96, p = 0.006). The positive effect endured for at least one month. Theta-tACS also showed efficacies for cognitive symptoms, WM capacity, and psychosocial functions. Online theta-tACS offers a novel approach to modulate frontoparietal networks to treat negative symptoms of schizophrenia. The promising results require large-scale replication studies in patients with predominantly negative symptoms.

What could we learn from SARS when facing the mental health issues related to the COVID-19 outbreak? A nationwide cohort study in Taiwan.

There were several studies about the psychiatric and mental health issues related to the severe adult respiratory syndrome (SARS) outbreak in 2003, however, the association between SARS and the overall risk of psychiatric disorders and suicides has, as yet, to be studied in Taiwan. The aim of this study is to examine as to whether SARS is associated with the risk of psychiatric disorders and suicide. A total of 285 patients with SARS and 2850 controls without SARS (1:10) matched for sex, age, insurance premium, comorbidities, residential regions, level of medical care, and index date were selected between February 25 and June 15, 2003 from the Inpatient Database Taiwan's National Health Insurance Research Database. During the 12-year follow-up, in which 79 in the SARS cohort and 340 in the control group developed psychiatric disorders or suicide (4047.41 vs. 1535.32 per 100,000 person-years). Fine and Gray's survival analysis revealed that the SARS cohort was associated with an increased risk of psychiatric disorders and suicide, and the adjusted subdistribution HR (sHR) was 2.805 (95% CI: 2.182-3.605, p < 0.001) for psychiatric disorders and suicide. The SARS cohort was associated with anxiety, depression, sleep disorders, posttraumatic stress disorder/acute stress disorder (PTSD/ASD), and suicide. The sensitivity analysis revealed that the SARS group was associated with anxiety, depression, sleep disorders, PTSD/ASD, and suicide after the individuals with a diagnosis of psychiatric disorders and suicide were excluded within the first year, and with anxiety, depression, and sleep disorders, while those in the first five years were excluded. In conclusion, SARS was associated with the increased risk of psychiatric disorders and suicide.

A higher degree of insight impairment in stabilized schizophrenia patients is associated with reduced cardiac vagal tone as indexed by resting-state high-frequency heart rate variability.

Varying degrees of impaired clinical insight in schizophrenia differentially impact medication adherence and clinical outcomes, prompting in-depth investigations of the deficits. Research is scarce on the differences in peripheral physiological markers between varying degrees of impaired insight. The aims of this study were to examine the differences in (1) resting-state high-frequency heart rate variability (HF-HRV) and (2) crucial clinical outcomes between schizophrenia patients with varying degrees of insight impairment as measured by the Positive and Negative Syndrome Scale (PANSS) item G12 (lack of judgment and insight). The study recruited a sample of 95 stabilized schizophrenia patients with insight impairment. Patients were divided into 2 groups of either minimal insight impairment (n = 25, PANSS G12 = 2-3) or moderate-to-severe insight impairment (n = 70, PANSS G12 ≥ 4). Patients with moderate-to-severe insight impairment displayed lower HF-HRV, clinician-rated psychosocial function, medication adherence, and working memory capacity, and higher self-reported psychosocial function and life quality, but comparable cognitive insight compared to those with minimal insight impairment. A logistic regression model predicted moderate-to-severe insight impairment based on HF-HRV values at the optimal cut-off point of 3.655, with the sensitivity and specificity 84% and 72%, respectively. HF-HRV seems a peripheral marker sensitively reflecting central pathophysiology implicated in insight impairment of schizophrenia.

Modulation of self-appraisal of illness, medication adherence, life quality and autonomic functioning by transcranial direct current stimulation in schizophrenia patients.

OBJECTIVES: Little is known about the impact of fronto-temporal transcranial direct current stimulation (tDCS) on attitudes toward mental illness, psychosocial and autonomic functioning, life quality, and medication adherence among schizophrenia patients. METHODS: Sixty schizophrenia patients were randomly allocated to receive 10 sessions of active (2 mA, 20 min, 2 sessions/day for five weekdays) or sham fronto-temporal tDCS. Self-Appraisal of Illness Questionnaire (SAIQ), Medication Adherence Rating Scale (MARS), World Health Organization Quality of Life-BREF (WHOQOL-BREF) and indices of heart rate variability (HRV) were measured at baseline, immediately after tDCS and at one-month follow-up visit. RESULTS: There were significant group-by-time interactions for scores of SAIQ presence/outcome subscale, total MARS and its subscale of subjective response to taking medication, WHOQOL-BREF psychological domain. Relative to sham, tDCS significantly improved self-awareness of presence/outcome of schizophrenia (Cohen's d = 0.465, p = 0.0011), subjective response to taking medication (Cohen's d = 0.639, p < 0.001) and psychological domain of life quality (Cohen's d = 0.459, p = 0.00114). These effects lasted for less than one month. The group-by-time interactions were non-significant for clinician-rated psychosocial functioning, mean RR intervals, and all HRV indices. CONCLUSION: Fronto-temporal tDCS briefly optimizes self-reported insight levels, beliefs about treatment adherence, and psychological domain of life quality in patients with schizophrenia. Further studies are required to confirm whether patients treated with 5-day, 10-session tDCS in combination with multisession "maintenance" stimulation every month would attain favourable outcomes. SIGNIFICANCE: We provide novel evidence for the potential utility of tDCS in schizophrenia.

Examining bi-anodal transcranial direct current stimulation (tDCS) over bilateral dorsolateral prefrontal cortex coupled with bilateral extracephalic references as a treatment for negative symptoms in non-acute schizophrenia patients: A randomized, double-blind, sham-controlled trial.

No studies have examined the efficacy of bi-anodal transcranial direct current stimulation (tDCS) over bilateral dorsolateral prefrontal cortex (DLPFC) coupled with bilateral extracephalic references in treating negative symptoms of non-acute schizophrenia patients. This study aimed to investigate the therapeutic effects of the new approach of tDCS on negative symptoms, other schizophrenia symptoms, cognitive deficits and psychosocial functioning in a double-blind, randomized, sham-controlled trial. Patients with non-acute schizophrenia (N = 60) in randomized order received sham treatment or bilaterally provided tDCS (2 mA, twice-daily sessions for five consecutive days) with the anode over the DLPFC and the reference (cathode) over the ipsilateral forearm. The negative symptoms as measured by a dimensional approach of Positive and Negative Syndrome Scale (PANSS) were rapidly reduced by bimodal tDCS relative to sham stimulation (F = 24.86, Cohen's d = 0.661, p = 6.11 × 10-6). The beneficial effect on negative symptoms lasted for up to 3 months. The authors also observed improvement with tDCS of psychosocial functioning as measured by the global score of Personal and Social Performance scale (PSP) and psychopathological symptoms especially for disorganization and cognitive symptoms as measured by the PANSS. No effects were observed on other schizophrenia symptom dimensions and the performance on a series of neurocognitive tests. Our results show promise for bi-anodal tDCS over bilateral DLPFC using bilateral extracephalic references in treating negative symptoms and other selected manifestations of schizophrenia. Further studies with electrophysiological or imaging evaluation help unravel the exact mechanism of action of this novel stimulation parameter of tDCS in schizophrenia patients. (ClinicalTrials.gov ID:NCT03701100).