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.

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.

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.

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.

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.

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.

Age-dependent association of polymorphisms in the promoter and 5'-untranslated region of the norepinephrine transporter gene with generalized anxiety disorder.

BACKGROUND: Norepinephrine transporter (NET), which regulates synaptic norepinephrine for noradrenergic signaling, is involved in the pathogenesis of anxiety, while expression of the NET gene differs at different ages. Here, we examine whether genetic variants in the NET gene are associated, in an age-specific manner, with increased risk of generalized anxiety disorder (GAD), one of the most disabling anxiety disorders. METHODS: Three common single-nucleotide polymorphisms (SNPs) in the promoter (rs168924: A/G; rs2242446: T/C) and 5'-untranslated region (5'-UTR) (rs2397771: G/C) of the NET gene were genotyped in 2,317 Han-Chinese participants (791 GAD patients and 1,526 controls; age: 20-65). Potential confounding factors, such as gender, stress levels and psychiatric comorbidities, were included as covariates. RESULTS: An interaction between age and NET genotypes and haplotypes was found for the risk of GAD. In the younger participants, rs168924 minor allele G homozygotes had the lowest incidence of GAD; however, older subjects displayed an inverse pattern, with homozygous G/G carriers presenting the highest prevalence of GAD. Additionally, younger individuals carrying 2 copies of the GGT haplotype composed of rs2397771-rs168924-rs2242446 had the lowest rate of GAD. However, those with 2 copies of the same haplotype exhibited the highest risk of GAD in the older groups. LIMITATIONS: Only 3 common SNPs in the promoter and 5'-UTR of the NET gene were analyzed. CONCLUSIONS: Our findings are the first to demonstrate that potentially functional SNPs in the NET promoter and 5'-UTR are associated with an increased risk of GAD, and that such associations are determined in an age-specific way.

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.

BDNF Val66Met polymorphism to generalized anxiety disorder pathways: Indirect effects via attenuated parasympathetic stress-relaxation reactivity.

The valine66methionine (Val66Met) polymorphism (rs6265) of the brain-derived neurotrophic factor (BDNF) gene has been shown to influence autonomic arousal pathways, which in turn predict elevated syndromal anxiety in healthy humans. We examined whether the BDNF variant is associated with an increased risk of generalized anxiety disorder (GAD), one of the most prevalent anxiety disorders, through altering parasympathetic stress/relaxation reactivity. A total of 2,250 Han Chinese adults (750 GAD patients and 1,500 healthy controls) were included in the genotyping. High-frequency heart rate variability, an index of vagal (parasympathetic) activity, was measured during the supine-standing-supine test (5 min in each position); vagal withdrawal and vagal activation were calculated as baseline supine minus standing and recovery supine minus standing, respectively. Analysis of healthy participants indicated that Val/Val homozygotes displayed significantly blunted vagal withdrawal and vagal activation compared with Met allele carriers. After analyzing the entire sample, these effects remained significant. Furthermore, both attenuated vagal response patterns were found to be significantly associated with a higher incidence of GAD. Lastly, the path analysis identified a significant indirect effect of BDNF on the risk of GAD via diminishing vagal response to either orthostatic stress or supine relaxation. Even when further testing the subsample comprising only comorbidity- and medication-free GAD patients and healthy controls to minimize the confounding bias, the results still remained. Our findings demonstrate that individuals carrying the BDNF Val/Val genotype, compared to Met-carriers, may be at higher risk of GAD due to blunted vagal reactivity in response to both stress and relaxation. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

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).

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.

Age-specific associations among functional COMT Val158Met polymorphism, resting parasympathetic nervous control and generalized anxiety disorder.

The functional Val158Met polymorphism (rs4680) of the Catechol-O-Methyltransferase (COMT) gene has been implicated in generalized anxiety disorder (GAD); however, the underlying neural mechanisms remain unexamined. Recent evidence reveals that low resting parasympathetic (vagal) control is an endophenotypic predictor of anxiety, while the effect of COMT rs4680 differs at different ages. Thus, we examined whether the COMT Val158Met variant could increase the risk of GAD through decreased resting parasympathetic nervous control in an age-specific manner. COMT rs4680 polymorphism was genotyped in 1,655 Han Chinese adults (1,142 healthy subjects and 513 patients with GAD; age: 20-65). High-frequency power (HF) of heart rate variability (HRV) was used to measure resting state parasympathetic nervous regulation. Non-genetic factors, such as gender, smoking status, medication use and comorbidity conditions, were treated as covariates. After adjusting for relevant covariates, there was a significant age x COMT genotype interaction on resting HF of HRV. In younger adults, Met allele carriers had a significantly lower HF index; however, older adults exhibited the opposite pattern, with Val/Val homozygotes exhibiting decreased HF values. Moreover, reduced HF-HRV is associated with increased risk of GAD. Finally, pathway analysis revealed a significant indirect effect of COMT on the risk of GAD via reduced resting HF-HRV, in the aforementioned age-dependent manner. Our findings are the first to demonstrate that COMT Val158Met polymorphism is associated with risk of GAD via reduced resting parasympathetic nervous control, an age-specific risk pathway.

Obstructive Sleep Apnea in Children and Adolescents and the Risk of Major Adverse Cardiovascular Events: A Nationwide Cohort Study in Taiwan.

STUDY OBJECTIVES: This study has investigated the risk of major adverse cardiovascular events (MACEs), including acute myocardial infarction, coronary artery disease, peripheral artery disease, and acute stroke, among children and adolescents (age younger than 20 years) with obstructive sleep apnea (OSA). METHODS: In this study, the population-based National Health Insurance Research Database of Taiwan was used to identify patients in whom OSA had been first diagnosed between 2000 and 2015. Children and adolescents with OSA (n = 6,535) were included with 1:3 ratio by age, sex, and index year of control participants without OSA (n = 19,605). The Cox proportional regression model was used to evaluate the risk of MACEs in this cohort study. RESULTS: After a 15-year follow-up, the incidence rate of MACEs was higher in the OSA cohort when compared with the non-OSA control cohort (15.97 and 8.20 per 100,000 person-years, respectively). After adjusting for covariates, the risk of MACEs among children and adolescents with OSA was still significantly higher (hazard ratio = 2.050; 95% confidence interval = 1.312-3.107; P = .010). No MACEs were found in the children and adolescents with OSA who received continuous airway positive pressure treatment or pharyngeal surgery. CONCLUSIONS: This study found a significantly higher risk of MACEs in children and adolescents with OSA. These findings strongly suggest that clinicians should provide careful follow-up and medical treatment for children and adolescents with OSA.

Subchronic administration of aripiprazole improves fear extinction retrieval of Pavlovian conditioning paradigm in rats experiencing psychological trauma.

People may suffer from an intruded fear memory when the attributable traumatic events no longer exist. This is of highly clinical relevance to trauma-induced mental disorders, such as posttraumatic stress disorder (PTSD). Mechanism underlying PTSD largely lies in the abnormal process of fear extinction and a functional imbalance within amygdala associated fear circuit areas. Previous evidence suggested central dopamine plays a key role in the regulation of the fear memory process, yet it remains unclear whether the intervention of dopamine modulators would be beneficial for the fear extinction abnormalities. The present study examined the performance of Pavlovian conditioned fear and the changes of dopamine profiles following a subchronic 14-day regimen of aripiprazole (a partial agonist of dopamine D2 receptors to normalize the condition caused by dopamine imbalance) in rats previously experienced a psychologically traumatic procedure of single prolonged stress (SPS). The results demonstrated that aripiprazole at 5.0 mg/kg reversed the SPS-impaired fear memory dysfunction and the SPS-reduced dopamine efflux in the amygdala. The present study suggests a therapeutic potential of subchronic treatment with aripiprazole in managing patients suffered from fear extinction problem.

Enhancement of cognitive insight and higher-order neurocognitive function by fronto-temporal transcranial direct current stimulation (tDCS) in patients with schizophrenia.

No studies have examined the effects of fronto-temporal transcranial direct current stimulation (tDCS) on cognitive insight and neurocognitive function in schizophrenia patients and the dynamic interplay between tDCS-induced changes in these two outcomes. In this double-blind, randomized, sham-controlled study, we investigated the effects of fronto-temporal tDCS [anode corresponding to left dorsolateral prefrontal cortex and cathode to left temporo-parietal junction; 2-mA, twice-daily sessions for 5 days] on illness severity, psychosocial functioning, cognitive insight and neurocognitive function in schizophrenia patients (N = 60). The authors observed significant trends that tDCS ameliorated the severity of total and general psychopathology as measured by the Positive and Negative Syndrome Scale. No significant effects were observed for other psychopathological symptoms and psychosocial functioning. Cognitive insight as measured by the Beck Cognitive Insight Scale (BCIS) was rapidly enhanced by 10-session tDCS (F = 10.80, Cohen's d = 0.44, p = 0.002) but the beneficial effect became borderline significant 1 month after stimulation. A trend-level improvement with tDCS of planning ability (F = 6.40, Cohen's d = 0.339, p = 0.014) as measured by the accuracy in Tower of London task was also observed. In the active tDCS group, the change in cognitive insight from baseline to immediately after tDCS assessment was positively correlated with that in planning ability (r = 0.46, p = 0.015), which was independent of the corresponding change in illness severity. The promising results regarding the fast-acting beneficial effects of tDCS on cognitive insight and planning ability in schizophrenia require confirmation in future replication studies.