Aberrant brain dynamics in individuals with clinical high risk of psychosis.

Background: Resting-state network (RSN) functional connectivity analyses have profoundly influenced our understanding of the pathophysiology of psychoses and their clinical high risk (CHR) states. However, conventional RSN analyses address the static nature of large-scale brain networks. In contrast, novel methodological approaches aim to assess the momentum state and temporal dynamics of brain network interactions. Methods: Fifty CHR individuals and 33 healthy controls (HC) completed a resting-state functional MRI scan. We performed an Energy Landscape analysis, a data-driven method using the pairwise maximum entropy model, to describe large-scale brain network dynamics such as duration and frequency of, and transition between, different brain states. We compared those measures between CHR and HC, and examined the association between neuropsychological measures and neural dynamics in CHR. Results: Our main finding is a significantly increased duration, frequency, and higher transition rates to an infrequent brain state with coactivation of the salience, limbic, default mode and somatomotor RSNs in CHR as compared to HC. Transition of brain dynamics from this brain state was significantly correlated with processing speed in CHR. Conclusion: In CHR, temporal brain dynamics are attracted to an infrequent brain state, reflecting more frequent and longer occurrence of aberrant interactions of default mode, salience, and limbic networks. Concurrently, more frequent and longer occurrence of the brain state is associated with core cognitive dysfunctions, predictors of future onset of full-blown psychosis.

Six-month safety and effectiveness of tofacitinib in patients with rheumatoid arthritis in Japan: Interim analysis of post-marketing surveillance.

OBJECTIVES: We evaluated the real-world safety/effectiveness of tofacitinib, an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), in patients with RA in Japan registered in a post-marketing surveillance study. METHODS: This interim analysis included data from July 2013 to December 2018. Adverse events (AEs), serious AEs (SAEs), Simplified Disease Activity Index (SDAI)/Clinical Disease Activity Index (CDAI)/Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4(ESR)] scores, and rates of SDAI/CDAI/DAS28-4(ESR)-defined remission and low disease activity were analysed using 6 months of data. Risk factors for serious infections were assessed by multivariable analyses. RESULTS: Safety and disease activity were evaluated in 6866 and 6649 patients, respectively. Overall, 32.73%/7.37% of patients reported AEs/SAEs. Clinically important AEs with tofacitinib included serious infections/infestations [3.13% of patients; incidence rate (IR; patients with events) 6.91/100 patient-years (PY)], herpes zoster (3.63%; IR 8.02/100 PY), and malignancies (0.68%; IR 1.45/100 PY). SDAI/CDAI/DAS28-4(ESR) scores and remission/low disease activity rates improved over 6 months. Male sex, older age, Steinbrocker's stage IV, history of infection, and diabetes mellitus at baseline were independent risk factors for serious infection. CONCLUSIONS: In patients with RA receiving tofacitinib in Japan, safety was consistent with the reported profile, and disease activity improved over 6 months. STUDY IDENTIFIER: NCT01932372.

Toll-Like Receptor mRNA Levels in Schizophrenia: Association With Complement Factors and Cingulate Gyrus Cortical Thinning.

BACKGROUND AND HYPOTHESES: Previous studies revealed innate immune system activation in people with schizophrenia (SZ), potentially mediated by endogenous pathogen recognition receptors, notably Toll-like receptors (TLR). TLRs are activated by pathogenic molecules like bacterial lipopolysaccharides (TLR1 and TLR4), viral RNA (TLR3), or both (TLR8). Furthermore, the complement system, another key component of innate immunity, has previously been linked to SZ. STUDY DESIGN: Peripheral mRNA levels of TLR1, TLR3, TLR4, and TLR8 were compared between SZ and healthy controls (HC). We investigated their relationship with immune activation through complement expression and cortical thickness of the cingulate gyrus, a region susceptible to immunological hits. TLR mRNA levels and peripheral complement receptor mRNA were extracted from 86 SZ and 77 HC white blood cells; structural MRI scans were conducted on a subset. STUDY RESULTS: We found significantly higher TLR4 and TLR8 mRNA levels and lower TLR3 mRNA levels in SZ compared to HC. TLRs and complemental factors were significantly associated in SZ and HC, with the strongest deviations of TLR mRNA levels in the SZ subgroup having elevated complement expression. Cortical thickness of the cingulate gyrus was inversely associated with TLR8 mRNA levels in SZ, and with TLR4 and TLR8 levels in HC. CONCLUSIONS: The study underscores the role of innate immune activation in schizophrenia, indicating a coordinated immune response of TLRs and the complement system. Our results suggest there could be more bacterial influence (based on TLR 4 levels) as opposed to viral influence (based on TLR3 levels) in schizophrenia. Specific TLRs were associated with brain cortical thickness reductions of limbic brain structures.

Reduced anterior callosal white matter in risk for psychosis associated with processing speed as a fundamental cognitive impairment.

BACKGROUND: Previous research in psychotic disorders discovered associations between reduced integrity of white matter (WM) in the corpus callosum (CC) and impaired cognitive functions, suggesting processing speed as a central construct. However, it is still largely unexplored to what extent disruption in callosal WM is related to cognitive deficits during the risk stage prior to psychosis. METHODS: To address this gap, we measured the WM integrity in CC by fractional anisotropy (FA) and assessed cognition in 60 clinical-high risk for psychosis (CHR) patients during adolescence/young adulthood and 38 healthy control (HC) subjects. We employed tract based spatial statistics to examine group differences and associations between CC-FA and processing speed, executive function, and spatial working memory. RESULTS: We revealed deficits in processing speed, executive function, and spatial working memory of CHR patients, and reductions in FA of the genu and the body of the CC (p < 0.05, corrected for multiple comparisons) compared to HC. A mediation analysis using the combined sample (CHR + HC) showed that processing speed mediates the associations between the impaired CC structure and executive function and spatial working memory, respectively. Exploratory analyses between CC-FA and the cognitive domains located associations of processing speed in the genu and the body of CC with distinct spatial distributions of executive function and spatial working memory. CONCLUSION: We suggest processing speed as a subordinate cognitive factor contributing to the associations between callosal WM, executive function and working memory. These results extend findings in psychotic disorders to the prior risk stage.

Feasibility, efficacy, and functional relevance of automated auditory closed-loop suppression of slow-wave sleep in humans.

Slow-wave sleep (SWS) is a fundamental physiological process, and its modulation is of interest for basic science and clinical applications. However, automatised protocols for the suppression of SWS are lacking. We describe the development of a novel protocol for the automated detection (based on the whole head topography of frontal slow waves) and suppression of SWS (through closed-loop modulated randomised pulsed noise), and assessed the feasibility, efficacy and functional relevance compared to sham stimulation in 15 healthy young adults in a repeated-measure sleep laboratory study. Auditory compared to sham stimulation resulted in a highly significant reduction of SWS by 30% without affecting total sleep time. The reduction of SWS was associated with an increase in lighter non-rapid eye movement sleep and a shift of slow-wave activity towards the end of the night, indicative of a homeostatic response and functional relevance. Still, cumulative slow-wave activity across the night was significantly reduced by 23%. Undisturbed sleep led to an evening to morning reduction of wake electroencephalographic theta activity, thought to reflect synaptic downscaling during SWS, while suppression of SWS inhibited this dissipation. We provide evidence for the feasibility, efficacy, and functional relevance of a novel fully automated protocol for SWS suppression based on auditory closed-loop stimulation. Future work is needed to further test for functional relevance and potential clinical applications.

Computational analysis on verbal fluency reveals heterogeneity in subjective language interests and brain structure.

Language is an essential higher cognitive function in humans and is often affected by psychiatric and neurological disorders. Objective measures like the verbal fluency test are often used to determine language dysfunction. Recent applications of computational approaches broaden insights into language-related functions. In addition, individuals diagnosed with a psychiatric or neurological disorder also often report subjective difficulties in language-related functions. Therefore, we investigated the association between objective and subjective measures of language functioning, on the one hand, and inter-individual structural variations in language-related brain areas, on the other hand. We performed a Latent Semantic analysis (LSA) on a semantic verbal fluency task in 101 healthy adult participants. To investigate if these objective measures are associated with a subjective one, we examined assessed subjective natural tendency of interest in language-related activity with a study-specific questionnaire. Lastly, a voxel-based brain morphometry (VBM) was conducted to reveal associations between objective (LSA) measures and structural changes in language-related brain areas. We found a positive correlation between the LSA measure cosine similarity and the subjective interest in language. Furthermore, we found that higher cosine similarity corresponds to higher gray matter volume in the right cerebellum. The results suggest that people with higher interests in language access semantic knowledge in a more organized way exhibited by higher cosine similarity and have larger grey matter volume in the right cerebellum, when compared to people with lower interests. In conclusion, we demonstrate that there is inter-individual diverseness of accessing the semantic knowledge space and that it is associated with subjective language interests as well as structural differences in the right cerebellum.

Right Inferior Frontal Activation During Alcohol-Specific Inhibition Increases With Craving and Predicts Drinking Outcome in Alcohol Use Disorder.

Alcohol use disorder (AUD) is characterized by enhanced cue-reactivity and the opposing control processes being insufficient. The ability to inhibit reactions to alcohol-related cues, alcohol-specific inhibition, is thus crucial to AUD; and trainings strengthening this ability might increase treatment outcome. The present study investigated whether neurophysiological correlates of alcohol-specific inhibition (I) vary with craving, (II) predict drinking outcome in AUD and (III) are modulated by alcohol-specific inhibition training. A total of 45 recently abstinent patients with AUD and 25 controls participated in this study. All participants underwent functional magnetic resonance imaging (fMRI) during a Go-NoGo task with alcohol-related as well as neutral conditions. Patients with AUD additionally participated in a double-blind RCT, where they were randomized to either an alcohol-specific inhibition training or an active control condition (non-specific inhibition training). After the training, patients participated in a second fMRI measurement where the Go-NoGo task was repeated. Percentage of days abstinent was assessed as drinking outcome 3 months after discharge from residential treatment. Whole brain analyses indicated that in the right inferior frontal gyrus (rIFG), activation related to alcohol-specific inhibition varied with craving and predicted drinking outcome at 3-months follow-up. This neurophysiological correlate of alcohol-specific inhibition was however not modulated by the training version. Our results suggest that enhanced rIFG activation during alcohol-specific (compared to neutral) inhibition (I) is needed to inhibit responses when craving is high and (II) fosters sustained abstinence in patients with AUD. As alcohol-specific rIFG activation was not affected by the training, future research might investigate whether potential training effects on neurophysiology are better detectable with other methodological approaches.

Disentangling cognitive inflexibility in major depressive disorder: A transcranial direct current stimulation study.

BACKGROUND: Cognitive dysfunction is a persistent residual symptom in major depressive disorders (MDDs) that hinders social and occupational recovery. Cognitive inflexibility is a typical cognitive dysfunction in MDD and refers to difficulty in switching tasks, which requires two subcomponents: forgetting an old task and adapting to a new one. Here, we aimed to disentangle the subcomponents of cognitive inflexibility in MDD and investigate whether they can be improved by transcranial direct current stimulation (tDCS) on the prefrontal cortex. METHODS: The current study included 20 patients with MDD (seven females) and 22 age-matched healthy controls (HCs) (seven females). The participants received anodal tDCS on either the dorsomedial prefrontal cortex (DMPFC) or dorsolateral prefrontal cortex (DLPFC) in a crossover design. Before and after the application of tDCS, the participants performed a modified Wisconsin Card Sorting Test, in which the task-switching rules were explicitly described and proactive interference from a previous task rule was occasionally released. RESULTS: We found that the behavioral cost of a task switch was increased in patients with MDD, but that of proactive interference was comparable between patients with MDD and HCs. The response time for anodal DMPFC tDCS was decreased compared with that for anodal tDCS on the DLPFC in MDD. CONCLUSIONS: These findings suggest that cognitive inflexibility in MDD is primarily explained by the difficulty to adapt to a new task and environment, and that tDCS on the DMPFC improves behavioral performance during cognitively demanding tasks that require conflict resolution.

Phase-Synchronized Transcranial Alternating Current Stimulation-Induced Neural Oscillations Modulate Cortico-Cortical Signaling Efficacy.

Introduction: Synchronized oscillatory brain activity is considered a basis for flexible neuronal network communication. However, the causal role of inter-regional oscillatory phase relations in modulating signaling efficacy in cortical networks has not been directly demonstrated in humans so far. Aim: The current study addresses the causal role of transcranial alternating current stimulation (tACS)-induced oscillatory cross-network phase relations in modulating signaling efficacy across human cortical networks. Methods: To this end, concurrent tACS, transcranial magnetic stimulation (TMS), and electroencephalography (EEG) were employed to measure the modulation of excitability and signaling efficacy across cortical networks during externally induced neural oscillations. Theta oscillatory activity was introduced through tACS in two nodes of the human frontoparietal network: the dorsolateral prefrontal cortex (DLPFC) and the posterior parietal cortex (PPC). Six Hertz tACS was applied to the DLPFC and PPC simultaneously in an in-phase or antiphase manner. In addition, single-pulse TMS was administered over the DLPFC at four different phases of tACS and the propagation of TMS-evoked neuronal activity was measured with EEG. Results: We show that tACS-induced theta oscillations modulate TMS-evoked potentials (TEPs) in a phase-dependent manner, and that the induced oscillatory phase relation across the frontoparietal network affects the propagation of phase-dependent TEPs within as well as beyond the frontoparietal network. Conclusion: We show that the effect of tACS-induced phase relation across the frontoparietal network on signal transmission extends beyond the frontoparietal network. The results support a causal role of inter-nodal oscillatory phase synchrony in routing cortico-cortical information flow. Impact statement Theoretical models have proposed that phase relations of cross-network neural oscillations control communication efficacy across human cortical networks. The current study introduced concurrent transcranial alternating current stimulation-transcranial magnetic stimulation-electroencephalography (tACS-TMS-EEG) to experimentally study the theoretical framework. Dual-site in-phase or antiphase 6 Hz tACS was applied to the frontoparietal network. Synchronized tACS was shown to affect signaling within as well as beyond the targeted network. The study demonstrates how inter-regional oscillatory coherence supports the control of brain network signaling.

Mindfulness augmentation for anxiety through concurrent use of transcranial direct current stimulation: a randomized double-blind study.

Transcranial direct current stimulation (tDCS) have revealed the capability to augment various types of behavioural interventions. We aimed to augment the effects of mindfulness, suggested for reducing anxiety, with concurrent use of tDCS. We conducted a double-blind randomized study with 58 healthy individuals. We introduced treadmill walking for focused meditation and active or sham tDCS on the left dorsolateral prefrontal cortex for 20 min. We evaluated outcomes using State-Trait Anxiety Inventory-State Anxiety (STAI) before the intervention as well as immediately, 60 min, and 1 week after the intervention, and current density from electroencephalograms (EEG) before and after the intervention. The linear mixed-effect models demonstrated that STAI-state anxiety showed a significant interaction effect between 1 week after the intervention and tDCS groups. As for alpha-band EEG activity, the current density in the rostral anterior cingulate cortex (rACC) was significantly reduced in the active compared with the sham stimulation group, and a significant correlation was seen between changes in STAI-trait anxiety and the current density of the rACC in the active stimulation group. Our study provided that despite this being a one-shot and short intervention, the reduction in anxiety lasts for one week, and EEG could potentially help predict its anxiolytic effect.

Bi-Temporal Anodal Transcranial Direct Current Stimulation during Slow-Wave Sleep Boosts Slow-Wave Density but Not Memory Consolidation.

Slow-wave sleep (SWS) has been shown to promote long-term consolidation of episodic memories in hippocampo-neocortical networks. Previous research has aimed to modulate cortical sleep slow-waves and spindles to facilitate episodic memory consolidation. Here, we instead aimed to modulate hippocampal activity during slow-wave sleep using transcranial direct current stimulation in 18 healthy humans. A pair-associate episodic memory task was used to evaluate sleep-dependent memory consolidation with face-occupation stimuli. Pre- and post-nap retrieval was assessed as a measure of memory performance. Anodal stimulation with 2 mA was applied bilaterally over the lateral temporal cortex, motivated by its particularly extensive connections to the hippocampus. The participants slept in a magnetic resonance (MR)-simulator during the recordings to test the feasibility for a future MR-study. We used a sham-controlled, double-blind, counterbalanced randomized, within-subject crossover design. We show that stimulation vs. sham significantly increased slow-wave density and the temporal coupling of fast spindles and slow-waves. While retention of episodic memories across sleep was not affected across the entire sample of participants, it was impaired in participants with below-average pre-sleep memory performance. Hence, bi-temporal anodal direct current stimulation applied during sleep enhanced sleep parameters that are typically involved in memory consolidation, but it failed to improve memory consolidation and even tended to impair consolidation in poor learners. These findings suggest that artificially enhancing memory-related sleep parameters to improve memory consolidation can actually backfire in those participants who are in most need of memory improvement.

Converging Resting State Networks Unravels Potential Remote Effects of Transcranial Magnetic Stimulation for Major Depression.

Despite being a commonly used protocol to treat major depressive disorder (MDD), the underlying mechanism of repetitive transcranial magnetic stimulation (rTMS) on dorsolateral prefrontal cortex (DLPFC) remains unclear. In the current study, we investigated the resting-state fMRI data of 100 healthy subjects by exploring three overlapping functional networks associated with the psychopathologically MDD-related areas (the nucleus accumbens, amygdala, and ventromedial prefrontal cortex). Our results showed that these networks converged at the bilateral DLPFC, which suggested that rTMS over DLPFC might improve MDD by remotely modulating the MDD-related areas synergistically. Additionally, they functionally converged at the DMPFC and bilateral insula which are known to be associated with MDD. These two areas could also be potential targets for rTMS treatment. Dynamic causal modelling (DCM) and Granger causality analysis (GCA) revealed that all pairwise connections among bilateral DLPFC, DMPFC, bilateral insula, and three psychopathologically MDD-related areas contained significant causality. The DCM results also suggested that most of the functional interactions between MDD-related areas and bilateral DLPFC, DMPFC, and bilateral insula can predominantly be explained by the effective connectivity from the psychopathologically MDD-related areas to the rTMS stimulation sites. Finally, we found the conventional functional connectivity to be a more representative measure to obtain connectivity parameters compared to GCA and DCM analysis. Our research helped inspecting the convergence of the functional networks related to a psychiatry disorder. The results identified potential targets for brain stimulation treatment and contributed to the optimization of patient-specific brain stimulation protocols.

Subclinical paranoid beliefs and enhanced neural response during processing of unattractive faces.

The perception of faces and consequent social inferences are fundamental for interpersonal communication. While facial expression is important for interindividual communication, constitutional and acquired features are crucial for basic emotions of attraction or repulsion. An emotional bias in face processing has been shown in schizophrenia, but the neurobiological mechanisms are unclear. Studies on the interaction between face processing and the emotional state of healthy individuals may help to elucidate the pathogenesis of the paranoid syndrome in psychosis. This study addressed facial attractiveness and paranoid ideas in a non-clinical population. Using functional magnetic resonance imaging (fMRI), we investigated neural activation patterns of 99 healthy subjects during the passive perception of a dynamic presentation of faces with different attractiveness. We found that the perceived attractiveness of faces was linked to the activity of face processing and limbic regions including the fusiform gyrus, amygdala, and prefrontal areas. Paranoid beliefs interacted with perceived attractiveness in these regions resulting in a higher response range and increased activation after the presentation of unattractive faces. However, no behavioral interactions between reported subjective attractiveness and paranoid beliefs were found. The results showed that increased activation of limbic brain regions is linked to paranoid beliefs. Since similar correlations were found in clinical populations with paranoid syndromes, we suggest a dimension of emotional dysregulation ranging from subclinical paranoid beliefs to paranoid schizophrenia.

Glucocorticoids and cortical decoding in the phobic brain.

Glucocorticoids reduce phobic fear in anxiety disorders and enhance psychotherapy, possibly by reducing the retrieval of fear memories and enhancing the consolidation of new corrective memories. Glucocorticoid signaling in the basolateral amygdala can influence connected fear and memory-related cortical regions, but this is not fully understood. Previous studies investigated specific pathways moderated by glucocorticoids, for example, visual-temporal pathways; however, these analyses were limited to a-priori selected regions. Here, we performed whole-brain pattern analysis to localize phobic stimulus decoding related to the fear-reducing effect of glucocorticoids. We reanalyzed functional magnetic resonance imaging (fMRI) data from a previously published study with spider-phobic patients and healthy controls. The patients received glucocorticoids or a placebo before the exposure to spider images. There was moderate evidence that patients with phobia had higher decoding of phobic content in the anterior cingulate cortex (ACC) and the left and right anterior insula compared to controls. Decoding in the ACC and the right insula showed strong evidence for correlation with experienced fear. Patients with cortisol reported a reduction of fear by 10-13%; however, there was only weak evidence for changes in neural decoding compared to placebo which was found in the precuneus, the opercular cortex, and the left cerebellum.

Pre-stimulus Brain Activity Is Associated With State-Anxiety Changes During Single-Session Transcranial Direct Current Stimulation.

Transcranial direct current stimulation is a promising neuromodulation method for treating depression. However, compared with pharmacological treatment, previous studies have reported that a relatively limited proportion of patients respond to tDCS treatment. In addition, the neurophysiological mechanisms underlying tDCS treatment remain unclear, making it difficult to identify response predictors for tDCS treatment based on neurophysiological function. Because treatment effects are achieved by repetitive application of tDCS, studying the immediate effects of tDCS in depressive patients could extend understanding of its treatment mechanisms. However, immediate changes in a single session of tDCS are not well documented. Thus, in the current study, we focused on the immediate impact of tDCS and its association with pre-stimulus brain activity. To address this question, we applied anodal tDCS to the left dorsolateral prefrontal cortex (DLPFC) or dorsomedial prefrontal cortex (DMPFC) in 14 patients with major depressive disorder (MDD) and 19 healthy controls (HCs), at an intensity of 1.0 mA for 20 min in a single session. To evaluate anxiety, the state trait anxiety inventory was completed before and after tDCS. We recorded resting electroencephalography before tDCS, and calculated electrical neuronal activity in the theta and alpha frequency bands using standardized low-resolution electromagnetic tomography. We found that, during application of left DLPFC tDCS to patients with MDD, the anxiety reduction effect of tDCS was related to higher baseline theta-band activity in the rostral anterior cingulate cortex (rACC) and no medication with benzodiazepine used as hypnotic. For DMPFC stimulation in MDD, the anxiety reduction effect was associated with lower baseline alpha-band activity in the left inferior parietal lobule. In contrast, in HCs, the anxiety reduction effect was associated with higher baseline alpha activity in the precuneus during DMPFC stimulation. The current results suggest that the association between pre-tDCS brain activity and the anxiety reduction effect of tDCS depends on psychopathology (depressed or non-depressed) as well as the site of stimulation (DMPFC or left DLPFC) and insomnia. Furthermore, the results suggest that tDCS response might be associated with baseline resting state electrophysiological neural activity.

Three-year safety and two-year effectiveness of etanercept in patients with rheumatoid arthritis in Japan: Results of long-term postmarketing surveillance.

Objectives: To evaluate the real-world safety and effectiveness of etanercept (ETN) in Japanese patients with rheumatoid arthritis. Methods: This postmarketing surveillance study (NCT00503139) assessed the safety and effectiveness of ETN treatment over 3 and 2 years (from June 2007 to September 2011), respectively. Safety was evaluated by occurrence and seriousness of adverse drug reactions (ADRs), and of adverse events (AEs) for malignancies. Effectiveness was assessed using the Disease Activity Score in 28 joints based on the erythrocyte sedimentation rate (ESR) with four variables (swollen and tender joint counts, ESR, and patient global assessment; DAS28-4/ESR). Treatment was considered effective if patients had a good/moderate response by the European League Against Rheumatism response criteria. Results: ADRs occurred in 256/675 (37.9%) patients, the most common being injection site reactions (4.4%) and nasopharyngitis (3.3%). Serious ADRs occurred in 60/675 (8.9%) patients, the most frequent being pneumonia (1.2%). The incident rate of malignancies (AEs) was 1.06 per 100 patient-years. Mean baseline DAS28-4/ESR for the 581 patients included in effectiveness analysis was 5.42, which decreased to 3.32 at 2 years. Eighty-two percent of patients achieved a moderate/good response at 2 years. Conclusion: Long-term ETN treatment safety and effectiveness were sustained over 3 and 2 years, respectively.

No Effect of Transcranial Direct Current Stimulation of the Auditory Cortex on Auditory-Evoked Potentials.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique to change cortical excitability. Its effects are shown for cognitive processing, and behavior in the motor and perceptual domains. However, evidence of tDCS effects in the perceptual domain particularly for auditory processing is rare. Therefore, and in the context of disturbances in auditory processing in psychiatric populations, e.g., in patients with auditory verbal hallucinations, we aimed to investigate the potential modulatory effect of tDCS on the excitability of left posterior temporal cortex in detail. We included 24 healthy participants in a crossover design, applying sham and anodal stimulation in two measurement sessions 1 week apart. Electroencephalography (EEG) was recorded while participants listened to tones before, during, and after stimulation. Amplitudes and latencies of P50, N100, and P200 auditory-evoked potentials (AEP) were compared between anodal and sham stimulation, and between time points before, during, and after tDCS. In contrast to previous studies, results demonstrate no significant differences between stimulation types or time points for any of the investigated AEP amplitudes or latencies. Furthermore, a topographical analysis did not show any topographical differences during peak time periods of the investigated AEP for stimulation types and time points besides a habituation effect. Thus, our results suggest that tDCS modulation of excitability of the left posterior temporal cortex, targeting the auditory cortex, does not have any effect on AEP. This is particularly interesting in the context of tDCS as a potential treatment for changed electrophysiological parameters and symptoms of psychiatric diseases, e.g., lower N100 or auditory verbal hallucinations in schizophrenia.

Safety and effectiveness of etanercept for treatment of juvenile idiopathic arthritis: Results from a postmarketing surveillance.

OBJECTIVES: The objectives of this surveillance were to determine safety and effectiveness of etanercept in patients with juvenile idiopathic arthritis (JIA). METHODS: In this postmarketing surveillance, patients aged 5-16 years with active polyarthritis JIA were treated with etanercept at the doses approved in the Japanese package insert. The occurrence and seriousness of adverse events (AEs) were assessed using the Japanese Medical Dictionary for Regulatory Activities version 15.1. Effectiveness was determined as the improvement from baseline in disease activity score in 28 joints (DAS28)-erythrocyte sedimentation rate (ESR), remission, and physician's assessment of overall improvement. The number of responders was expressed as a percentage. The last observation carried forward method was used to impute missing data. RESULTS: Safety analysis included 102 patients; 22 patients experienced 36 treatment-related AEs, three of which were unexpected. None of the AEs were deemed to need special safety warnings. Effectiveness analysis included 87 patients. At 24 weeks, 29/46 (63.0%) patients demonstrated either good or moderate response in DAS28-4/ESR and treatment was assessed to be markedly effective or effective by physicians in 79/83 (95.2%) patients. CONCLUSIONS: These data are consistent with earlier reports showing that etanercept was effective and demonstrated no safety signals in patients with JIA.

Neural Correlates of Impaired Reward-Effort Integration in Remitted Bulimia Nervosa.

The integration of reward magnitudes and effort costs is required for an effective behavioral guidance. This reward-effort integration was reported to be dependent on dopaminergic neurotransmission. As bulimia nervosa has been associated with a dysregulated dopamine system and catecholamine depletion led to reward-processing deficits in remitted bulimia nervosa, the purpose of this study was to identify the role of catecholamine dysfunction and its relation to behavioral and neural reward-effort integration in bulimia nervosa. To investigate the interaction between catecholamine functioning and behavioral, and neural responses directly, 17 remitted bulimic (rBN) and 21 healthy individuals (HC) received alpha-methyl-paratyrosine (AMPT) over 24 h to achieve catecholamine depletion in a randomized, crossover study design. We used functional magnetic resonance imaging (fMRI) and the monetary incentive delay (MID) task to assess reward-effort integration in relation to catecholaminergic neurotransmission at the behavioral and neural level. AMPT reduced the ability to integrate rewards and efforts effectively in HC participants. In contrast, in rBN participants, the reduced reward-effort integration was associated with illness duration in the sham condition and unrelated to catecholamine depletion. Regarding neural activation, AMPT decreased the reward anticipation-related neural activation in the anteroventral striatum. This decrease was associated with the AMPT-induced reduction of monetary earning in HC in contrast to rBN participants. Our findings contributed to the theory of a desensitized dopaminergic system in bulimia nervosa. A disrupted processing of reward magnitudes and effort costs might increase the probability of maintenance of bulimic symptoms.

Phase-Dependent Modulation of Signal Transmission in Cortical Networks through tACS-Induced Neural Oscillations.

Oscillatory neural activity is considered a basis of signal transmission in brain networks. However, the causal role of neural oscillations in regulating cortico-cortical signal transmission has so far not been directly demonstrated. To date, due to methodological limitations, studies on the online modulatory mechanisms of transcranial alternating current stimulation (tACS)-induced neural oscillations are confined to the primary motor cortex. To address the causal role of oscillatory activity in modulating cortico-cortical signal transmission, we have established a new method using concurrent tACS, transcranial magnetic stimulation (TMS) and electroencephalography (EEG). Through tACS, we introduced 6-Hz (theta) oscillatory activity in the human dorsolateral prefrontal cortex (DLPFC). During tACS, we applied single-pulse TMS over the DLPFC at different phases of tACS and assessed propagation of TMS-induced neural activity with EEG. We show that tACS-induced theta oscillations modulate the propagation of TMS-induced activity in a phase-dependent manner and that phase-dependent modulation is not simply explained by the instantaneous amplitude of tACS. The results demonstrate a phase-dependent modulatory mechanism of tACS at a cortical network level, which is consistent with a causal role of neural oscillations in regulating the efficacy of signal transmission in the brain.