Dynamic brain communication underwriting face pareidolia.

Face pareidolia is a tendency to seeing faces in nonface images that reflects high tuning to a face scheme. Yet, studies of the brain networks underwriting face pareidolia are scarce. Here, we examined the time course and dynamic topography of gamma oscillatory neuromagnetic activity while administering a task with nonface images resembling a face. Images were presented either with canonical orientation or with display inversion that heavily impedes face pareidolia. At early processing stages, the peaks in gamma activity (40 to 45 Hz) to images either triggering or not face pareidolia originate mainly from the right medioventral and lateral occipital cortices, rostral and caudal cuneus gyri, and medial superior occipital gyrus. Yet, the difference occurred at later processing stages in the high-frequency range of 80 to 85 Hz over a set of the areas constituting the social brain. The findings speak rather for a relatively late neural network playing a key role in face pareidolia. Strikingly, a cutting-edge analysis of brain connectivity unfolding over time reveals mutual feedforward and feedback intra- and interhemispheric communication not only within the social brain but also within the extended large-scale network of down- and upstream regions. In particular, the superior temporal sulcus and insula strongly engage in communication with other brain regions either as signal transmitters or recipients throughout the whole processing of face-pareidolia images.

Reading language of the eyes in female depression.

Aberrations in non-verbal social cognition have been reported to coincide with major depressive disorder. Yet little is known about the role of the eyes. To fill this gap, the present study explores whether and, if so, how reading language of the eyes is altered in depression. For this purpose, patients and person-by-person matched typically developing individuals were administered the Emotions in Masked Faces task and Reading the Mind in the Eyes Test, modified, both of which contained a comparable amount of visual information available. For achieving group homogeneity, we set a focus on females as major depressive disorder displays a gender-specific profile. The findings show that facial masks selectively affect inferring emotions: recognition of sadness and anger are more heavily compromised in major depressive disorder as compared with typically developing controls, whereas the recognition of fear, happiness, and neutral expressions remains unhindered. Disgust, the forgotten emotion of psychiatry, is the least recognizable emotion in both groups. On the Reading the Mind in the Eyes Test patients exhibit lower accuracy on positive expressions than their typically developing peers, but do not differ on negative items. In both depressive and typically developing individuals, the ability to recognize emotions behind a mask and performance on the Reading the Mind in the Eyes Test are linked to each other in processing speed, but not recognition accuracy. The outcome provides a blueprint for understanding the complexities of reading language of the eyes within and beyond the COVID-19 pandemic.

Aberrant neuronal connectivity and network activity of neurons derived from patients with idiopathic schizophrenia.

Schizophrenia (SCZ) is a psychiatric disorder with a strong genetic determinant. A major hypothesis to explain disease aetiology comprises synaptic dysfunction associated with excitatory-inhibitory imbalance of synaptic transmission, ultimately contributing to impaired network oscillation and cognitive deficits associated with the disease. Here, we studied the morphological and functional properties of a highly defined co-culture of GABAergic and glutamatergic neurons derived from induced pluripotent stem cells (iPSC) from patients with idiopathic SCZ. Our results indicate upregulation of synaptic genes and increased excitatory synapse formation on GABAergic neurons in co-cultures. In parallel, we observed decreased lengths of axon initial segments, concordant with data from postmortem brains from patients with SCZ. In line with increased synapse density, patch-clamp analyses revealed markedly increased spontaneous excitatory postsynaptic currents (EPSC) recorded from GABAergic SCZ neurons. Finally, MEA recordings from neuronal networks indicate increased strength of network activity, potentially in response to altered synaptic transmission and E-I balance in the co-cultures. In conclusion, our results suggest selective deregulation of neuronal activity in SCZ samples, providing evidence for altered synapse formation and synaptic transmission as a potential base for aberrant network synchronization.

Prediction of estimated risk for bipolar disorder using machine learning and structural MRI features.

BACKGROUND: Individuals with bipolar disorder are commonly correctly diagnosed a decade after symptom onset. Machine learning techniques may aid in early recognition and reduce the disease burden. As both individuals at risk and those with a manifest disease display structural brain markers, structural magnetic resonance imaging may provide relevant classification features. METHODS: Following a pre-registered protocol, we trained linear support vector machine (SVM) to classify individuals according to their estimated risk for bipolar disorder using regional cortical thickness of help-seeking individuals from seven study sites (N = 276). We estimated the risk using three state-of-the-art assessment instruments (BPSS-P, BARS, EPIbipolar). RESULTS: For BPSS-P, SVM achieved a fair performance of Cohen's κ of 0.235 (95% CI 0.11-0.361) and a balanced accuracy of 63.1% (95% CI 55.9-70.3) in the 10-fold cross-validation. In the leave-one-site-out cross-validation, the model performed with a Cohen's κ of 0.128 (95% CI -0.069 to 0.325) and a balanced accuracy of 56.2% (95% CI 44.6-67.8). BARS and EPIbipolar could not be predicted. In post hoc analyses, regional surface area, subcortical volumes as well as hyperparameter optimization did not improve the performance. CONCLUSIONS: Individuals at risk for bipolar disorder, as assessed by BPSS-P, display brain structural alterations that can be detected using machine learning. The achieved performance is comparable to previous studies which attempted to classify patients with manifest disease and healthy controls. Unlike previous studies of bipolar risk, our multicenter design permitted a leave-one-site-out cross-validation. Whole-brain cortical thickness seems to be superior to other structural brain features.

Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10-12, R2 = 1.9%) and continuous (P = 6.4 × 10-9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10-4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

Neural circuits underpinning face tuning in male depression.

Reading bodies and faces is essential for efficient social interactions, though it may be thought-provoking for individuals with depression. Yet aberrations in the face sensitivity and underwriting neural circuits are not well understood, in particular, in male depression. Here, we use cutting-edge analyses of time course and dynamic topography of gamma oscillatory neuromagnetic cortical activity during administration of a task with Arcimboldo-like images. No difference in face tuning was found between individuals with depression and their neurotypical peers. Furthermore, this behavioral outcome nicely dovetails with magnetoencephalographic data: at early processing stages, the gamma oscillatory response to images resembling a face was rather similar in patients and controls. These bursts originated primarily from the right medioventral occipital cortex and lateral occipital cortex. At later processing stages, however, its topography altered remarkably in depression with profound engagement of the frontal circuits. Yet the primary difference in depressive individuals as compared with their neurotypical peers occurred over the left middle temporal cortices, a part of the social brain, engaged in feature integration and meaning retrieval. The outcome suggests compensatory recruitment of neural resources in male depression.

Patient iPSC-derived neural progenitor cells display aberrant cell cycle control, p53, and DNA damage response protein expression in schizophrenia.

BACKGROUND: Schizophrenia (SCZ) is a severe psychiatric disorder associated with alterations in early brain development. Details of underlying pathomechanisms remain unclear, despite genome and transcriptome studies providing evidence for aberrant cellular phenotypes and pathway deregulation in developing neuronal cells. However, mechanistic insight at the protein level is limited. METHODS: Here, we investigate SCZ-specific protein expression signatures of neuronal progenitor cells (NPC) derived from patient iPSC in comparison to healthy controls using high-throughput Western Blotting (DigiWest) in a targeted proteomics approach. RESULTS: SCZ neural progenitors displayed altered expression and phosphorylation patterns related to Wnt and MAPK signaling, protein synthesis, cell cycle regulation and DNA damage response. Consistent with impaired cell cycle control, SCZ NPCs also showed accumulation in the G2/M cell phase and reduced differentiation capacity. Furthermore, we correlated these findings with elevated p53 expression and phosphorylation levels in SCZ patient-derived cells, indicating a potential implication of p53 in hampering cell cycle progression and efficient neurodevelopment in SCZ. CONCLUSIONS: Through targeted proteomics we demonstrate that SCZ NPC display coherent mechanistic alterations in regulation of DNA damage response, cell cycle control and p53 expression. These findings highlight the suitability of iPSC-based approaches for modeling psychiatric disorders and contribute to a better understanding of the disease mechanisms underlying SCZ, particularly during early development.

[The German Center for Mental Health : Innovative translational research to promote prevention, targeted intervention and resilience]. / Das Deutsche Zentrum für Psychische Gesundheit : Innovative Translationsforschung zur Förderung von Prävention, zielgerichteter Intervention und Resilienz.

BACKGROUND: Due to the high disease burden, the early onset and often long-term trajectories mental disorders are among the most widespread diseases with growing significance. The German Center for Mental Health (DZPG) was established to enhance research conditions and expedite the translation of clinically relevant findings into practice. OBJECTIVE: The aim of the DZPG is to optimize mental healthcare in Germany, influence modifiable social causes and to develop best practice models of care for vulnerable groups. It seeks to promote mental health and resilience, combat the stigmatization associated with mental disorders, and contribute to the enhancement of treatment across all age groups. MATERIAL AND METHODS: The DZPG employs a translational research program that accelerates the translation of basic research findings into clinical studies and general practice. University hospitals and outpatient departments, other university disciplines, and extramural research institutions are working together to establish a collaboratively coordinated infrastructure for accelerated translation and innovation. RESEARCH PRIORITIES: The research areas encompass 1) the interaction of somatic and mental risk and resilience factors and disorders across the lifespan, 2) influencing relevant modifiable environmental factors and 3) based on this personalized prevention and intervention. CONCLUSION: The DZPG aims to develop innovative preventive and therapeutic tools that enable an improvement in care for individuals with mental disorders. It involves a comprehensive integration of experts with experience at all levels of decision-making and employs trilogue and participatory approaches in all research projects.

Inhibitory Control Training Enhanced by Transcranial Direct Current Stimulation to Reduce Binge Eating Episodes: Findings from the Randomized Phase II ACCElect Trial.

INTRODUCTION: Binge eating disorder (BED) is characterized by recurrent binge eating (BE) episodes with loss of control. Inhibitory control impairments, including alterations in dorsolateral prefrontal cortex (dlPFC) functioning, have been described for BED. A targeted modulation of inhibitory control circuits by the combination of inhibitory control training and transcranial brain stimulation could be promising. OBJECTIVE: The aim of the study was to demonstrate feasibility and clinical effects of a transcranial direct current stimulation (tDCS)-enhanced inhibitory control training to reduce BE episodes and to generate an empirical basis for a confirmatory trial. METHODS: We performed a monocentric clinical phase II double-blind randomized trial with two parallel arms. Forty-one adult outpatients with full-syndrome BED according to DSM-5 received six sessions of food-related inhibitory control training, randomly combined with 2 mA verum or sham tDCS of the right dlPFC. The main outcome was BE frequency within a 4-week interval after treatment termination (T8; primary) and at 12-week follow-up (T9; secondary) as compared to baseline. RESULTS: BE frequency was reduced in the sham group from 15.5 to 5.9 (T8) and to 6.8 (T9); in the verum group, the reduction was 18.6 to 4.4 (T8) resp. 3.8 (T9). Poisson regression with the study arm as the factor and baseline BE frequency as the covariate revealed a p value of 0.34 for T8 and 0.026 for T9. Sham and real tDCS differed at T9 in BE frequency. CONCLUSIONS: Inhibitory control training enhanced by tDCS is safe in patients with BED and results in a substantial and sustainable reduction in BE frequency which unfolds over several weeks post-treatment. These results constitute the empirical basis for a confirmatory trial.

Food-related reward sensitivity across the spectrum of body weight and impulsive eating: Pilot findings from a multi-method approach.

Overweight with and without comorbid binge-eating disorder (BED) has been associated with increased reward sensitivity, though evidence is heterogeneous. To disentangle this heterogeneity and gain insights into mechanisms of impaired reward processing, this study applied multi-method neuro-behavioural techniques. Reward sensitivity was investigated in N = 49 participants allocated to three subgroups: overweight individuals with BED (BED+, n = 17), overweight individuals without BED (BED-, n = 15), and normal-weight controls (NWC, n = 17). Applying a free exploration paradigm (food vs. non-food stimuli), eye tracking and electroencephalographic data were gathered. A valid cue before stimulus onset indicated the position of food, and the end points analysed after the cue and stimulus onset were attentional approach, attention allocation, and conflict processing (e.g., conflict between looking at the potentially rewarding food stimulus or not). The effect of negative mood was tested using mood induction. The study's main hypothesis was that individuals with overweight, particularly under negative mood, would have increased food-related reward sensitivity. All participants showed increased food-specific attentional approach (p < .001). BED + allocated more attention to food stimuli than non-food stimuli compared to the healthy control (p = .045). For individuals with overweight but without BED (BED-), results indicate that conflict processing might be prolonged after the stimulus onset (p = .011). No group-specific effect of negative mood was found. Preliminary results in overweight individuals with and without comorbid BED suggest that food stimuli are generally rewarding stimuli, but even more so for participants with binge eating psychopathology. Prolonged conflict processing during the confrontation with competing food and non-food stimuli was solely found in the BED- sample and might indicate a compensation mechanism. Replication is warranted. The multi-method approach seems to be promising to give indications for the development of psychotherapeutic treatment.

Brain circuits signaling the absence of emotion in body language.

Adaptive social behavior and mental well-being depend on not only recognizing emotional expressions but also, inferring the absence of emotion. While the neurobiology underwriting the perception of emotions is well studied, the mechanisms for detecting a lack of emotional content in social signals remain largely unknown. Here, using cutting-edge analyses of effective brain connectivity, we uncover the brain networks differentiating neutral and emotional body language. The data indicate greater activation of the right amygdala and midline cerebellar vermis to nonemotional as opposed to emotional body language. Most important, the effective connectivity between the amygdala and insula predicts people's ability to recognize the absence of emotion. These conclusions extend substantially current concepts of emotion perception by suggesting engagement of limbic effective connectivity in recognizing the lack of emotion in body language reading. Furthermore, the outcome may advance the understanding of overly emotional interpretation of social signals in depression or schizophrenia by providing the missing link between body language reading and limbic pathways. The study thus opens an avenue for multidisciplinary research on social cognition and the underlying cerebrocerebellar networks, ranging from animal models to patients with neuropsychiatric conditions.

Investigating mechanisms of cognitive control training: neural signatures of PASAT performance in depressed patients.

Major depression disorder (MDD) is characterized by cognitive control (CC) dysfunctions associated with increased attention toward negative information. The paced auditory serial addition task (PASAT) has been used as a targeted training of CC and studies show promising effects on depressive symptoms. However, neural mechanisms underlying its efficacy are still unclear. Based on previous findings of feedback-locked event-related potentials in healthy subjects, we investigated neural signatures during PASAT performance in 46 depressed patients. We found significantly larger amplitudes after negative than positive feedback for the P300 and late positive potential (LPP). However, this difference was not significant for the feedback-related negativity (FRN). Moreover, no associations of valence-specific ERPs and PASAT performance nor depressive symptoms were found. This indicates that depressed patients seem unable to use neural activation in late feedback processing stages (P300, LPP) to adapt accordingly. Moreover, lack of valence-specific neural reaction in early feedback processing stages (FRN) might point toward emotional indifference in depressed patients.Trial registration number: NCT03518749 Date of registration: May 8, 2018.

The role of comorbid depressive symptoms on long-range temporal correlations in resting EEG in adults with ADHD.

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder, characterized by core symptoms of inattention, hyperactivity and impulsivity. Comorbid depression is commonly observed in ADHD-patients. Psychostimulants are recommended as first-line treatment for ADHD. Aberrant long-range temporal correlations (LRTCs) of neuronal activities in resting-state are known to be associated with disorganized thinking and concentrating difficulties (typical in ADHD) and with maladaptive thinking (typical in depression). It has yet to be examined whether (1) LRTC occur in ADHD-patients, and if so, (2) whether LRTC might be a competent biomarker in ADHD comorbid with current depression and (3) how depression affects psychostimulant therapy of ADHD symptoms. The present study registered and compared LRTCs in different EEG frequency bands in 85 adults with ADHD between groups with (n = 28) and without (n = 57) additional depressive symptoms at baseline. Treatment-related changes in ADHD, depressive symptoms and LRTC were investigated in the whole population and within each group. Our results revealed significant LRTCs existed in all investigated frequency bands. There were, however, no significant LRTC-differences between ADHD-patients with and without depressive symptoms at baseline and no LRTC-changes following treatment. However, depressed ADHD patients did seem to benefit more from the therapy with psychostimulant based on self-report.

Face Tuning in Depression.

The latest COVID-19 pandemic reveals that unexpected changes elevate depression bringing people apart, but also calling for social sharing. Yet the impact of depression on social cognition and functioning is not well understood. Assessment of social cognition is crucial not only for a better understanding of major depressive disorder (MDD), but also for screening, intervention, and remediation. Here by applying a novel experimental tool, a Face-n-Food task comprising a set of images bordering on the Giuseppe Arcimboldo style, we assessed the face tuning in patients with MDD and person-by-person matched controls. The key benefit of these images is that single components do not trigger face processing. Contrary to common beliefs, the outcome indicates that individuals with depression express intact face responsiveness. Yet, while in depression face sensitivity is tied with perceptual organization, in typical development, it is knotted with social cognition capabilities. Face tuning in depression, therefore, may rely upon altered behavioral strategies and underwriting brain mechanisms. To exclude a possible camouflaging effect of female social skills, we examined gender impact. Neither in depression nor in typical individuals had females excelled in face tuning. The outcome sheds light on the origins of the face sensitivity and alterations in social functioning in depression and mental well-being at large. Aberrant social functioning in depression is likely to be the result of deeply-rooted maladaptive strategies rather than of poor sensitivity to social signals. This has implications for mental well-being under the current pandemic conditions.

Open Doors by Fair Means: a quasi-experimental controlled study on the effects of an open-door policy on acute psychiatric wards.

BACKGROUND: Psychiatric wards treating involuntarily admitted patients are traditionally locked to prevent absconding. However, on the basis of observational evidence, the necessity for locked units in psychiatric hospitals has increasingly been questioned. Updated Mental Health Laws in several Federal States of Germany legitimate involuntary commitment without generally locked doors. METHODS: We examined the effects of an open-door policy in a quasi-experimental, prospective design. For the first time, at each of two locations, two identical wards serving as control and intervention could be compared. After a baseline period of three months, one ward at each location started the 12 month intervention period with the implementation of an open-door policy, while the respective control ward, as before, used open doors only facultatively. Primary outcomes were average opening times of the four wards between 8 a.m. and 8 p.m., and the number of involuntary treatment days with the doors open. Secondary outcomes were adverse events including aggressive incidents, absconding, suicide attempts and coercive measures. RESULTS: Overall, door-opening times increased significantly at both sites´ intervention wards. The number of adverse events did not increase during intervention period. Frequencies of coercive measures decreased in Friedrichshafen and remained unchanged in Tuebingen. In case of the intervention ward in Friedrichshafen, doors were open in up to 91% of all involuntary treatment days, whereas in the control ward, this was only the case in 67% of all involuntary treatment days (p < .001). In case of the intervention ward in Tuebingen, 45% of involuntary treatment days had open doors, compared to 30% in the control ward (p < .001). CONCLUSIONS: It is possible to manage psychiatric wards with open doors without taking inappropriate risks. The extent to which open-door policies are achievable is be dependent on staffing and patient characteristics. Further research is necessary to explore the role of staff attitudes. TRIAL REGISTRATION: Our trial "Open Doors by Fair Means" is retrospectively registered with DRKS ( DRKS00015154 ) on Sept. 10th 2018 and displayed on the public web site. It is searchable via its meta-registry ( http://apps.who.int/trialsearch/ ).

The Neural Bases of Tinnitus: Lessons from Deafness and Cochlear Implants.

Subjective tinnitus is the conscious perception of sound in the absence of any acoustic source. The literature suggests various tinnitus mechanisms, most of which invoke changes in spontaneous firing rates of central auditory neurons resulting from modification of neural gain. Here, we present an alternative model based on evidence that tinnitus is: (1) rare in people who are congenitally deaf, (2) common in people with acquired deafness, and (3) potentially suppressed by active cochlear implants used for hearing restoration. We propose that tinnitus can only develop after fast auditory fiber activity has stimulated the synapse formation between fast-spiking parvalbumin positive (PV+) interneurons and projecting neurons in the ascending auditory path and coactivated frontostriatal networks after hearing onset. Thereafter, fast auditory fiber activity promotes feedforward and feedback inhibition mediated by PV+ interneuron activity in auditory-specific circuits. This inhibitory network enables enhanced stimulus resolution, attention-driven contrast improvement, and augmentation of auditory responses in central auditory pathways (neural gain) after damage of slow auditory fibers. When fast auditory fiber activity is lost, tonic PV+ interneuron activity is diminished, resulting in the prolonged response latencies, sudden hyperexcitability, enhanced cortical synchrony, elevated spontaneous γ oscillations, and impaired attention/stress-control that have been described in previous tinnitus models. Moreover, because fast processing is gained through sensory experience, tinnitus would not exist in congenital deafness. Electrical cochlear stimulation may have the potential to reestablish tonic inhibitory networks and thus suppress tinnitus. The proposed framework unites many ideas of tinnitus pathophysiology and may catalyze cooperative efforts to develop tinnitus therapies.

Analysis of structural brain asymmetries in attention-deficit/hyperactivity disorder in 39 datasets.

OBJECTIVE: Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. METHODS: We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. RESULTS: There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen's d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing. CONCLUSION: Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.

Neural correlates of attentional control in social anxiety disorder: the impact of early-life adversity and DNA methylation.

BACKGROUND: Social anxiety disorder is characterized by intense fear and avoidance of social interactions and scrutiny by others. Although alterations in attentional control seem to play a central role in the psychopathology of social anxiety disorder, the neural underpinnings in prefrontal brain regions have not yet been fully clarified. METHODS: The present study used functional MRI in participants (age 18-50 yr) with social anxiety disorder (n = 42, 31 female) and without (n = 58, 33 female). It investigated the interrelation of the effects of social anxiety disorder and early-life adversity (a main environmental risk factor of social anxiety disorder) on brain activity during an attentional control task. We applied DNA methylation analysis to determine whether epigenetic modulation in the gene encoding the glucocorticoid receptor, NR3C1, might play a mediating role in this process. RESULTS: We identified 2 brain regions in the left and medial prefrontal cortex that exhibited an interaction effect of social anxiety disorder and early-life adversity. In participants with low levels of early-life adversity, neural activity in response to disorder-related stimuli was increased in association with social anxiety disorder. In participants with high levels of early-life adversity, neural activity was increased only in participants without social anxiety disorder. NR3C1 DNA methylation partly mediated the effect of social anxiety disorder on brain activity as a function of early-life adversity. LIMITATIONS: The absence of behavioural correlates associated with social anxiety disorder limited functional interpretation of the results. CONCLUSION: These findings demonstrate that the neurobiological processes that underlie social anxiety disorder might be fundamentally different depending on experiences of early-life adversity. Long-lasting effects of early-life adversity might be encoded in NR3C1 DNA methylation and entail alterations in social anxiety disorder-related activity patterns in the neural network of attentional control.

Treatment of major depressive disorder with bilateral theta burst stimulation: study protocol for a randomized, double-blind, placebo-controlled multicenter trial (TBS-D).

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (dlPFC) is currently evolving as an effective and safe therapeutic tool in the treatment of major depressive disorder (MDD). However, already established rTMS treatment paradigms are rather time-consuming. With theta burst stimulation (TBS), a patterned form of rTMS, treatment time can be substantially reduced. Pilot studies and a randomized controlled trial (RCT) demonstrate non-inferiority of TBS to 10 Hz rTMS and support a wider use in MDD. Still, data from placebo-controlled multicenter RCTs are lacking. In this placebo-controlled multicenter study, 236 patients with MDD will be randomized to either intermittent TBS (iTBS) to the left and continuous TBS (cTBS) to the right dlPFC or bilateral sham stimulation (1:1 ratio). The treatment will be performed with 80% resting motor threshold intensity over six consecutive weeks (30 sessions). The primary outcome is the treatment response rate (Montgomery-Asberg Depression Rating Scale reduction ≥ 50%). The aim of the study is to confirm the superiority of active bilateral TBS compared to placebo treatment. In two satellite studies, we intend to identify possible MRI-based and (epi-)genetic predictors of responsiveness to TBS therapy. Positive results will support the clinical use of bilateral TBS as an advantageous, efficient, and well-tolerated treatment and pave the way for further individualization of MDD therapy.Trial registration: ClinicalTrials.gov (NCT04392947).

Effects of 1 mA and 2 mA transcranial direct current stimulation on working memory performance in healthy participants.

Anodal transcranial current stimulation (tDCS) to the left dorsolateral prefrontal cortex (DLPFC) has been shown to enhance working memory (WM) in neuropsychiatric patients. In healthy populations, however, tDCS obtains inconclusive results, mostly due to heterogeneous study and stimulation protocols. Here, we approached these issues by investigating effects of tDCS intensity on simultaneous WM performance with three cognitive loads by directly comparing findings of two double-blind, cross-over, sham-controlled experiments. TDCS was administrated to the left DLPFC at intensity of 1 mA (Experiment 1) or 2 mA (Experiment 2), while participants completed a verbal n-back paradigm (1-, 2-, 3-back). Analysis showed no overall effects of tDCS on WM, but a significant interaction with cognitive load. The present study suggests that cognitive load rather than tDCS intensity could be a decisive factor for effects on WM. Moreover, it emphasizes the need of thorough investigation on study parameters to develop more efficient stimulation protocols.