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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.

Social anxiety disorder (SAD) is a psychiatric disorder characterized by severe fear in social situations and avoidance of these. Multiple genetic as well as environmental factors contribute to the etiopathology of SAD. One of the main risk factors for SAD is stress, especially during early periods of life (early life adversity; ELA). ELA leads to structural and regulatory alterations contributing to disease vulnerability. This includes the dysregulation of the immune response. However, the molecular link between ELA and the risk for SAD in adulthood remains largely unclear. Evidence is emerging that long-lasting changes of gene expression patterns play an important role in the biological mechanisms linking ELA and SAD. Therefore, we conducted a transcriptome study of SAD and ELA performing RNA sequencing in peripheral blood samples. Analyzing differential gene expression between individuals suffering from SAD with high or low levels of ELA and healthy individuals with high or low levels of ELA, 13 significantly differentially expressed genes (DEGs) were identified with respect to SAD while no significant differences in expression were identified with respect to ELA. The most significantly expressed gene was MAPK3 (p = 0.003) being upregulated in the SAD group compared to control individuals. In contrary, weighted gene co-expression network analysis (WGCNA) identified only modules significantly associated with ELA (p ≤ 0.05), not with SAD. Furthermore, analyzing interaction networks of the genes from the ELA-associated modules and the SAD-related MAPK3 revealed complex interactions of those genes. Gene functional enrichment analyses indicate a role of signal transduction pathways as well as inflammatory responses supporting an involvement of the immune system in the association of ELA and SAD. In conclusion, we did not identify a direct molecular link between ELA and adult SAD by transcriptional changes. However, our data indicate an indirect association of ELA and SAD mediated by the interaction of genes involved in immune-related signal transduction.

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).

There are only a few validated chronotype and morningness-eveningness questionnaires for adolescents. We evaluated three such questionnaires, namely Morningness-Eveningness Stability Scale improved; reduced Morningness-Eveningness Questionnaire for Children and Adolescents; and Composite Scale of Morningness in adolescents against actigraphy. Fifty-five healthy 13- to 16-year-old adolescents completed the Morningness-Eveningness Stability Scale improved, reduced Morningness-Eveningness Questionnaire for Children and Adolescents, Composite Scale of Morningness, and Pediatric Daytime Sleepiness Scale, and provided a 7-day actigraphy and sleep diary recording about their sleep-wake patterns. We examined the correlations between sleep-wake and activity parameters, and the questionnaires. The influence of age and sex on chronotype classification was studied using uni- and multivariate analyses. All three chronotype questionnaires showed good internal consistency and convergent validity. Spearman correlations reflected less daytime sleepiness, earlier sleep times, midpoints of sleep, and acrophase in morning-oriented participants. Evening-oriented participants had more sleepiness and later respective sleep-wake times. Chronotype classification differed significantly between questionnaires. The Composite Scale of Morningness classified more participants as morning types when compared with the reduced Morningness-Eveningness Questionnaire for Children and Adolescents (12 versus 7, respectively), and fewer adolescents as evening types (5 versus 9, respectively). Age and sex had no significant influence on questionnaire scores. The Morningness-Eveningness Stability Scale improved, reduced Morningness-Eveningness Questionnaire for Children and Adolescents, and Composite Scale of Morningness are valid instruments to determine circadian preference in adolescents; however, chronotype classification from the Composite Scale of Morningness and reduced Morningness-Eveningness Questionnaire for Children and Adolescents cannot be used interchangeably.

BACKGROUND: The neuropeptide oxytocin (OXT) plays a role in the regulation of eating behavior and metabolism. OXT functioning is altered in patients with eating and weight disorders, and a variant of the oxytocin receptor gene (OXTR) has been associated with impulsive eating behavior as it is seen in patients with binge eating disorder (BED). Gene × environment interactions could play a role in BED. One mechanism mediating this interaction is the epigenetic alteration of gene expression. We therefore investigated if DNA methylation of the OXTR differs between individuals with obesity depending on a comorbid BED. We analyzed DNA methylation of the OXTR in peripheral blood of 227 individuals on the obesity spectrum (mean age: 40.3 ± 13.1 yrs; mean BMI: 38.6 ± 7.3kg/m2), 130 of which were diagnosed with BED. RESULTS: There were no overall differences in OXTR methylation between participants with and those without BED (p > 0.05), while both subgroups were comparable regarding age and body mass index (BMI), but significantly differed in sex distribution (p = 0.035). We found no relationship between mean DNA methylation and BMI or self-reported eating disorder (ED) pathology. Analyzing potential sex differences revealed a significantly lower OXTR DNA methylation in male participants with BED ascompared to those without BED (p = 0.017). No such difference was found in the female subsample (p > 0.05). CONCLUSIONS: Clinically significant binge eating pathology might be associated with lower OXTR DNA methylation exclusively in males. The differential DNA methylation of OXTR in males with BED supports the view that BED represents a phenotype within the obesity spectrum that is characterized by specific vulnerability factors. A better understanding of the epigenetic underpinnings of the OXT system might contribute to the refinement of OXT administration approaches as potential interventions in eating and weight disorders.

Differential DNA methylation in peripheral tissues has been associated with Borderline Personality Disorder (BPD). Alterations have been found in several genes, among them the Catechol-O-methyltransferase (COMT) gene. COMT is a known neuropsychiatric candidate gene, which contains a genotype variant (Val108/158Met) that affects protein function and has been found associated with several psychiatric disorders. In addition, this variant also affects COMT DNA methylation. However, in previous epigenetic studies, the DNA methylation results have not always been controlled for genotype, even though overrepresentation of the Met allele has been frequently reported in cohorts of BPD patients. Therefore, in the present study, we investigated whether alteration of COMT DNA methylation in BPD patients is indeed associated with mental health status or merely influenced by a differential distribution of the COMT genotype between BPD patients and healthy control individuals. We found significant group differences, as well as a strong effect of genotype on COMT DNA methylation. While the direction of effect was different compared to a previous study, our study supports the finding of altered COMT DNA methylation in patients with BPD and reinforces the need to include genotype information in future DNA methylation studies of COMT.

Introduction Sex differences in stress reactions are often reported in the literature. However, the sex-dependent interplay of different facets of stress is still not fully understood. Particularly in neuroimaging research, studies on large samples combining different indicators of stress remain scarce. Materials and Methods In a functional magnetic resonance imaging study, a sample of 140 healthy participants (67 females using oral contraceptives) underwent a standardized stress induction protocol, the ScanSTRESS. During the experiment, salivary cortisol and subjective ratings were obtained at multiple time points and heart rate was recorded. Results Sex differences emerged in different facets of the stress response:Women reacted with enhanced subjective feelings of stress and increases in heart rate, while men showed more pronounced neural activation in stress-related brain regions such as the inferior frontal gyrus and insula. Subjective feelings of stress and (para) hippocampal activity were negatively related in women,whereas a slightly positive association was observed in men. Discussion These results provide further insight in the sex-specific stress response patterns. Moreover, they emphasize the role of the hippocampus in the regulation of the stress response. This paves the way for the identification of sex-dependent vulnerability factors that can, in the future, be implemented in the prevention and treatment of stress-related disorders.

As early detection of symptoms in the subclinical to clinical psychosis spectrum may improve health outcomes, knowing the probabilistic susceptibility of developing a disorder could guide mitigation measures and clinical intervention. In this context, polygenic risk scores (PRSs) quantifying the additive effects of multiple common genetic variants hold the potential to predict complex diseases and index severity gradients. PRSs for schizophrenia (SZ) and bipolar disorder (BD) were computed using Bayesian regression and continuous shrinkage priors based on the latest SZ and BD genome-wide association studies (Psychiatric Genomics Consortium, third release). Eight well-phenotyped groups (n = 1580; 56% males) were assessed: control (n = 305), lower (n = 117) and higher (n = 113) schizotypy (both groups of healthy individuals), at-risk for psychosis (n = 120), BD type-I (n = 359), BD type-II (n = 96), schizoaffective disorder (n = 86), and SZ groups (n = 384). PRS differences were investigated for binary traits and the quantitative Positive and Negative Syndrome Scale. Both BD-PRS and SZ-PRS significantly differentiated controls from at-risk and clinical groups (Nagelkerke’s pseudo-R2: 1.3–7.7%), except for BD type-II for SZ-PRS. Out of 28 pairwise comparisons for SZ-PRS and BD-PRS, 9 and 12, respectively, reached the Bonferroni-corrected significance. BD-PRS differed between control and at-risk groups, but not between at-risk and BD type-I groups. There was no difference between controls and schizotypy. SZ-PRSs, but not BD-PRSs, were positively associated with transdiagnostic symptomology. Overall, PRSs support the continuum model across the psychosis spectrum at the genomic level with possible irregularities for schizotypy. The at-risk state demands heightened clinical attention and research addressing symptom course specifiers. Continued efforts are needed to refine the diagnostic and prognostic accuracy of PRSs in mental healthcare.

Cognitive deficits are a core feature of psychiatric disorders like schizophrenia and bipolar disorder. Evidence supports a genome-wide polygenic score (GPS) for educational attainment (GPSEDU) can be used to explain variability in cognitive performance. We aimed to identify different cognitive domains associated with GPSEDU in a transdiagnostic clinical cohort of chronic psychiatric patients with known cognitive deficits. Bipolar and schizophrenia patients from the PsyCourse cohort (N = 730; 43% female) were used. Likewise, we tested whether GPSs for schizophrenia (GPSSZ) and bipolar disorder (GPSBD) were associated with cognitive outcomes. GPSEDU explained 1.5% of variance in the backward verbal digit span, 1.9% in the number of correctly recalled words of the Verbal Learning and Memory Test, and 1.1% in crystallized intelligence. These effects were robust to the influences of treatment and diagnosis. No significant associations between GPSSZ or GPSBD with cognitive outcomes were found. Furthermore, these risk scores did not confound the effect of GPSEDU on cognitive outcomes. GPSEDU explains a small fraction of cognitive performance in adults with psychiatric disorders, specifically for domains related to linguistic learning and working memory. Investigating such a proxy-phenotype longitudinally, could give intriguing insight into the disease course, highlighting at what time genes play a more influential role on cognitive performance. Better understanding the origin of these deficits might help identify those patients at risk for lower levels of functioning and poor social outcomes. Polygenic estimates may in the future be part of predictive models for more personalized interventions.

Cognitive control of information processing is an essential prerequisite of human behavior. Particularly, focusing attention in the face of failure poses a common challenge. Previous work has demonstrated that transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (dlPFC) can improve cognitive control in a challenging and repeatedly frustrating task. In a randomized, sham-controlled, crossover design 22 healthy, male participants performed an adaptive 2-back version of the Paced Auditory Serial Addition Task (PASAT), parallel to anodal or sham tDCS over the left dlPFC and the return electrode on the right upper arm. Before and after the 2-back PASAT, the affective state was assessed by means of the Positive and Negative Affective Schedule (PANAS). We observed an interaction between stimulation condition and task performance driven by an increase in performance with anodal tDCS and no improvement with sham stimulation. In addition, after the 2-back PASAT we found a higher positive and a trend towards lower negative affect with anodal as compared to sham tDCS. Our data support and extend previous results showing improved processing speed under anodal stimulation associated with a reduced task-induced negative affect indicating an improvement of cognitive control. Further studies will investigate long-term effects and clinical applicability.

Processing of acute stress has potential implications for mental and physical health. At the same time, individuals differ largely in how strongly they react to stress. Neuroimaging paradigms have been developed to characterize the neural underpinnings of the stress response in general and to understand the mechanisms that differentiate high and low susceptible individuals. The goal of the present review was to summarize the current literature on psychosocial stress in the brain imaging environment. That is, we focused on the most common neuroimaging paradigms that have been used to induce acute stress and map out the questions that have been addressed with respect to the determinants, the consequences, and the processing of stress. We identified four major paradigms that have been used with different scientific aims. The Montreal Imaging Stress Test and the ScanSTRESS involve cognitive challenge and social-evaluative threat and yielded a stress-related network including most significantly the perigenual ACC, the hippocampus, and the amygdala. The social-evaluative threat paradigm was used to predict the autonomic stress response on the basis of multivariate pattern analysis. The aversive video paradigm, on the other hand, was mainly used to investigate the consequences of stress on emotional and cognitive processes and their neural correlates. We conclude our review with a critical evaluation of methodological and conceptual issues in the study of the neural correlates of acute stress.

Social anxiety disorder (SAD) is a psychiatric disorder characterized by extensive fear in social situations. Multiple genetic and environmental factors are known to contribute to its pathogenesis. One of the main environmental risk factors is early life adversity (ELA). Evidence is emerging that epigenetic mechanisms such as DNA methylation might play an important role in the biological mechanisms underlying SAD and ELA. To investigate the relationship between ELA, DNA methylation, and SAD, we performed an epigenome-wide association study for SAD and ELA examining DNA from whole blood of a cohort of 143 individuals using DNA methylation arrays. We identified two differentially methylated regions (DMRs) associated with SAD located within the genes SLC43A2 and TNXB. As this was the first epigenome-wide association study for SAD, it is worth noting that both genes have previously been associated with panic disorder. Further, we identified two DMRs associated with ELA within the SLC17A3 promoter region and the SIAH3 gene and several DMRs that were associated with the interaction of SAD and ELA. Of these, the regions within C2CD2L and MRPL28 showed the largest difference in DNA methylation. Lastly, we found that two DMRs were associated with both the severity of social anxiety and ELA, however, neither of them was found to mediate the contribution of ELA to SAD later in life. Future studies are needed to replicate our findings in independent cohorts and to investigate the biological pathways underlying these effects.

IMPORTANCE: Identifying psychosis subgroups could improve clinical and research precision. Research has focused on symptom subgroups, but there is a need to consider a broader clinical spectrum, disentangle illness trajectories, and investigate genetic associations. OBJECTIVE: To detect psychosis subgroups using data-driven methods and examine their illness courses over 1.5 years and polygenic scores for schizophrenia, bipolar disorder, major depression disorder, and educational achievement. DESIGN, SETTING, AND PARTICIPANTS: This ongoing multisite, naturalistic, longitudinal (6-month intervals) cohort study began in January 2012 across 18 sites. Data from a referred sample of 1223 individuals (765 in the discovery sample and 458 in the validation sample) with DSM-IV diagnoses of schizophrenia, bipolar affective disorder (I/II), schizoaffective disorder, schizophreniform disorder, and brief psychotic disorder were collected from secondary and tertiary care sites. Discovery data were extracted in September 2016 and analyzed from November 2016 to January 2018, and prospective validation data were extracted in October 2018 and analyzed from January to May 2019. MAIN OUTCOMES AND MEASURES: A clinical battery of 188 variables measuring demographic characteristics, clinical history, symptoms, functioning, and cognition was decomposed using nonnegative matrix factorization clustering. Subtype-specific illness courses were compared with mixed models and polygenic scores with analysis of covariance. Supervised learning was used to replicate results in validation data with the most reliably discriminative 45 variables. RESULTS: Of the 765 individuals in the discovery sample, 341 (44.6%) were women, and the mean (SD) age was 42.7 (12.9) years. Five subgroups were found and labeled as affective psychosis (n = 252), suicidal psychosis (n = 44), depressive psychosis (n = 131), high-functioning psychosis (n = 252), and severe psychosis (n = 86). Illness courses with significant quadratic interaction terms were found for psychosis symptoms (R(2) = 0.41; 95% CI, 0.38-0.44), depression symptoms (R(2) = 0.28; 95% CI, 0.25-0.32), global functioning (R(2) = 0.16; 95% CI, 0.14-0.20), and quality of life (R(2) = 0.20; 95% CI, 0.17-0.23). The depressive and severe psychosis subgroups exhibited the lowest functioning and quadratic illness courses with partial recovery followed by reoccurrence of severe illness. Differences were found for educational attainment polygenic scores (mean [SD] partial η(2) = 0.014 [0.003]) but not for diagnostic polygenic risk. Results were largely replicated in the validation cohort. CONCLUSIONS AND RELEVANCE: Psychosis subgroups were detected with distinctive clinical signatures and illness courses and specificity for a nondiagnostic genetic marker. New data-driven clinical approaches are important for future psychosis taxonomies. The findings suggest a need to consider short-term to medium-term service provision to restore functioning in patients stratified into the depressive and severe psychosis subgroups.

In current diagnostic systems, schizophrenia and bipolar disorder are still conceptualized as distinct categorical entities. Recently, both clinical and genomic evidence have challenged this Kraepelinian dichotomy. There are only few longitudinal studies addressing potential overlaps between these conditions. Here, we present design and first results of the PsyCourse study (N = 891 individuals at baseline), an ongoing transdiagnostic study of the affective-to-psychotic continuum that combines longitudinal deep phenotyping and dimensional assessment of psychopathology with an extensive collection of biomaterial. To provide an initial characterization of the PsyCourse study sample, we compare two broad diagnostic groups defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) classification system, that is, predominantly affective (n = 367 individuals) versus predominantly psychotic disorders (n = 524 individuals). Depressive, manic, and psychotic symptoms as well as global functioning over time were contrasted using linear mixed models. Furthermore, we explored the effects of polygenic risk scores for schizophrenia on diagnostic group membership and addressed their effects on nonparticipation in follow-up visits. While phenotypic results confirmed expected differences in current psychotic symptoms and global functioning, both manic and depressive symptoms did not vary between both groups after correction for multiple testing. Polygenic risk scores for schizophrenia significantly explained part of the variability of diagnostic group. The PsyCourse study presents a unique resource to research the complex relationships of psychopathology and biology in severe mental disorders not confined to traditional diagnostic boundaries and is open for collaborations.

OBJECTIVES: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients. METHODS: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models. RESULTS: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. CONCLUSIONS: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype. peerReviewed

Borderline personality disorder (BPD) is a severe and complex mental disease associated with high suicidal tendencies and hospitalization rates. Accumulating evidence suggests that epigenetic mechanisms are implicated in the etiology of BPD. A recent epigenome-wide study identified several novel genes which are epigenetically dysregulated in BPD. Those genes include APBA3 and MCF2. Psychotherapy such as Dialectical Behavior Therapy (DBT), an established treatment for BPD, provides an excellent setting to investigate environmental influences on epigenetic mechanisms in order to identify biomarkers for disease status and therapy success. However, the effects of DBT on epigenetic regulation has only been researched in one previous study analyzing BDNF. In the present study, we aimed to investigate the role of DNA methylation of APBA3 and MCF2 as possible biomarkers for treatment outcome in BPD, whilst validating the previous findings of differential DNA methylation in a cohort of 44 BPD patients and 44 well-matched healthy control individuals. Unexpectedly, we did not detect significant DNA methylation differences between patients and control individuals. However, we found a high correlation between the methylation status of APBA3 and MCF2 and therapy outcome: before DBT treatment, both genes were significantly higher methylated in patients responding to therapy compared to patients that did not respond. Our study is the first to report results pointing to possible predictive epigenetic biomarkers of DBT outcome in BPD patients. Following replication in independent cohorts, our finding could facilitate the development of more personalized therapy concepts for BPD patients by including epigenetic information.

The androgen derivative androstadienone (AND) is present in human sweat and may act as human chemosignal. Though effects of AND have been reported with respect to emotional and cognitive processes, results have been highly inconsistent. For this reason, it is likely that AND-action is dependent on modulatory factors. Here we wanted to specifically investigate the impact of genotypic variations of the AND-receptor OR7D4, as well as the influence of participant sex and concomitant hormonal fluctuations on AND-action during emotional interference processing, olfactory performance and mood assessments. To this end 80 healthy individuals (women taking oral contraceptives; naturally cycling women measured during the luteal phase and men) were tested twice on two consecutive days (AND vs. placebo exposure) with an emotional Stroop task. Also, olfactory performance and mood was assessed. Participants provided saliva samples to measure testosterone, progesterone and estradiol and a blood sample to assess genotypic variations of the AND-receptor OR7D4. We found a small task-dependent reduction of overall error rates under AND but no modulation of effects by genetic variation or group (female OC, female NC, male) with respect to olfactory performance and mood. Additional analyses with help of Bayesian statistics gave strong evidence in favor of specific null hypotheses suggesting that the action of AND was not modulated by either genotypic variations or sex of participants with respect to interference control (bias indices), olfactory self-reports and mood parameters. Additional effects of AND in connection with hormonal fluctuations are reported.

Recent research has emphasized rumination as an important maintaining factor in various mental disorders. However, operationalization and therefore induction of rumination in experimental settings poses a major challenge in terms of ecological validity. As stress seems to play a key role in everyday situations eliciting rumination, we conducted two stress paradigms while assessing behavioral and neurophysiological measures. Aiming to replicate previous findings on induced rumination by means of the Trier Social Stress Test (TSST) and comparing them to physiological (pain) stress, a clinical sample of patients with Major Depressive Disorder (MDD; n = 22) and healthy controls (HC; n = 23) was recruited. Cortical blood oxygenation was assessed during the stress paradigms using functional near-infrared spectroscopy (fNIRS). Further, we used ecological momentary assessment (EMA) of stress, rumination and mood to be able to correlate ruminative responses during induced stress and everyday rumination. Our results showed that social stress but not physiological stress induced depressive rumination in MDD but not in HC. Further, rumination reactivity in response to social stress but not to physiological stress was significantly associated with rumination reactivity in everyday life as assessed with EMA. With respect to cortical oxygenation, MDD subjects showed hypoactivity in the Cognitive Control Network during the TSST, which mediated the differences between MDD and HC in post-stress rumination. Our findings emphasize the role of negative social triggers in depressive rumination and validate the TSST as an induction method for depressive rumination. The results inform future developments in psychotherapeutic treatment for depressive rumination.

Deficits in perception of emotional prosody have been described in patients with affective disorders at behavioral and neural level. In the current study, we use an imaging genetics approach to examine the impact of CACNA1C, one of the most promising genetic risk factors for psychiatric disorders, on prosody processing on a behavioral, functional and microstructural level. Using functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) we examined key areas involved in prosody processing, i.e. the amygdala and voice areas, in a healthy population. We found stronger activation to emotional than neutral prosody in the voice areas and the amygdala, but CACNA1C rs1006737 genotype had no influence on fMRI activity. However, significant microstructural differences (i.e. mean diffusivity) between CACNA1C rs1006737 risk allele carriers and non carriers were found in the amygdala, but not the voice areas. These modifications in brain architecture associated with CACNA1C might reflect a neurobiological marker predisposing to affective disorders and concomitant alterations in emotion perception., Highlights • Emotional prosody increases activation irrespective of genotype. • CACNA1C rs1006737 influences mean diffusivity in amygdala, not voice areas • CACNA1C rs1006737 results in changes of brain microstructure rather than function.

Background The importance of epigenetic alterations in psychiatric disorders is increasingly acknowledged and the use of DNA methylation patterns as markers of disease is a topic of ongoing investigation. Recent studies suggest that patients suffering from Borderline Personality Disorder (BPD) display differential DNA methylation of various genes relevant for neuropsychiatric conditions. For example, several studies report differential methylation in the promoter region of the brain-derived neurotrophic factor gene (BDNF) in blood. However, little is known about BDNF methylation in other tissues. Results In the present study, we analyzed DNA methylation of the BDNF IV promoter in saliva and blood of 41 BPD patients and 41 matched healthy controls and found significant hypermethylation in the BPD patient’s saliva, but not blood. Further, we report that BDNF methylation in saliva of BPD patients significantly decreased after a 12-week psychotherapeutic intervention. Conclusions Providing a direct comparison of BDNF methylation in blood and saliva of the same individuals, our results demonstrate the importance of choice of tissue for the study of DNA methylation. In addition, they indicate a better suitability of saliva for the study of differential BDNF methylation in BPD patients. Further, our data appear to indicate a reversal of disease-specific alterations in BDNF methylation in response to psychotherapy, though further experiments are necessary to validate these results and determine the specificity of the effect. Electronic supplementary material The online version of this article (10.1186/s13148-018-0544-6) contains supplementary material, which is available to authorized users.

Background Alcohol Dependence (AD) is a severe disorder that has long-lasting detrimental consequences, resulting in considerable health, economic and societal burden. According to the World Health Organization, alcohol related diseases account for approximately 3.3 million deaths per year (WHO, 2014). The pathogenesis of AD is complex, as the disease arises from the interaction of genetic as well as environmental factors. One of the most compelling candidate mechanisms for the mediation of such gene x environment effects is epigenetic regulation, among which DNA methylation is the most frequently studied mechanism. In fact, several recent studies have shown an association of alcohol dependence with DNA methylation (DNAm), suggesting that environmentally-induced changes on epigenomic variation may play an important role in alcohol dependence. Methods In the present study, we assessed genome-wide DNAm profiles of purified CD3+ T-cells of a well-characterized cohort of long-term chronic AD patients participating in a clinical 3-week alcohol treatment program, along with the profiles of healthy controls closely matched for sex, age, ethnicity and smoking behaviour. 42,43 Furthermore, by comparing the patients before and after 3 weeks of participating in a clinical alcohol treatment program, we sought to identify differentially methylated sites that may play a potential role in alcohol withdrawal and early recovery. In order to test whether our findings were robust, we validated four of our top-ranked hits by pyrosequencing, replicated the top-ranking hits in an independent second cohort of AD patients and matched controls and additionally confirmed the top-ranking hits in whole blood DNA of our cohort samples. Results We identified 59 differentially methylated CpG sites comparing patients prior to treatment with healthy controls and were able to confirm 8 of those sites in additional analyses for differentially methylated regions. Comparing patients before and after a 3-week alcohol treatment program we revealed another unique set of 48 differentially methylated CpG sites. Additionally, we found that the mean global DNAm was significantly lower in patients prior to treatment compared to controls, but reverted back to levels similar to controls after treatment. We validated top-ranked hits derived from the epigenome-wide analysis by pyrosequencing and further replicated two of them in an independent cohort and confirmed differential DNAm of HECW2 and SRPK3 in whole blood. Discussion The reduction in mean global DNAm observed in AD patients and our finding that DNAm in patients reverts back to levels comparable to those in controls after alcohol treatment are supported by previous studies. However, the top hits of differentially methylated sites derived from T-cells did not overlap with previously reported associations of AD with DNAm.This can at least in part be explained by the use of heterogeneous biological material (i.e. whole blood, PBMCs), differences in the cohorts used or in the strategies applied to match patients and controls as well as by varying methodologies for DNAm measurement, with reduced or discordant coverage of CpG sites in previous studies. Still, our top-ranking hits in HECW2 and SRPK3 might contribute to reveal mechanisms that may play a role in AD. This study is the first to show widespread DNAm variation in a disease-relevant blood cell type and implicates HECW2 and SRPK3 DNAm as promising blood-based candidates to follow up in future studies.

Background Coping with the complexity of our daily life requires cognitive flexibility and control over emotions and behavior. Deficits in cognitive control are often involved in the psychopathology of psychiatric diseases, e.g. Major Depressive Disorder (MDD), a severe mental illness characterized by increased receptiveness for negative stimuli and unbalanced emotion processing. On a neural basis, MDD as well as deficient cognitive control are associated with hypoactivity of the Dorsolateral Prefrontal Cortex (dlPFC). Transcranial Direct Current Stimulation (tDCS) is a well-established brain stimulation technique inducing targeted modulation of cortical activity. It is discussed as promising approach to support conventional psychiatric therapies but so far little is known about the underlying molecular mechanisms. Epigenetic changes might be a potential mechanism how tDCS effects manifest as long-lasting cognitive improvements and amelioration of psychiatric symptoms. In two previous stimulation genetics studies, we demonstrated an influence of the COMT genotype, which renders this gene an interesting candidate for a stimulation epigenetics study. Methods For the present study, healthy male participants performed a potentially frustrating and challenging task, a 2-back version of the Paced Auditory Serial Addition Task (PASAT), once under sham stimulation and once under anodal tDCS over the left dlPFC. Participants’ affective states were assessed several times throughout the experiment. To investigate epigenetic effects of the stimulation protocol, one blood sample was collected before the PASAT and five blood samples were collected after task completion. DNA methylation status of the COMT gene promoter region was assessed by pyrosequencing. Results Our results provide further evidence that anodal tDCS applied to the left dlPFC improves task performance. In addition, tDCS seems to prevent task-induced decline in positive affect, whereas task-related negative affect was suppressed. Furthermore, our data suggest a dynamic increase in DNA methylation of the COMT gene promoter region in response to the task. Depending on the type of stimulation (anodal or sham) participants received during their first session, they showed different methylation levels in their second session. Discussion Together, our data extend previous findings showing improved cognitive performance under anodal stimulation, which correlates with enhanced control over emotions. In response to stimulation, we observed increased positive affect and reduced negative affect, which supports the idea of tDCS as a potential treatment approach for MDD targeting the negativity bias. In addition, we observed dynamic methylation changes in the COMT gene promoter region in response to a challenging cognitive task, which might be differentially modulated by tDCS. COMT is an enzyme involved in the degradation of dopamine and dopamine levels are critical in executive functioning. Therefore, the observed changes in COMT promoter methylation might indicate an adaptive process to the task and they might indicate an underlying mechanism to induce long-lasting tDCS effects.

In current diagnostic systems, schizophrenia and bipolar disorder are still conceptualized as distinct categorical entities. Recently, both clinical and genetic evidence have challenged this Kraepelinian dichotomy. There are only few longitudinal studies addressing the potential overlaps between these conditions. Here, we present design and first results of the PsyCourse study, an ongoing transdiagnostic study of the affective-to-psychotic continuum that combines longitudinal deep phenotyping and dimensional assessment of psychopathology with an extensive collection of biomaterial. Within the DSM-IV framework, we compare two broad diagnostic groups: one consisting of predominantly affective and one of predominantly psychotic disorders. Depressive, manic, and psychotic symptoms as well as global functioning over time were analyzed. Furthermore, we explore the effects of polygenic risk scores for schizophrenia on diagnostic group membership and address their effects on non-participation in follow-up visits. While phenotypic results show differences in both current psychotic and manic symptoms, depressive symptoms did not vary between both groups. Polygenic risk scores for schizophrenia significantly explained part of the variability of the diagnostic group. Furthermore, there was a trend that a higher polygenic loading for schizophrenia was associated with attrition. Because of its unique properties, the PsyCourse study presents a prime resource for the interrogation of complex genotype-phenotype relationships.