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While standard polysomnography has revealed the importance of the sleeping brain in health and disease, more specific insight into the relevant brain circuits requires high-density electroencephalography (EEG). However, identifying and handling sleep EEG artifacts becomes increasingly challenging with higher channel counts and/or volume of recordings. Whereas manual cleaning is time-consuming, subjective, and often yields data loss (e.g., complete removal of channels or epochs), automated approaches suitable and practical for overnight sleep EEG remain limited, especially when control over detection and repair behavior is desired. Here, we introduce a flexible approach for automated cleaning of multichannel sleep recordings, as part of the free Matlab-based toolbox SleepTrip. Key functionality includes 1) channel-wise detection of various artifact types encountered in sleep EEG, 2) channel- and time-resolved marking of data segments for repair through interpolation, and 3) visualization options to review and monitor performance. Functionality for Independent Component Analysis is also included. Extensive customization options allow tailoring cleaning behavior to data properties and analysis goals. By enabling computationally efficient and flexible automated data cleaning, this tool helps to facilitate fundamental and clinical sleep EEG research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cox, Weber and Van Someren.)

Objectives: The human oral microbiome may play a role in the development of oral squamous cell carcinoma. The aim of this scoping review was to examine microbial diversity and differences in the composition of the oral microbiome between OSCC patients and healthy controls., Methods: A literature search (in PubMed and Embase.com) was performed on January 9, 2023. The outcome variables used from the included studies of this review were alpha- and beta diversity and oral microbiome composition profiles for each taxonomic level (phylum-, class-, order-, genus- and species level)., Results: Thirteen out of 423 studies were included in this review compromising 1,677 subjects, of which 905 (54.0%) were OSCC patients and 772 (46.0%) were healthy controls. Most studies found a higher alpha diversity in the OSCC patient group and significantly different beta diversities between OSCC patient samples and healthy control samples. Studies reported more abundant Fusobacteria (on phylum level), Fusobacterium (on genus level), Fusobacterium nucleatum, Porphyromonas endodontalis and Prevotella intermedia (on species level) in OSCC patients. The healthy control group had more abundant Actinobacteria (on phylum level), Streptococcus and Veilonella (on genus level) and Veilonella parvula (on species level) according to most studies., Conclusions: Our findings show differences in oral microbiome diversity and composition in OSCC patients. Clinical implications demand continuing study. Development of internationally accepted standard procedures for oral sample collection and oral microbiota analysis is needed for more conclusive and clinically relevant comparisons in future research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 van Dijk, Petersen, Raber-Durlacher, Epstein and Laheij.)

Objective: Comorbid post-traumatic stress disorder in patients with anorexia nervosa may negatively affect the course of anorexia nervosa treatment, which is already challenging. There are currently no guidelines or recommendations on concurrent treatment approaches for both anorexia nervosa and post-traumatic stress disorder. This systematic scoping review aims to explore the feasibility, acceptability and effectiveness of psychological trauma-focused treatment concurrently offered to underweight patients receiving anorexia nervosa treatment., Method: A multi-step literature search, according to an a priori protocol was performed. Databases PubMed, Embase, APA PsycINFO, Web of Science, Scopus and Cochrane Central were searched up to September 19 th 2022, and the search was rerun June 19 th 2023. For quality assessment, Risk of Bias in Non-randomised Studies-of Interventions tool was used., Results: The extensive search yielded 1769 reports, out of which only three observational pilot studies, both English and German, published between 2004 and 2022, could be included. The included studies reported on a total of 13 female participants between 16 and 58 years old, with anorexia nervosa or otherwise specified feeding or eating disorder, baseline BMI ranging between 14.6 and 16.5, who received concurrent anorexia and post-traumatic stress disorder treatment. In all participants, the emotional and cognitive functioning was sufficient to process the offered trauma-focused interventions, despite their significantly low body weight., Discussion: The findings of this review identify a dearth of treatment research on knowledge of concurrent trauma-focused treatments for patients with anorexia nervosa. Refraining patients with anorexia nervosa from trauma-focused treatment may not be warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 van den Berg, Pellemans, Planting, Daansen, van Beers, de Jonge, Christ and Dekker.)

Vanishing white matter (VWM) is a devastating autosomal recessive leukodystrophy, resulting in neurological deterioration and premature death, and without curative treatment. Pathogenic hypomorphic variants in subunits of the eukaryotic initiation factor 2B (eIF2B) cause VWM. eIF2B is required for regulating the integrated stress response (ISR), a physiological response to cellular stress. In patients' central nervous system, reduced eIF2B activity causes deregulation of the ISR. In VWM mouse models, the extent of ISR deregulation correlates with disease severity. One approach to restoring eIF2B activity is by inhibition of GSK3β, a kinase that phosphorylates eIF2B and reduces its activity. Lithium, an inhibitor of GSK3β, is thus expected to stimulate eIF2B activity and ameliorate VWM symptoms. The effects of lithium were tested in zebrafish and mouse VWM models. Lithium improved motor behavior in homozygous eif2b5 mutant zebrafish. In lithium-treated 2b4 he 2b5 ho mutant mice, a paradoxical increase in some ISR transcripts was found. Furthermore, at the dosage tested, lithium induced significant polydipsia in both healthy controls and 2b4 he 2b5 ho mutant mice and did not increase the expression of other markers of lithium efficacy. In conclusion, lithium is not a drug of choice for further development in VWM based on the limited or lack of efficacy and significant side-effect profile., Competing Interests: JB is on the board of wFluidx, Inc., owns stock in Orchard Therapeutics, and has consulted for Bluebird bio, Calico Life Sciences, Denali Therapeutics, Enzyvant, and Neurogene. MK and TEMA have a patent PCT/NL2018/050293 on guanabenz in VWM pending to VUmc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Witkamp, Oudejans, Hoogterp, Hu-A-Ng, Glaittli, Stevenson, Huijsmans, Abbink, van der Knaap and Bonkowsky.)

Research has shown that the impact of traumatic events and circumstances on individuals is cumulative and potentially has a wide range of harmful consequences, including negative consequences on mental health. One such consequence is the development of a personality disorder, a persistent mental condition characterized by a pronounced pattern of difficulties in impulse control, emotional regulation, cognitive functions, self-esteem, and interpersonal relationships. A wide array of studies indicates that the personal history of individuals with a personality disorder is often marked by exposure to traumatic events or other types of adverse childhood experiences (ACEs). Because existing treatments for personality disorders are usually long and costly, it is essential to continue exploring alternative and complementary interventions. Nowadays, knowledge and clinical experience in regard to personality disorders have been gained in addressing ACEs by processing memories of these events through eye movement desensitization and reprocessing (EMDR) therapy. In this paper, we present a theoretical framework for this treatment approach, based on Shapiro's Adaptive Information Processing (AIP) model, describe its current empirical basis, and provide guidance on how to formulate a useful case conceptualization that can serve as a basis for the treatment of personality disorders with EMDR therapy. This approach is illustrated with a case example., Competing Interests: AJ receives income from published books on EMDR therapy and from the training of postdoctoral professionals in this method. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 De Jongh, Hafkemeijer, Hofman, Slotema and Hornsveld.)

Objective: Evidence suggests that many adults with type 1 diabetes (T1D) experience clinically relevant levels of diabetes distress, indicating coping difficulties. Studies have primarily focused on emotion regulation as a possible construct to be addressed in psychological interventions to alleviate diabetes distress. This study extends the literature by investigating the cross-sectional association between emotion regulation, diabetes distress and the construct of emotional self-awareness as an additional variable to be considered in potentially reducing diabetes distress., Methods: Via an online survey, data was collected on emotional self-awareness dimensions (attention to feelings, clarity of feelings), emotion regulation strategies (cognitive reappraisal, expressive suppression, mood repair) and diabetes distress, along with self-reported clinical and sociodemographic information. Multiple linear regression with stepwise backward method was used to examine associations, controlling for country., Results: N  = 262 Italian and Dutch adults with T1D (80.5% women, M  = 38.12 years, SD = 12.14) participated. Clarity of feelings was significantly negatively associated with diabetes distress, resulting in a medium effect size ( β  = -0.22, p  < 0.001). Likewise, mood repair was negatively related to diabetes distress, showing a small effect size ( β  = -0.26, p  < 0.001)., Conclusion: These findings shed light on the importance of a dimension of emotional self-awareness, namely clarity of feelings. This represents the ability to identify one's emotional states and discriminate between them. Thus, it should be considered in psychological interventions, such as mentalization-based treatment, that might contribute to alleviating T1D-related distress., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Bassi, Embaye, de Wit, Snoek and Salcuni.)

Background: Several widely studied therapies have proven to be effective in the treatment of post-traumatic stress disorder (PTSD). However, there is still room for improvement because not all patients benefit from trauma-focused treatments. Improvements in the treatment of PTSD can be achieved by investigating ways to enhance existing therapies, such as eye movement desensitization and reprocessing (EMDR) therapy, as well as exploring novel treatments. The purpose of the current study is to determine the differential effectiveness, efficiency, and acceptability of EMDR therapy, an adaptation of EMDR therapy, referred to as EMDR 2.0, and a novel intervention for PTSD, the so-called Flash technique. The second aim is to identify the moderators of effectiveness for these interventions. This study will be conducted among individuals diagnosed with PTSD using a randomized controlled trial design., Methods: A total of 130 patients diagnosed with (complex) PTSD will be randomly allocated to either six sessions of EMDR therapy, EMDR 2.0, or the Flash technique. The primary outcomes used to determine treatment effectiveness include the presence of a PTSD diagnosis and the severity of PTSD symptoms. The secondary outcomes of effectiveness include symptoms of depression, symptoms of dissociation, general psychiatric symptoms, and experiential avoidance. All patients will be assessed at baseline, at 4-week post-treatment, and at 12-week follow-up. Questionnaires indexing symptoms of PTSD, depression, general psychopathology, and experiential avoidance will also be assessed weekly during treatment and bi-weekly after treatment, until the 12-week follow-up. Efficiency will be assessed by investigating the time it takes both to lose the diagnostic status of PTSD, and to achieve reliable change in PTSD symptoms. Treatment acceptability will be assessed after the first treatment session and after treatment termination., Discussion: This study is the first to investigate EMDR 2.0 therapy and the Flash technique in a sample of participants officially diagnosed with PTSD using a randomized controlled trial design. This study is expected to improve the available treatment options for PTSD and provide therapists with alternative ways to choose a therapy beyond its effectiveness by considering moderators, efficiency, and acceptability., Trial Registration: The trial was retrospectively registered in the ISRCTN registry at 10th November 2022 under registration number ISRCTN13100019., Competing Interests: SM and AJ earned income from presenting workshops in EMDR 2.0 and the Flash technique, and from giving training and/or consultation in EMDR therapy. AJ also earned income from book royalties on EMDR therapy. SM was also a board member for the ‘Vereniging EMDR Nederland’ (English: Dutch EMDR Association). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Alting van Geusau, de Jongh, Nuijs, Brouwers, Moerbeek and Matthijssen.)

Background: Individuals with posttraumatic stress disorder (PTSD) often experience sexual disturbances., Objective: To determine whether intensive trauma-focused treatment is associated with an improvement in sexual functioning (i.e., sexual satisfaction and sexual desire) in individuals with PTSD., Method: In total, 227 patients with PTSD (68.7% women, mean age = 40.97) participated in an intensive eight-day trauma-focused treatment program consisting of prolonged exposure, eye movement and desensitization and reprocessing (EMDR) therapy, physical activity, and psychoeducation. Patients were assessed (i.e., Clinician Administered PTSD Scale and Sexual Functioning Questionnaire) pre- and post-treatment and at 6-months follow-up., Results: Sexual satisfaction and sexual desire increased significantly associated with trauma-focused treatment from pre-treatment to 6-months follow-up, albeit the effect sizes were small (Cohen's d = 0.39 and 0.17, respectively). Although men reported greater overall sexual desire than women, sexual functioning improved after treatment in both men and women. Furthermore, those with remission of PTSD reported greater sexual functioning post-treatment and at 6-months follow-up, than those without remission. However, changes in PTSD symptoms associated with treatment were not predictive of the level of sexual satisfaction or sexual desire 6 months after treatment., Conclusion: The results of this uncontrolled study suggest that intensive treatment for PTSD can have beneficial effects on sexual satisfaction and desire in both men and women; however, this may not necessarily be due to a decrease in PTSD symptoms., Competing Interests: AM receives income from published book chapters on PTSD and from the training of postdoctoral professionals with prolonged exposure. AJ received income from published books on EMDR therapy and from the training of postdoctoral professionals in this method. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer DF declared a shared parent affiliation with the author AJ to the handling editor at the time of review., (Copyright © 2023 van Woudenberg, Voorendonk, Tunissen, van Beek, Rozendael, Van Minnen and De Jongh.)

Introduction: This randomized controlled trial examined the effectiveness of physical activity added to an intensive trauma-focused treatment (TFT) for post-traumatic stress disorder (PTSD) in comparison to adding non-physical control activities., Methods: A total of 119 patients with PTSD were randomly assigned to a physical activity condition (PA; n = 59) or a non-physical activity control condition (nPA; n = 60). The 8-day intensive TFT programme consisted of daily prolonged exposure, EMDR therapy, and psychoeducation, which was complemented with physical activities versus controlled mixtures of guided (creative) tasks. As a primary outcome, the change in clinician and self-reported PTSD symptoms from pre-to post-treatment and at 6 months follow-up were measured., Results: Intent-to-treat linear mixed-effects models showed no significant differences between the PA and nPA conditions on change in PTSD severity. Clinician and self-reported PTSD symptoms significantly decreased for both conditions, with large effect sizes (e.g., CAPS-5 d pre-post  = 2.28). At post-treatment, 80.0% in the PA, and 82.7% in the nPA condition no longer met the diagnostic criteria for PTSD. Regarding the loss of Complex PTSD diagnoses this was 92.5% and 95.0%, respectively., Conclusion: Either with additional physical or non-physical activities, intensive TFT is very effective for the treatment of (Complex) PTSD, as reflected by large effect sizes and loss of diagnostic status in both groups., Clinical Trial Registration: Trialregister.nl Identifier: Trial NL9120., Competing Interests: AM receives income from published book chapters on PTSD and from the training of postdoctoral professionals in prolonged exposure. AJ receives income from published books on EMDR therapy and from the training of postdoctoral professionals using this method. AM, AJ, and EV are employed at PSYTREC.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Voorendonk, Sanches, Tollenaar, Hoogendoorn, de Jongh and van Minnen.)

Objectives: A supportive social network is associated with better mental health and wellbeing, and less criminal behavior. Therefore, this study examined the effectiveness of an additive informal social network intervention to treatment as usual (TAU) among forensic psychiatric outpatients., Materials and Methods: An randomized controlled trial (RCT) was conducted in forensic psychiatric care, allocating eligible outpatients ( N = 102) to TAU with an additive informal social network intervention or TAU alone. Participants receiving the additive intervention were matched to a trained community volunteer over 12 months. TAU consisted of forensic care (e.g., cognitive behavioral therapy and/or forensic flexible assertive community treatment). Follow-up assessments were conducted at 3, 6, 9, 12, and 18 months after baseline. The primary outcome was the between-group effect on mental wellbeing at 12 months. Between-group effects on secondary outcomes (e.g., general psychiatric functioning, hospitalization, criminal behavior) were explored., Results: Intention-to-treat analyses showed non-significant between-group effects on mental wellbeing on average over time and at 12 months. However, significant between-group effects were found on hospitalization duration and criminal behavior. Specifically, TAU participants were hospitalized 2.1 times more days within 12 months and 4.1 more days within 18 months than participants in the additive intervention. Furthermore, TAU participants reported 2.9 times more criminal behaviors on average over time. There were no significant effects on other outcomes. Exploratory analyses revealed that sex, comorbidity, and substance use disorders moderated effects., Conclusion: This is the first RCT examining the effectiveness of an additive informal social network intervention in forensic psychiatric outpatients. Although no improvements were found on mental wellbeing, the additive intervention was effective in reducing hospitalization and criminal behavior. The findings suggest that forensic outpatient treatment can be optimized by collaborating with informal care initiatives aimed at improving social networks within the community. Future research is warranted to determine which specific patients might benefit from the intervention and if effects can be improved by extending the intervention duration and enhancing patient compliance. Clinical Trial Registration: [https://trialsearch.who.int/Trial2.aspx?TrialID=NTR7163], identifier [NTR7163]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Swinkels, van der Pol, Twisk, ter Harmsel, Dekker and Popma.)

Purpose: This study explores the association between the duration and variation of infant sleep trajectories and subsequent cognitive school readiness at 48-50 months., Methods: Participants were 288 multi-ethnic children, within the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort. Caregiver-reported total, night and day sleep durations were obtained at 3, 6, 9, 12, 18, 24 using the Brief Infant Sleep Questionnaire and 54 months using the Child Sleep Habits Questionnaire. Total, night and day sleep trajectories with varying durations (short, moderate, or long) and variability (consistent or variable; defined by standard errors) were identified. The cognitive school readiness test battery was administered when the children were between 48 and 50 months old. Both unadjusted adjusted analysis of variance models and adjusted analysis of covariance models (for confounders) were performed to assess associations between sleep trajectories and individual school readiness tests in the domains of language, numeracy, general cognition and memory., Results: In the unadjusted models, children with short variable total sleep trajectories had poorer performance on language tests compared to those with longer and more consistent trajectories. In both unadjusted and adjusted models, children with short variable night sleep trajectories had poorer numeracy knowledge compared to their counterparts with long consistent night sleep trajectories. There were no equivalent associations between sleep trajectories and school readiness performance for tests in the general cognition or memory domains. There were no significant findings for day sleep trajectories., Conclusion: Findings suggest that individual differences in longitudinal sleep duration patterns from as early as 3 months of age may be associated with language and numeracy aspects of school readiness at 48-50 months of age. This is important, as early school readiness, particularly the domains of language and mathematics, is a key predictor of subsequent academic achievement., Competing Interests: NS was employed by Société des Produits Nestlé SA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tham, Xu, Fu, Goh, Gluckman, Chong, Yap, Shek, Teoh, Gooley, Goh, Schneider, Meaney, Cai and Broekman.)

Introduction: Enamel mineralization requires calcium transport into the extracellular matrix for the synthesis of hydroxyapatite (HA) crystals. Formation of HA releases protons into the matrix, which are then neutralized when ameloblasts modulate from cells with apical invaginations, the so-called ruffle-ended ameloblasts (RE), to smooth-ended ameloblasts (SE). Ameloblast modulation is associated with the translocation of the calcium exchanger Nckx4 to the apical border of RE, to remove Na + from the enamel matrix in exchange for Ca 2+ and K + . As enamel matures, Na + and K + in the matrix progressively decrease. However, the transporter to remove K + from mineralizing enamel has not been identified. Methods: Expression of K + exchangers and channels in secretory and maturation stage of enamel organs were compared following an RNA-seq analysis. Kcnj15, which encodes the Kir4.2 inwardly rectifying K + channel, was found to be the most upregulated internalizing K + transporter in maturation stage of enamel organs. Kir4.2 was immunolocalized in wt, Nckx4 -/- , Wdr72 -/- , and fluorosed ameloblasts. Regulation of Wdr72 expression by pH was characterized in vitro and in vivo . Results: Kir4.2 immunolocalized to the apical border of wild type (wt) mouse RE and cytosol of SE, a spatial distribution pattern shared by NCKX4. In Nckx4 -/- ameloblasts, Kir4.2 also localized to the apical surface of RE and cytosol of SE. However, in fluorosed and Wdr72 -/- ameloblasts, in which vesicle trafficking is disrupted, Kir4.2 remained in the cytosol. In vitro , Wdr72 was upregulated in LS8 cells cultured in medium with a pH 6.2, which is the pH of the enamel matrix underlying RE, as compared to pH 7.2 under SE. Conclusion: Taken together these results suggest that Kir4.2 participates in K + uptake by maturation ameloblasts, and that K + and Na + uptake by Kir4.2 and Nckx4, respectively, may be regulated by pH through WDR72-mediated endocytosis and membrane trafficking., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ngu, Bronckers, Katsura, Zhang and Den Besten.)

Studying gene flow between different livestock breeds will benefit the discovery of genes related to production traits and provide insight into human historical breeding. Chinese pigs have played an indispensable role in the breeding of Western commercial pigs. However, the differences in the timing and volume of the contribution of pigs from different Chinese regions to Western pigs are not yet apparent. In this paper, we combine the whole-genome sequencing data of 592 pigs from different studies and illustrate patterns of gene flow from Chinese pigs into Western commercial pigs. We describe introgression patterns from four distinct Chinese indigenous groups into five Western commercial groups. There were considerable differences in the number and length of the putative introgressed segments from Chinese pig groups that contributed to Western commercial pig breeds. The contribution of pigs from different Chinese geographical locations to a given western commercial breed varied more than that from a specific Chinese pig group to different Western commercial breeds, implying admixture within Europe after introgression. Within different Western commercial lines from the same breed, the introgression patterns from a given Chinese pig group seemed highly conserved, suggesting that introgression of Chinese pigs into Western commercial pig breeds mainly occurred at an early stage of breed formation. Finally, based on analyses of introgression signals, allele frequencies, and selection footprints, we identified a ∼2.65 Mb Chinese-derived haplotype under selection in Duroc pigs (CHR14: 95.68-98.33 Mb). Functional and phenotypic studies demonstrate that this PRKG1 haplotype is related to backfat and loin depth in Duroc pigs. Overall, we demonstrate that the introgression history of domestic pigs is complex and that Western commercial pigs contain distinct traces of mixed ancestry, likely derived from various Chinese pig breeds., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Peng, Derks, Groenen, Zhao and Bosse.)

The impact of adverse childhood experiences (ACEs) differs between individuals and depends on the type and timing of the ACE. The aim of this study was to assess the relation between various recently occurred ACEs and morphology in the developing brain of children between 8 and 11 years of age. We measured subcortical volumes, cortical thickness, cortical surface area and fractional anisotropy in regions of interest in brain scans acquired in 1,184 children from the YOUth cohort. ACEs were based on parent-reports of recent experiences and included: financial problems; parental mental health problems; physical health problems in the family; substance abuse in the family; trouble with police, justice or child protective services; change in household composition; change in housing; bereavement; divorce or conflict in the family; exposure to violence in the family and bullying victimization. We ran separate linear models for each ACE and each brain measure. Results were adjusted for the false discovery rate across regions of interest. ACEs were reported for 83% of children in the past year. Children were on average exposed to two ACEs. Substance abuse in the household was associated with larger cortical surface area in the left superior frontal gyrus, t (781) = 3.724, p FDR = 0.0077, right superior frontal gyrus, t (781) = 3.409, p FDR = 0.0110, left pars triangularis, t (781) = 3.614, p FDR = 0.0077, left rostral middle frontal gyrus, t (781) = 3.163, p FDR = 0.0195 and right caudal anterior cingulate gyrus, t (781) = 2.918, p FDR = 0.0348. Household exposure to violence (was associated with lower fractional anisotropy in the left and right cingulum bundle hippocampus region t (697) = -3.154, p FDR = 0.0101 and t (697) = -3.401, p FDR = 0.0085, respectively. Lower household incomes were more prevalent when parents reported exposure to violence and the mean parental education in years was lower when parents reported substance abuse in the family. No other significant associations with brain structures were found. Longer intervals between adversity and brain measurements and longitudinal measurements may reveal whether more evidence for the impact of ACEs on brain development will emerge later in life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Buimer, Brouwer, Mandl, Pas, Schnack and Hulshoff Pol.)

Background: Acrophobia is a specific phobia characterized by a severe fear of heights. The purpose of the present study was to investigate the efficacy of two therapies that may ameliorate symptoms of acrophobia and anxiety sensitivity, i.e., virtual reality exposure therapy (VRET) and eye movement desensitization and reprocessing (EMDR) therapy with a Waiting List Control Condition (WLCC)., Methods: We applied a three-armed randomized controlled pre-post-test design with 45 female adolescent students. Students who met DSM-5 criteria for acrophobia were randomly assigned to either VRET (N = 15; M age = 17.26; SD = 1.32), EMDR (N = 15; M age = 17.15; SD = 1.57), or a WLCC (N = 15; M age = 17.50; SD = 1.26). The study groups were evaluated one week before the intervention and one week after the last intervention session regarding symptoms of acrophobia (Severity Measure for Acrophobia) and anxiety sensitivity (Anxiety Sensitivity Index)., Results: The data showed that both the application of VRET and EMDR therapy were associated with significantly reduced symptoms of acrophobia (d = 1.03 for VRET and d = 1.08 for EMDR) and anxiety sensitivity (d = 1.15 for VRET and d = 1.13 for EMDR) in comparison to the Waiting List., Limitations: The sample consisted only of adolescent women. Due to the recognizable differences between the two interventions, the therapists and the participants were not blind to the conditions., Conclusion: The results suggest that both VRET and EMDR are interventions that can significantly improve symptoms of acrophobia and anxiety sensitivity in female adolescents., Clinical Trial Registration: https://www.irct.ir/trial/57391, identifier: IRCT20210213050343N1., Competing Interests: AJ and SR receive income from published books on EMDR therapy and for training postdoctoral professionals in this method. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Azimisefat, de Jongh, Rajabi, Kanske and Jamshidi.)

Background: Interventions aimed at easing negative moral (social) emotions and restoring social bonds - such as amend-making and forgiving-have a prominent role in the treatment of moral injury. As real-life contact between persons involved in prior morally injurious situations is not always possible or desirable, virtual reality may offer opportunities for such interventions in a safe and focused way., Objective: To explore the effects of the use of deepfake technology in the treatment of patients suffering from PTSD and moral injury as a result of being forced by persons in authority to undergo and commit sexual violence (so-called betrayal trauma )., Methods: Two women who had experienced sexual violence underwent one session of confrontation with the perpetrator using deepfake technology. The women could talk via ZOOM with the perpetrator, whose picture was converted in moving images using deepfake technology. A therapist answered the questions of the women in the role of the perpetrator. Outcome measures were positive and negative emotions, dominance in relation to perpetrator, self-blame, self-forgiveness, and PTSD-symptom severity., Results: Both participants were positive about the intervention. Although they knew it was fake, the deepfaked perpetrator seemed very real to them. They both reported more positive and less negative emotions, dominance in relation to the perpetrator and self-forgiveness, and less self-blame and PTSD-symptoms after the intervention., Conclusion: Victim-perpetrator confrontation using deepfake technology is a promising intervention to influence moral injury-related symptoms in victims of sexual violence. Deepfake technology may also show promise in simulating other interactions between persons involved in morally injurious events., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 van Minnen, ter Heide, Koolstra, de Jongh, Karaoglu and Gevers.)

Extensive cattle livestock is advancing in Amazonia and its low productivity, with consequent pressure to open new areas, is partly due to sanitary problems and, among them, the periodontal diseases, whose environmental triggers or modifying factors are unknown. In this study, we used high-throughput sequencing, network analysis and predicted functions to investigate the dental and ruminal microbiota of cattle raised in new livestock areas in the Amazon and identify possible keystone pathogens and proteins associated with the disease. Ninety-three genera were common in dental and ruminal fluid microbiomes and among them periodontal pathogens such as Fusobacterium, Prevotella, Porphyromonas and Actinomyces were recognized. Network analysis showed that dental microbiomes of clinically healthy animals tend to comprise a group of OTUs in homeostasis and when analyzed together, dental and ruminal fluid microbiomes of animals with periodontitis had almost twice the number of negative edges, indicating possible competition between bacteria and dysbiosis. The incisor dental and ruminal fluid microbiomes were dominated by a core community composed of members of the phyla Firmicutes and Bacteroidetes. Network results showed that members of the Prevotella genus stood out among the top five OTUs, with the largest number of hubs in the dental and ruminal microbiota of animals with periodontitis. Protein families linked to an inflammatory environment were predicted in the dental and ruminal microbiota of cattle with periodontitis. The dissimilarity between dental microbiomes, discriminating between healthy cattle and those with periodontitis and the identification of possible key pathogens, represent an important reference to elucidate the triggers involved in the etiopathogenesis of bovine periodontitis, and possibly in the development of measures to control the disease and reduce the pressures for deforestation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Borsanelli, Athayde, Riggio, Brandt, Rocha, Jesus, Gaetti-Jardim, Schweitzer and Dutra.)

Purpose: The relation between fear of childbirth (FoC) and gestational age is inconclusive, and self-reported need for help regarding this fear has never been investigated. This study aimed to determine the prevalence and course of FoC according to gestational age, to identify risk factors for the development of FoC, the influence of this fear on preferred mode of delivery, and self-reported need for help., Methods: Nulliparous pregnant women of all gestational ages completed an online survey. The study consisted of a cross-sectional and a longitudinal analysis. Women who completed the survey in the first or second trimester (T 0 ) were approached again in their third trimester (T 1 ). The Wijma Delivery Expectancy Questionnaire Version A (W-DEQ A) was used with a cut-off score ≥ 85 to define presence of fear of childbirth. Questionnaires indexing social support, anxiety, symptoms of depression, preferred mode of delivery, and self-reported need for help were included., Results: In total, 364 women were enrolled at T 0 , and 118 out of 184 eligible women were included in the longitudinal analysis. Point prevalence of FoC at T 0 was 18.4% with no significant difference between trimesters. In the longitudinal sample, the prevalence of FoC decreased from 18.6% (T 0 ) to 11.0% (T 1 ), p  = 0.004. Although mean scores for FoC decreased significantly, p  < 0.001, scores increased in 41 (34.7%) women. The presence of FoC was associated with elevated anxiety, less family support, prenatal care of the obstetrician by choice, preference for a cesarean section, and for pain relief. Women with FoC were more likely to actively seek for help compared to women without FoC., Conclusion: While FoC is common in each trimester, prevalence decreases over the course of pregnancy. Women with FoC are often actively seeking for help, suggesting that this fear should be addressed better, and help should be offered accordingly., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hendrix, Baas, Vanhommerig, de Jongh and Van Pampus.)

Introduction: Globally, women with dementia have a higher disease burden than men with dementia. In addition, women with diabetes especially are at higher risk for cognitive impairment and dementia compared to men with diabetes. Differences in the influence of diabetes on the cerebral vasculature and brain structure may contribute to these sex-specific differences. We examined sex-specific patterns in the relationship between diabetes and brain structure, as well as diabetes and cognitive function., Methods: In total, 893 patients [age 79 ± 6.6 years, 446 (50%) women] from the Amsterdam Ageing Cohort with available data on brain structures (assessed by an MRI or CT scan) and cognitive function were included. All patients underwent a thorough standardized clinical and neuropsychological assessment (including tests on memory, executive functioning, processing speed, language). Brain structure abnormalities were quantified using visual scales., Results: Cross-sectional multivariable regression analyses showed that diabetes was associated with increased incidence of cerebral lacunes and brain atrophy in women (OR 2.18 (1.00-4.72) but not in men. Furthermore, diabetes was associated with decreased executive function, processing speed and language in women [B -0.07 (0.00-0.13), -0.06 (0.02-0.10) and -0.07 (0.01-0.12) resp.] but not in men., Conclusions: Diabetes is related to increased risk of having lacunes, brain atrophy and impaired cognitive function in women but not in men. Further research is required to understand the time trajectory leading up to these changes and to understand the mechanisms behind them in order to improve preventive health care for both sexes., Competing Interests: HR-M performs contract research for Combinostics. All funding is paid to her institution. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Thomas, Rhodius-Meester, Exalto, Peters, van Bloemendaal, Ponds and Muller.)

Neuronal excitation-inhibition (E/I) imbalances are considered an important pathophysiological mechanism in neurodevelopmental disorders. Preclinical studies on tuberous sclerosis complex (TSC), suggest that altered chloride homeostasis may impair GABAergic inhibition and thereby E/I-balance regulation. Correction of chloride homeostasis may thus constitute a treatment target to alleviate behavioral symptoms. Recently, we showed that bumetanide-a chloride-regulating agent-improved behavioral symptoms in the open-label study Bumetanide to Ameliorate Tuberous Sclerosis Complex Hyperexcitable Behaviors trial (BATSCH trial; Eudra-CT: 2016-002408-13). Here, we present resting-state EEG as secondary analysis of BATSCH to investigate associations between EEG measures sensitive to network-level changes in E/I balance and clinical response to bumetanide. EEGs of 10 participants with TSC (aged 8-21 years) were available. Spectral power, long-range temporal correlations (LRTC), and functional E/I ratio ( f E/I) in the alpha-frequency band were compared before and after 91 days of treatment. Pre-treatment measures were compared against 29 typically developing children (TDC). EEG measures were correlated with the Aberrant Behavioral Checklist-Irritability subscale (ABC-I), the Social Responsiveness Scale-2 (SRS-2), and the Repetitive Behavior Scale-Revised (RBS-R). At baseline, TSC showed lower alpha-band absolute power and f E/I than TDC. Absolute power increased through bumetanide treatment, which showed a moderate, albeit non-significant, correlation with improvement in RBS-R. Interestingly, correlations between baseline EEG measures and clinical outcomes suggest that most responsiveness might be expected in children with network characteristics around the E/I balance point. In sum, E/I imbalances pointing toward an inhibition-dominated network are present in TSC. We established neurophysiological effects of bumetanide although with an inconclusive relationship with clinical improvement. Nonetheless, our results further indicate that baseline network characteristics might influence treatment response. These findings highlight the possible utility of E/I-sensitive EEG measures to accompany new treatment interventions for TSC., Clinical Trial Registration: EU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016., Competing Interests: KL-H is shareholder of NBT Analytics BV, which provides EEG-analysis services for clinical trials. HB and KL-H are shareholders of Aspect Neuroprofiles BV, which develops physiology-informed prognostic measures for neurodevelopmental disorders. KL-H has filed the patent claim (PCT/NL2019/050167) “Method of determining brain activity”; with priority date 16 March 2018. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Juarez-Martinez, van Andel, Sprengers, Avramiea, Oranje, Scheepers, Jansen, Mansvelder, Linkenkaer-Hansen and Bruining.)

Volitional suppression of responses to distracting external stimuli enables us to achieve our goals. This volitional inhibition of a specific behavior is supposed to be mainly mediated by the cerebral cortex. However, recent evidence supports the involvement of the cerebellum in this process. It is currently not known whether different parts of the cerebellar cortex play differential or synergistic roles in the planning and execution of this behavior. Here, we measured Purkinje cell (PC) responses in the medial and lateral cerebellum in two rhesus macaques during pro- and anti-saccade tasks. During an antisaccade trial, non-human primates (NHPs) were instructed to make a saccadic eye movement away from a target, rather than toward it, as in prosaccade trials. Our data show that the cerebellum plays an important role not only during the execution of the saccades but also during the volitional inhibition of eye movements toward the target. Simple spike (SS) modulation during the instruction and execution periods of pro- and anti-saccades was prominent in PCs of both the medial and lateral cerebellum. However, only the SS activity in the lateral cerebellar cortex contained information about stimulus identity and showed a strong reciprocal interaction with complex spikes (CSs). Moreover, the SS activity of different PC groups modulated bidirectionally in both of regions, but the PCs that showed facilitating and suppressive activity were predominantly associated with instruction and execution, respectively. These findings show that different cerebellar regions and PC groups contribute to goal-directed behavior and volitional inhibition, but with different propensities, highlighting the rich repertoire of the cerebellar control in executive functions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Avila, Flierman, Holland, Roelfsema, Frens, Badura and De Zeeuw.)

Background: Work stress is a serious problem in primary education. Decades of research underline the importance of participatory, organizational-level work stress prevention approaches. In this approach, measures are planned to tackle causes of work stress in a participatory manner and implemented by a working group consisting of members of the organization. This approach can only be effective if the measures contain effective ingredients to decrease work stress risks and are successfully implemented. The aim of this paper is to present an outline of a work stress prevention approach that is evaluated in primary education. To ensure the appropriateness of measures, a logic model of change is built as part of the risk assessment to facilitate the selection of appropriate measures. Progression on target behaviors as well as implementation factors are real-time monitored during implementation and fed back to the working groups, to provide the opportunity to adjust action plans when needed to optimize implementation., Methods: The approach consists of five steps: (1) preparation : installing an advisory board and working groups, (2) risk assessment : inventory of work stress risks (questionnaires and focus groups). In addition, a behavioral analysis is performed to build a logic model of change to facilitate selection of measures, (3) action planning : conducting an action plan with appropriate measures (focus groups), (4) implementation : implementing the action plan. During implementation progression on target behaviors and implementation factors are monthly monitored and fed back to the working groups, and (5) evaluation : effects of the approach are studied in a controlled trial with measurements at baseline (T0), 1 year (T1), and 2 years (T2) follow-up. A process evaluation is carried out using quantitative (questionnaires and real-time monitoring data) and qualitative (interviews and data logs) data to study the implementation process of all steps of the work stress approach., Discussion: We believe that building a logic model of change and real-time monitoring of implementation could be of added value to improve the success of the work stress prevention approach. With this study, we aim to provide more insights into work stress intervention research, especially in primary education., Clinical Trial Registration: The study is registered in Netherlands Trial Register (ClinicalTrials.gov #NL9797, October 18, 2021)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bakhuys Roozeboom, Niks, Schelvis, Wiezer and Boot.)

Background: Promising results from a trauma reactivation study on post-traumatic stress disorder suggest that propranolol is capable of attenuating symptoms of traumatically induced mental disorders by blocking memory reconsolidation., Methods: A randomized, parallel, placebo-controlled, quadruple-blind trial was designed to determine the effectiveness of perioperative propranolol during exposure to dental extractions in reducing dental anxiety in patients with dental anxiety or dental phobia. Between November 2014 and December 2018, 52 patients with high levels of fear in anticipation of dental extractions who were referred to a department of oral and maxillofacial surgery for at least two tooth and/or molar removals with 1 month in between were included. On the first visit participants received either 120 mg of perioperative oral propranolol ( n = 19) or placebo ( n = 17), and a core fear memory was reactivated 1 h preoperatively. The primary outcome was change in severity of dental anxiety from baseline to 1-month follow-up, as indexed by the short version of the dental anxiety inventory (S-DAI). Secondary outcome measures were change in intra-operative state anxiety and specific phobia diagnoses., Results: Linear mixed model (LMM) yielded no statistically significant difference in change of dental trait anxiety from baseline to 1-month follow-up between propranolol and placebo groups (Cohen's d = 0.23). S-DAI scores decreased in both study arms from baseline to follow-up (propranolol arm: from 32.1 [SD = 7.3] to 29.1 [SD = 8.8]; placebo arm: from 31.6 [SD = 7.5] to 27.1 [SD = 6.5]). Also, administering propranolol was not associated with a significant difference in change of intra-operative state anxiety or phobia diagnoses between groups over time., Conclusions: The results do not concur with earlier findings regarding post-traumatic stress disorder, and suggest that individuals with traumatically induced fears or phobias do not benefit from the application of perioperative propranolol., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Steenen, Su, van Westrhenen, van Wijk, Tjia, de Lange and de Jongh.)

Introduction: The Flash technique is a novel intervention aimed at rapidly decreasing the subjective disturbance of an aversive memory, thereby serving as a potential way of treating post-traumatic stress disorder (PTSD). The protocol is used to stimulate clients to engage in positive imagery while being discouraged to actively recollect the targeted disturbing memory. Previous research into the Flash technique's efficacy shows promising results, yet controlled studies are lacking. Objectives: To test the efficacy of the Flash technique, it was compared to an abbreviated eye movement desensitization and reprocessing (EMDR) therapy protocol in a controlled experimental setting. We hypothesized that the Flash technique would lead to a larger decrease in the emotionality and vividness of an aversive autobiographical memory when compared to EMDR therapy. Our second hypothesis was that the procedure of the Flash technique would be evaluated more pleasant by its receiver. Method: The sample consisted of 60 non-clinical participants (mean age = 25.28 years; 73.33% female) who were able to recall an aversive autobiographical memory. They were randomized to either the Flash technique or the EMDR therapy condition. Measurements consisted of emotionality and vividness-ratings pre and post intervention, and at 1-week follow-up. Results: Bayesian analyses showed no differences between Flash and EMDR to the extent to which the emotionality and vividness of their memory was reduced. Afterward, the Flash technique was rated more pleasant than EMDR. Conclusion: The results support the claim that the Flash technique might be used as a brief and efficacious intervention for individuals suffering from disturbing memories. Although the results suggest that its efficacy does not differ from EMDR, the Flash technique seems to yield similar outcomes in a more pleasant way. Further research into its working mechanisms and in a clinical sample is required., Competing Interests: AJ receives income from published books on EMDR therapy and for training postdoctoral professionals in this method. AJ and SM received income from a webinar on the Flash technique. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Brouwers, de Jongh and Matthijssen.)

STXBP1 syndrome is a rare neurodevelopmental disorder caused by heterozygous variants in the STXBP1 gene and is characterized by psychomotor delay, early-onset developmental delay, and epileptic encephalopathy. Pathogenic STXBP1 variants are thought to alter excitation-inhibition (E/I) balance at the synaptic level, which could impact neuronal network dynamics; however, this has not been investigated yet. Here, we present the first EEG study of patients with STXBP1 syndrome to quantify the impact of the synaptic E/I dysregulation on ongoing brain activity. We used high-frequency-resolution analyses of classical and recently developed methods known to be sensitive to E/I balance. EEG was recorded during eyes-open rest in children with STXBP1 syndrome ( n  = 14) and age-matched typically developing children ( n  = 50). Brain-wide abnormalities were observed in each of the four resting-state measures assessed here: (i) slowing of activity and increased low-frequency power in the range 1.75-4.63 Hz, (ii) increased long-range temporal correlations in the 11-18 Hz range, (iii) a decrease of our recently introduced measure of functional E/I ratio in a similar frequency range (12-24 Hz), and (iv) a larger exponent of the 1/f-like aperiodic component of the power spectrum. Overall, these findings indicate that large-scale brain activity in STXBP1 syndrome exhibits inhibition-dominated dynamics, which may be compensatory to counteract local circuitry imbalances expected to shift E/I balance toward excitation, as observed in preclinical models. We argue that quantitative EEG investigations in STXBP1 and other neurodevelopmental disorders are a crucial step to understand large-scale functional consequences of synaptic E/I perturbations., Competing Interests: KL-H is a shareholder of NBT Analytics BV, which provides EEG-analysis services for clinical trials. HB and KL-H are shareholders of Aspect Neuroprofiles BV, which develops physiology-informed prognostic measures for neurodevelopmental disorders. KL-H has filed the patent claim (PCT/NL2019/050167) “Method of determining brain activity”; with priority date 16 March 2018. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Houtman, Lammertse, van Berkel, Balagura, Gardella, Ramautar, Reale, Møller, Zara, Striano, Misra-Isrie, van Haelst, Engelen, van Zuijen, Mansvelder, Verhage, Bruining and Linkenkaer-Hansen.)

We performed an EEG graph analysis on data from 31 typical readers (22.27 ± 2.53 y/o) and 24 dyslexics (22.99 ± 2.29 y/o), recorded while they were engaged in an audiovisual task and during resting-state. The task simulates reading acquisition as participants learned new letter-sound mappings via feedback. EEG data was filtered for the delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), and beta (13-30 Hz) bands. We computed the Phase Lag Index (PLI) to provide an estimate of the functional connectivity between all pairs of electrodes per band. Then, networks were constructed using a Minimum Spanning Tree (MST), a unique sub-graph connecting all nodes (electrodes) without loops, aimed at minimizing bias in between groups and conditions comparisons. Both groups showed a comparable accuracy increase during task blocks, indicating that they correctly learned the new associations. The EEG results revealed lower task-specific theta connectivity, and lower theta degree correlation over both rest and task recordings, indicating less network integration in dyslexics compared to typical readers. This pattern suggests a role of theta oscillations in dyslexia and may reflect differences in task engagement between the groups, although robust correlations between MST metrics and performance indices were lacking., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fraga-González, Smit, Van der Molen, Tijms, Stam, de Geus and Van der Molen.)

Background: Pharmacotherapy is a cornerstone in bipolar disorder (BD) treatment whereas borderline personality disorder (BPD) is treated primarily with psychotherapy. Given the overlap in symptomatology, patients with BD may benefit from psychotherapy designed for BPD. Aims: This paper reports the findings of a non-controlled open feasibility study of STEPPS training in patients with BD and borderline personality features (BPF). Methods: Outpatients with BD were screened for BPD, and if positive interviewed with SCID-II. Patients with at least three BPF, always including impulsivity and anger burst, were included in the intervention study. Severity of BD and BPD and quality of life were assessed. Descriptive statistics were performed. Results: Of 111 patients with BD 49.5% also screened positive on BPD according to PDQ-4+, and 52.3% of these had BPD according to SCID-II. Very few participants entered the intervention study, and only nine patients completed STEPPS. Descriptive statistics showed improvement on all outcome variables post treatment, but no longer at 6-month follow up. We reflect on the potential reasons for the failed inclusion. Conclusion: Features of BPD were highly prevalent in patients with BD. Still, recruiting patients for a psychological treatment originally designed for BPD proved to be difficult. Feedback of participants suggests that the association of STEPPS with "borderline" had an aversive effect, which may have caused limited inclusion for screening and subsequent drop-out for the treatment. Therefore, STEPPS should be adapted for BD to be an acceptable treatment option. Clinical Trial Registration: www.ClinicalTrials.gov/3856, identifier: NTR4016., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Riemann, Chrispijn, Weisscher, Regeer and Kupka.)

The reproducibility crisis (or replication crisis) in biomedical research is a particularly existential and under-addressed issue in the field of behavioral neuroscience, where, in spite of efforts to standardize testing and assay protocols, several known and unknown sources of confounding environmental factors add to variance. Human interference is a major contributor to variability both within and across laboratories, as well as novelty-induced anxiety. Attempts to reduce human interference and to measure more "natural" behaviors in subjects has led to the development of automated home-cage monitoring systems. These systems enable prolonged and longitudinal recordings, and provide large continuous measures of spontaneous behavior that can be analyzed across multiple time scales. In this review, a diverse team of neuroscientists and product developers share their experiences using such an automated monitoring system that combines Noldus PhenoTyper ® home-cages and the video-based tracking software, EthoVision ® XT, to extract digital biomarkers of motor, emotional, social and cognitive behavior. After presenting our working definition of a "home-cage", we compare home-cage testing with more conventional out-of-cage tests (e.g., the open field) and outline the various advantages of the former, including opportunities for within-subject analyses and assessments of circadian and ultradian activity. Next, we address technical issues pertaining to the acquisition of behavioral data, such as the fine-tuning of the tracking software and the potential for integration with biotelemetry and optogenetics. Finally, we provide guidance on which behavioral measures to emphasize, how to filter, segment, and analyze behavior, and how to use analysis scripts. We summarize how the PhenoTyper has applications to study neuropharmacology as well as animal models of neurodegenerative and neuropsychiatric illness. Looking forward, we examine current challenges and the impact of new developments. Examples include the automated recognition of specific behaviors, unambiguous tracking of individuals in a social context, the development of more animal-centered measures of behavior and ways of dealing with large datasets. Together, we advocate that by embracing standardized home-cage monitoring platforms like the PhenoTyper, we are poised to directly assess issues pertaining to reproducibility, and more importantly, measure features of rodent behavior under more ethologically relevant scenarios., Competing Interests: BB and QP were employed by F. Hoffman-La Roche Ltd. BK and ML are employed by Synaptologics BV. ED, FG, LN, RFR, and RT are employed by Noldus Information Technology BV. AS participates in a holding that owns shares of Synaptologics BV. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Grieco, Bernstein, Biemans, Bikovski, Burnett, Cushman, van Dam, Fry, Richmond-Hacham, Homberg, Kas, Kessels, Koopmans, Krashes, Krishnan, Logan, Loos, McCann, Parduzi, Pick, Prevot, Riedel, Robinson, Sadighi, Smit, Sonntag, Roelofs, Tegelenbosch and Noldus.)

Introduction: Cocaine users often present with repetitive events of cocaine-associated chest pain (CACP), clinically resembling acute coronary syndromes. The aim of the study is to describe the specific risk factors for CACP. Method: Cocaine users ( n = 316) were recruited for a multicenter cross-sectional study. Lifetime CACP history, sociodemographic factors, and lifetime use of cocaine and other substances were assessed. Thirty single nucleotide polymorphisms (SNPs) of NOS3, ROCK2, EDN1, GUCY1A3 , and ALDH2 genes, suggested by the literature on coronary spasms, were selected. The associations with CACP history were tested using the chi-square test, Student's t -test and logistic regression. Results: Among the 316 subjects [78.5% men, mean age 37.5 years, (standard-deviation ±8.7)], 190 (60.1%) were daily cocaine users and 103 (32.6%) reported a lifetime CACP history. Among those with a lifetime CACP history, the median was 10 events per individual. In multivariate analysis, lifetime CACP history was associated with daily cocaine use [odds-ratio (OR) 3.24; 95% confidence intervals (1.29-9.33)], rapid route of cocaine use [OR 2.33 (1.20-4.64) vs. intranasal use], and lifetime amphetamine use [daily amphetamine use: OR 2.80 (1.25-6.32) and non-daily amphetamine use: OR 2.14 (1.15-4.04) vs. never used]. Patients with lifetime opioid maintenance treatment (OMT) reported significantly less lifetime CACP history [OR 0.35 (0.16-0.76)]. None of the selected SNPs was associated with CACP history after multiple testing corrections. Conclusions: Clinical variables describing the intensity of stimulant use were positively associated with lifetime CACP history, while OMT was negatively associated with it. Specific harm reduction strategies can target these risk factors., Competing Interests: In the past 5 years, FV had congress fees paid by CAMURUS AB (2018, 2019), and RECORDATI (2020). FV gave a single lecture for RECORDATI (2020) and served in advisory boards for CAMURUS AB (2019), and ACCORD HEALTH CARE (2021). All payments were made to a research entity and not directly to FV. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Clergue-Duval, Nicolas-Sacy, Karsinti, Zerdazi, Laplanche, Brousse, Marees, Derks, Henry, Bellivier, Vorspan and Bloch.)

While the central nervous system compromises 2% of our body weight, it harbors up to 25% of the body's cholesterol. Cholesterol levels in the brain are tightly regulated for physiological brain function, but mounting evidence indicates that excessive cholesterol accumulates in Alzheimer's disease (AD), where it may drive AD-associated pathological changes. This seems especially relevant for late-onset AD, as several of the major genetic risk factors are functionally associated with cholesterol metabolism. In this review we discuss the different systems that maintain brain cholesterol metabolism in the healthy brain, and how dysregulation of these processes can lead, or contribute to, Alzheimer's disease. We will also discuss how AD-risk genes might impact cholesterol metabolism and downstream AD pathology. Finally, we will address the major outstanding questions in the field and how recent technical advances in CRISPR/Cas9-gene editing and induced pluripotent stem cell (iPSC)-technology can aid to study these problems., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Feringa and van der Kant.)

Bribery is a complex phenomenon rooted in both individual motives and the greater institutional context. Experimental research into causal mechanisms that drive bribing behavior is still scarce. To date, there is no empirical evidence on how the society-regarding motivational survey measure of Public Service Motivation (PSM) and the other-oriented motivational measure of Social Value Orientation (SVO) can help explain why some people are more susceptible to engage in the act of bribing than others. Based on a multi-site triple-replication, and a vignette-based research design, quasi-experimental evidence from Belgium, Germany, and the Netherlands shows that both measures interact and that-paradoxically-people with higher SVO are more likely to be willing to engage in bribery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 De Waele, Weißmüller and van Witteloostuijn.)

We investigated, by means of the Reverse Correlation Task (RCT), visual representations of the culturally dominating group of local people held by sojourners as a function of their degree of cross-cultural adaptation. In three studies, using three different methods (reduced RCT, full RCT, conceptual replication) with three independent samples of sojourners and seven independent samples of Portuguese and US-American raters, we gathered clear evidence that poor adaptation goes along with more negative representations of locals. This indicates that sojourner adaptation is reflected, at a social-cognitive level, in the valence of outgroup representations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bierwiaczonek, Waldzus and Zee.)

Background: Posttraumatic stress disorder (PTSD) is a serious and relatively common mental disorder causing a high burden of suffering. Whereas evidence-based treatments are available, dropout and non-response rates remain high. PTSD and Cluster C personality disorders (avoidant, dependent or obsessive-compulsive personality disorder; CPD) are highly comorbid and there is evidence for suboptimal treatment effects in this subgroup of patients. An integrated PTSD and CPD treatment may be needed to increase treatment efficacy. However, no studies directly comparing the efficacy of regular PTSD treatment and treatment tailored to PTSD and comorbid CPD are available. Whether integrated treatment is more effective than treatment focused on PTSD alone is important, since (1) no evidence-based guideline for PTSD and comorbid CPD treatment exists, and (2) treatment approaches to CPD are costly and time consuming. Present study design describes a randomized controlled trial (RCT) directly comparing trauma focused treatment with integrated trauma focused and personality focused treatment. Methods: An RCT with two parallel groups design will be used to compare the clinical efficacy and cost-effectiveness of "standalone" imagery rescripting ( n = 63) with integrated imagery rescripting and schema therapy ( n = 63). This trial is part of a larger research project on PTSD and personality disorders. Predictors, mediators and outcome variables are measured at regular intervals over the course of 18 months. The main outcome is PTSD severity at 12 months. Additionally, machine-learning techniques will be used to predict treatment outcome using biopsychosocial variables. Discussion: This study protocol outlines the first RCT aimed at directly comparing the clinical efficacy and cost-effectiveness of imagery rescripting and integrated imagery rescripting and schema therapy for treatment seeking adult patients with PTSD and comorbid cluster C personality pathology. Additionally, biopsychosocial variables will be used to predict treatment outcome. As such, the trial adds to the development of an empirically informed and individualized treatment indication process. Clinical Trial registration: ClinicalTrials.gov, NCT03833531., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 van den End, Dekker, Beekman, Aarts, Snoek, Blankers, Vriend, van den Heuvel and Thomaes.)

In this conceptual paper, we outline the many challenges on the road to personalized psychotherapy, using the example of cognitive behavior therapy (CBT) for depression. To optimize psychotherapy for the individual patient, we need to find out how therapy works (identification of mechanisms of change) and for whom it works (identification of moderators). To date, psychotherapy research has not resulted in compelling evidence for or against common or specific factors that have been proposed as mechanisms of change. Our central proposition is that we need to combine the "how does it work?"-question with the "for whom does it work?"-question in order to advance the field. We introduce the personalized causal pathway hypothesis that emphasizes the links and distinction between individual patient differences, therapeutic procedures and therapy processes as a paradigm to facilitate und understand the concept of personalized psychotherapy. We review the mechanism of change literature for CBT for depression to see what we have learned so far, and describe preliminary observational evidence supporting the personalized causal pathway hypothesis. We then propose a research agenda to push the ball forward: exploratory studies into the links between individual differences, therapeutic procedures, therapy processes and outcome that constitute a potential causal pathway, making use of experience sampling, network theory, observer ratings of therapy sessions, and moderated mediation analysis; testing and isolation of CBT procedures in experiments; and testing identified causal pathways of change as part of a personalized CBT package against regular CBT, in order to advance the application of personalized psychotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Huibers, Lorenzo-Luaces, Cuijpers and Kazantzis.)

Rationale: Despite interventions to improve detection rates, domestic violence, and abuse (DVA) remains largely undetected by healthcare services. We therefore aimed to examine the acceptability, feasibility, and sustainability of an intervention aiming to improve DVA detection rates, which included a clear referral pathway (i.e., the BRAVE intervention) and to explore the acceptability and feasibility of DVA management and referrals in general, in the context of low detection rates. Methods: Qualitative study design with four focus groups of 16 community mental health (CMH) clinicians from both control and intervention arms. The focus groups discussed managing DVA in clinical practice and staff experiences with the BRAVE intervention in particular. Focus groups continued until saturation of the subject was reached. Interviews were analyzed using a thematic analysis approach. Results: DVA was seen to be highly relevant to mental healthcare but is also a very sensitive subject. Barriers in CMH professionals, institutions, and society meant CMH professionals often refrained from asking about DVA in patients. Barriers included communication difficulties between CMH professionals and DVA professionals, a fear of disrupting the therapeutic alliance with the patient, and a lack of appropriate services to help victims of DVA. Conclusion: The BRAVE intervention was acceptable but not feasible or sustainable. Personal, institutional, and public barriers make it not feasible for CMH professionals to detect DVA in mental healthcare. To increase the detection of DVA, professional standards should be combined with training, feedback sessions with peers and DVA counselors, and routine enquiry about DVA. Clinical Trial Registration: ISRCTN, trial registration number: ISRCTN14115257., (Copyright © 2020 Ruijne, Kamperman, Trevillion, Garofalo, van der Gaag, Zarchev, Bogaerts, Howard and Mulder.)

Introduction: Subjective tinnitus that is influenced by the somatosensory system is called somatosensory tinnitus (ST). When ST is related to the temporomandibular area, multidisciplinary orofacial treatment can reduce tinnitus severity. It is, however, unknown if we can predict this positive outcome. The aim of this study is to look for prognostic indicators that can predict a positive outcome after multidisciplinary orofacial treatment in patients with ST., Methods: Patients were included when they were diagnosed with temporomandibular-related ST and received a maximum of 18 sessions of orofacial treatment during a 9-week program. Predictors for positive treatment outcome were identified using univariate and multiple logistic regression analyses with the Tinnitus Questionnaire (TQ) and the Tinnitus Functional Index (TFI) as dependent variables., Results: The results of 101 patients were included in the analysis. Immediately after multidisciplinary orofacial treatment, a clinically relevant decrease in TQ score was significantly associated with "shorter duration of tinnitus" [odds ratio (OR) 0.99], "higher initial score on the TQ somatic subscale" (OR 1.52), and "painful palpation of the temporomandibular joint (TMJ)" (OR 2.46). After 9 weeks of follow-up, the "higher initial score on the TQ somatic subscale" remained as the sole predictor (OR 1.44). A clinically relevant decrease on TFI after 9 weeks of follow-up was predicted by "female gender" (OR 2.70), "younger age" (OR 0.96), "shorter duration of the tinnitus" (OR 0.99), "lower pressure pain thresholds (PPT) on TMJ" (OR 0.99), "lower PPT on sternocleidomastoid origin" (OR 0.99), and "better speech in noise perception" (OR 0.88). A multivariate model comprising "shorter duration of tinnitus" and "higher initial score on the somatic subscale of the TQ" correctly predicts the clinically relevant decrease in TQ score after treatment in 68.5%. A second multivariate model comprising "female gender," "younger age," and "shorter duration of the tinnitus" correctly predicts a clinically significant decrease on TFI after follow-up in 68.1%., Conclusion: We were able to identify various prognostic indicators. "Younger female patients" with a "shorter duration of tinnitus" and a "higher initial score on the TQ somatic subscale" appear to have the best prognosis after multimodal orofacial therapy., (Copyright © 2020 van der Wal, Van de Heyning, Gilles, Jacquemin, Topsakal, Van Rompaey, Braem, Visscher, Truijen, Michiels and De Hertogh.)

Background: Maternal mental health problems often develop prenatally and predict post-partum mental health. However, the circumstances before and following childbirth differ considerably. We currently lack an understanding of dynamic variation in the profiles of depressive and anxiety symptoms over the perinatal period., Methods: Depressive and anxiety symptoms were self-reported by 980 women at 26-week pregnancy and 3 months post-partum. We used network analysis of depressive and anxiety symptoms to investigate if the symptoms network changed during and after pregnancy. The pre- and post-partum depressive-anxiety symptom networks were assessed for changes in structure, unique symptom-symptom interactions, central and bridging symptoms. We also assessed if central symptoms had stronger predictive effect on offspring's developmental outcomes outcomes at birth and 24, 54, and 72 months old than non-central symptoms. Bridging symptoms between negative and positive mental health were also assessed., Results: Though the depressive-anxiety network structures were stable during and after pregnancy, the post-partum network was more strongly connected. The central depressive-anxiety symptoms were also different between prenatal and post-partum networks. During pregnancy, central symptoms were mostly related to feeling worthless or useless; after pregnancy, central symptoms were mostly related to feeling overwhelmed or being punished. Central symptoms during pregnancy were associated with poorer developmental outcomes for the child. Anxiety symptoms were strongest bridging symptoms during and after pregnancy. The interactions between negative and positive mental health symptoms were also different during and after pregnancy., Conclusions: The differences between pre- and post-partum networks suggest that the presentation of maternal mental health problems varies over the peripartum period. This variation is not captured by traditional symptom scale scores. The bridging symptoms also suggest that anxiety symptoms may precede the development of maternal depression. Interventions and public health policies should thus be tailored to specific pre- and post-partum symptom profiles., (Copyright © 2020 Phua, Chen, Chong, Gluckman, Broekman and Meaney.)

Emotional tears are uniquely human and play an essential role in the communication of distress in adults. Several studies have shown that individuals are more willing to offer emotional support and help a person in tears. Preliminary evidence suggests that this greater willingness to provide support is mediated via perceived warmth and helplessness. Moreover, tearful individuals are regarded as more reliable and honest. In the current study, we examined whether people can reliably distinguish genuine and fake crying, and what the consequences for the further evaluation of the crier are. A total of 202 participants (73 men, 129 women) were exposed to brief movie clips of genuine and fake crying adults and were asked to assess the criers. Results show that women were slightly better at identifying fake and genuine crying. How the crying was perceived subsequently seemed to have a strong influence on the further evaluation of the "crier." Criers qualified as pretenders were perceived as significantly more manipulative, less reliable, less warm, and less competent. Further, the respondents felt less connected with the perceived pretenders, who also were less welcomed as friends, colleagues, neighbors, and babysitter. They were additionally qualified as significantly less fit for "reliable" professions (judge, teacher, police officer, scientist, and physician). In contrast, the ratings of their fitness for "unreliable" professions (banker, CEO, journalist, real estate salesman, and politician) yielded a significant difference in only one video clip (and contrary to expectations). Our findings thus indicate that the subjective labeling of crying as fake is associated with a significantly less positive perception of the "crying" person, regardless of whether the crying is actually fake or genuine. The qualification of tears as crocodile tears thus seems to affect the crier's image strongly negatively., (Copyright © 2020 van Roeyen, Riem, Toncic and Vingerhoets.)

Parallel meta-analysis is a popular approach for increasing the power to detect genetic effects in genome-wide association studies across multiple cohorts. Consortia studying the genetics of behavioral phenotypes are oftentimes faced with systematic differences in phenotype measurement across cohorts, introducing heterogeneity into the meta-analysis and reducing statistical power. This study investigated integrative data analysis (IDA) as an approach for jointly modeling the phenotype across multiple datasets. We put forth a bi-factor integration model (BFIM) that provides a single common phenotype score and accounts for sources of study-specific variability in the phenotype. In order to capitalize on this modeling strategy, a phenotype reference panel was utilized as a supplemental sample with complete data on all behavioral measures. A simulation study showed that a mega-analysis of genetic variant effects in a BFIM were more powerful than meta-analysis of genetic effects on a cohort-specific sum score of items. Saving the factor scores from the BFIM and using those as the outcome in meta-analysis was also more powerful than the sum score in most simulation conditions, but a small degree of bias was introduced by this approach. The reference panel was necessary to realize these power gains. An empirical demonstration used the BFIM to harmonize aggression scores in 9-year old children across the Netherlands Twin Register and the Child and Adolescent Twin Study in Sweden, providing a template for application of the BFIM to a range of different phenotypes. A supplemental data collection in the Netherlands Twin Register served as a reference panel for phenotype modeling across both cohorts. Our results indicate that model-based harmonization for the study of complex traits is a useful step within genetic consortia., (Copyright © 2019 Luningham, McArtor, Hendriks, van Beijsterveldt, Lichtenstein, Lundström, Larsson, Bartels, Boomsma and Lubke.)

Life on Earth has evolved under the influence of gravity. This force has played an important role in shaping development and morphology from the molecular level to the whole organism. Although aquatic life experiences reduced gravity effects, land plants have evolved under a 1- g environment. Understanding gravitational effects requires changing the magnitude of this force. One method of eliminating gravity''s influence is to enter into a free-fall orbit around the planet, thereby achieving a balance between centripetal force of gravity and the centrifugal force of the moving object. This balance is often mistakenly referred to as microgravity, but is best described as weightlessness. In addition to actually compensating gravity, instruments such as clinostats, random-positioning machines (RPM), and magnetic levitation devices have been used to eliminate effects of constant gravity on plant growth and development. However, these platforms do not reduce gravity but constantly change its direction. Despite these fundamental differences, there are few studies that have investigated the comparability between these platforms and weightlessness. Here, we provide a review of the strengths and weaknesses of these analogs for the study of plant growth and development compared to spaceflight experiments. We also consider reduced or partial gravity effects via spaceflight and analog methods. While these analogs are useful, the fidelity of the results relative to spaceflight depends on biological parameters and environmental conditions that cannot be simulated in ground-based studies., (Copyright © 2019 Kiss, Wolverton, Wyatt, Hasenstein and van Loon.)

Objectives: Our aim of this work was to investigate the regrowth of implant-related biofilms after various antimicrobial treatments in vitro . Methods: Saliva-derived microcosm biofilms were grown on titanium discs in an active attachment model. Treatments including hydrogen peroxide (HP), citric acid (CA), chlorhexidine (CHX), and distilled water (control), at different concentrations, were applied to 2-day biofilms for 1 or 5 min. The viability, lactic acid production, and composition of the biofilms were followed for 3 days. The biofilm composition was analyzed by 16S rDNA amplicon sequencing. Results: The short treatments of CA, CHX, and HP resulted in a 2-3 log reduction in biofilm viability and lactic acid production immediately. However, both parameters returned to the pre-treatment level within 2 days due to biofilm regrowth. The alpha diversity of the regrown biofilms in antimicrobial-treated groups tended to decrease, whereas the diversity of those in water-treated group increased. The composition of the regrown biofilms altered compared to those before treatments. Streptococcus and Enterobacteriaceae were enriched in the regrown biofilms. Conclusions: Although the antimicrobial treatments were efficient, the multi-species biofilms were indeed able to regrow within 2 days. The regrown biofilms display an altered microbial diversity and composition, which in the oral cavity may lead to an aggressive infection., (Copyright © 2019 Han, Jiang, Brandt, Yang, Chen, Buijs, Crielaard, Cheng and Deng.)

Fragile X syndrome (FXS) is the most prevalent inherited cause of autism and is accompanied by behavioral and sensory deficits. Errors in the wiring of the brain during early development likely contribute to these deficits, but the underlying mechanisms are unclear. Spontaneous activity patterns, which are required for fine-tuning neuronal networks before the senses become active, are perturbed in rodent models of FXS. Here, we investigated spontaneous network activity patterns in the developing visual cortex of the Fmr1 knockout mouse using in vivo calcium imaging during the second postnatal week, before eye opening. We found that while the frequency, mean amplitude and duration of spontaneous network events were unchanged in the knockout mouse, pair-wise correlations between neurons were increased compared to wild type littermate controls. Further analysis revealed that interneuronal correlations were not generally increased, rather that low-synchronization events occurred relatively less frequently than high-synchronization events. Low-, but not high-, synchronization events have been associated with retinal inputs previously. Since we found that spontaneous retinal waves were normal in the knockout, our results suggest that peripherally driven activity is underrepresented in the Fmr1 KO visual cortex. Therefore, we propose that central gating of retinal inputs may be affected in FXS and that peripherally and centrally driven activity patterns are already unbalanced before eye opening in this disorder., (Copyright © 2019 Cheyne, Zabouri, Baddeley and Lohmann.)

Autonomy-enhancing treatment (AET) is a person-centered, gender-sensitive treatment, targeting transdiagnostic personal autonomy deficits. The current study was set up as a first pilot randomized controlled trial (RCT) to investigate the preliminary efficacy of AET. Earlier small non-controlled plots showed AET to be feasible and acceptable. In the current study (Trial Code 3513), patients receiving 15-session group-based AET ( N = 43) were compared with those in a waitlist control condition ( N = 40). Both the intention-to-treat and completers analyses suggested a larger decrease in agoraphobic symptoms in the experimental treatment than in the waitlist condition. In both analyses, effect sizes were small. The completers analyses showed additional beneficial effects in two of three autonomy-connectedness components, as well as psychoneuroticism, anxiety, and depression, which disappeared after correcting for multiple testing. AET may alleviate agoraphobic symptoms in a patient sample with severe anxiety. Future research, including more stringent inclusion criteria and follow-up assessment, is needed to further evaluate whether AET may serve as a promising alternative or addition to existing approaches. Clinical Trial Registration: www.trialregister.nl, identifier NTR3513., (Copyright © 2019 Maas, van Balkom, van Assen, Rutten, Janssen, van Mastrigt and Bekker.)