An Open Pilot Study of Training Hostile Interpretation Bias to Treat Disruptive Mood Dysregulation Disorder

Objective: Irritability in disruptive mood dysregulation disorder (DMDD) may be associated with a biased tendency to judge ambiguous facial expressions as angry. We conducted three experiments to explore this bias as a treatment target. We tested: 1) whether youth with DMDD express this bias; 2) whether judgment of ambiguous faces can be altered in healthy youth by training; and 3) whether such training in youth with DMDD is associated with reduced irritability and associated changes in brain function. Methods: Participants in all experiments made happy versus angry judgments of faces that varied along a happy to angry continuum. These judgments were used to quantify a “balance point,” the facial expression at which a participant's judgment switches from predominantly happy to predominantly angry. We first compared balance points in youth with DMDD (n = 63) versus healthy youth (n = 26). We then conducted a double-blind, randomized controlled trial of active versus sham balance-point training in 19 healthy youth. Finally, we piloted open, active balance-point training in 14 youth with DMDD, with 10 completing an implicit functional MRI (fMRI) face-emotion processing task. Results: Relative to healthy youth, DMDD youth manifested a shifted balance point, expressed as a tendency to classify ambiguous faces as angry rather than happy. In both healthy and DMDD youth, active training is associated with a shift in balance point toward more happy judgments. In DMDD, evidence suggests that active training may be associated with decreased irritability and changes in activation in the lateral orbitofrontal cortex. Conclusions:These results set the stage for further research on computer-based treatment targeting interpretation bias of angry faces in DMDD. Such treatment may decrease irritability and alter neural responses to subtle expressions of happiness and anger

A double-blind, randomized, placebo-controlled trial of a computer-based Interpretation Bias Training for youth with severe irritability:a study protocol

Abstract Background Severe, chronic, and impairing irritability is a common presenting clinical problem in youth. Indeed, it was recently operationalized as disruptive mood dysregulation disorder (DMDD) in the DSM-5. However, to date, there are no evidence-based treatments that were specifically developed for DMDD. The current randomized controlled trial assesses the efficacy of a computer-based cognitive training intervention (Interpretation Bias Training; IBT) in youth with DMDD. IBT aims to reduce irritability by altering judgments of ambiguous face-emotions through computerized feedback. IBT is based on previous findings that youth with irritability-related psychopathology rate ambiguous faces as more hostile and fear producing. Methods/design This is a double-blind, randomized controlled trial of IBT in 40 youth with DMDD. Participants will be randomized to receive four IBT sessions (Active vs. Sham training) over 4 days. Active IBT provides computerized feedback to change ambiguous face-emotion interpretations towards happy interpretations. Face-emotion judgments are performed pre and post training, and for 2 weeks following training. Blinded clinicians will conduct weekly clinical ratings. Primary outcome measures assess changes in irritability using the clinician-rated Affective Reactivity Index (ARI) and Clinical Global Impressions-Improvement (CGI-I) scale for DMDD, as well as parent and child reports of irritability using the ARI. Secondary outcome measures include clinician ratings of depression, anxiety, and overall impairment. In addition, parent and child self-report measures of depression, anxiety, anger, social status, and aggression will be collected. Discussion The study described in this protocol will perform the first RCT testing the efficacy of IBT in reducing irritability in youth with DMDD. Developing non-pharmacological treatment options for youth suffering from severe, chronic irritability is important to potentially augment existing treatments. Trial registration ClinicalTrials.gov, ID: NCT02531893. Registered on 25 August 2015

Fibronectin Matrix Assembly Suppresses Dispersal of Glioblastoma Cells

Glioblastoma (GBM), the most aggressive and most common form of primary brain tumor, has a median survival of 12–15 months. Surgical excision, radiation and chemotherapy are rarely curative since tumor cells broadly disperse within the brain. Preventing dispersal could be of therapeutic benefit. Previous studies have reported that increased cell-cell cohesion can markedly reduce invasion by discouraging cell detachment from the tumor mass. We have previously reported that α5β1 integrin-fibronectin interaction is a powerful mediator of indirect cell-cell cohesion and that the process of fibronectin matrix assembly (FNMA) is crucial to establishing strong bonds between cells in 3D tumor-like spheroids. Here, we explore a potential role for FNMA in preventing dispersal of GBM cells from a tumor-like mass. Using a series of GBM-derived cell lines we developed an in vitro assay to measure the dispersal velocity of aggregates on a solid substrate. Despite their similar pathologic grade, aggregates from these lines spread at markedly different rates. Spreading velocity is inversely proportional to capacity for FNMA and restoring FNMA in GBM cells markedly reduces spreading velocity by keeping cells more connected. Blocking FNMA using the 70 KDa fibronectin fragment in FNMA-restored cells rescues spreading velocity, establishing a functional role for FNMA in mediating dispersal. Collectively, the data support a functional causation between restoration of FNMA and decreased dispersal velocity. This is a first demonstration that FNMA can play a suppressive role in GBM dispersal

A Randomized Controlled Trial of Computerized Interpretation Bias Training for Disruptive Mood Dysregulation Disorder:A Fast-Fail Study

OBJECTIVE: Probing targeted, mechanism-based interventions is the next generation of treatment innovation. Biased threat labeling of ambiguous face emotions (interpretation bias) is a potential behavioral treatment target for anger, aggression, and irritability. Changing biases in face-emotion labeling may improve irritability-related outcomes. Here, we report the first randomized, double-blind, placebo-controlled targeted trial (RCT) of interpretation bias training (IBT) in youth with chronic, severe irritability. METHOD: Patients with current Disruptive Mood Dysregulation Disorder (DMDD; N=44) were randomly assigned to complete four sessions of active (n=22) or sham (n=22) computerized IBT training within a one-week period. The first and last trainings were completed onsite, and two trainings were completed at home. We examined the effects of active IBT on labeling bias, primary outcome measures of irritability, and secondary outcome measures of anxiety, depression, and functional impairment. Follow-up assessments were completed immediately after the intervention and two weeks following the intervention. RESULTS: We found that active IBT engaged the behavioral target in the active relative to the sham condition, shown by a significant shift toward labeling ambiguous faces as happy. However, there was no consistent clinical improvement in active IBT relative to the sham condition, immediately after, or two weeks following training in either primary or secondary outcome measures. CONCLUSION: While this RCT of IBT in youth with DMDD engaged the proposed behavioral target, there was no statistically significant improvement on clinical outcome. Identifying and changing behavioral targets is a first step in novel treatment development; these results have broader implications for targeted-based intervention development. CLINICAL TRIAL REGISTRATION INFORMATION: Psychological Treatments for Youth With Severe Irritability; https://clinicaltrials.gov/; NCT02531893

Resting heart rate and incident heart failure and cardiovascular mortality in older adults: role of inflammation and endothelial dysfunction: the PROSPER study

<p>Aims: Resting heart rate is a promising modifiable cardiovascular risk marker in older adults, but the mechanisms linking heart rate to cardiovascular disease are not fully understood. We aimed to assess the association between resting heart rate and incident heart failure (HF) and cardiovascular mortality, and to examine whether these associations might be attributable to systemic inflammation and endothelial dysfunction.</p> <p>Methods and results: We studied 4084 older adults aged 70–82 years with known cardiovascular risk factors or previous cardiovascular disease, without pre-existing HF or beta-blockers in the PROSPER study. Over a 3.2-year follow-up period, we examined incident HF hospitalization and cardiovascular mortality according to resting heart rate, along with C-reactive protein (CRP), interleukin-6 (IL-6), tissue plasminogen activator (tPA), and von Willebrand factor (vWf). Mean heart rate was 67 b.p.m. for men and 70 b.p.m. for women. CRP, IL-6, tPA, and vWf levels were all positively correlated with heart rate. After multivariate adjustment, heart rate was associated with HF hospitalization [hazard ratio (HR) 1.78 for highest vs. lowest distribution third, 95% confidence interval (CI) 1.21–2.63, P= 0.003] and cardiovascular mortality (HR 1.74, 95% CI 1.23–2.47, P= 0.002). Further adjustment for both IL-6 and vWf levels decreased HR to 1.60 (95% CI 1.08–2.38, P= 0.020) for HF and to 1.50 (95% CI 1.04–2.15, P= 0.028) for cardiovascular mortality.</p> <p>Conclusion: Increased heart rate is associated with increased systemic inflammation and endothelial dysfunction. These factors are likely to contribute to, but do not fully explain, the risk of HF and cardiovascular death associated with increased heart rate in older age.</p&gt

Neural and behavioral responses to threatening emotion faces in children as a function of the short allele of the serotonin transporter gene

Data suggest that a genetic polymorphism in the promoter region (5-HTTLPR) of the serotonin transporter (5-HTT) gene (SLC6A4) mediates stress reactivity in adults. Little is known, however, about this gene-brain association in childhood and adolescence, generally conceptualized as a time of heightened stress reactivity. The present study examines the association between 5-HTT allelic variation and responses to emotional faces presented both sub- and supraliminally in 9- to 17-year-old participants. Behaviorally, carriers of the 5-HTTLPR short (s) allele exhibited significantly greater attentional bias to subliminally presented fear faces than did their long (l)-allele homozygous counterparts. Moreover, s-allele carriers showed greater neural activations to emotion faces than did l-allele homozygotes in various regions of association cortex previously linked to attention control in adults; no such associations were observed in the amygdala. These results indicate that child and young adolescent s-allele carriers can be distinguished from l-allele homozygotes on the basis of hypervigilant behavioral and neural processing of negative material in the environmen