Costs and correlates of storage in visual working memory

Visual working memory (VWM) refers to temporary storage of only a few items and it is intensely discussed how objects are represented. A less elaborated topic is how much effort is necessary to encode and maintain objects dependent on the type of task-relevant feature. In the first part of this dissertation project pupil sizes and event-related potentials (ERPs) were used to estimate storage effort during maintenance of visual information in change detection tasks (CDT) where set size and complexity of task-relevant features was manipulated. Either an easy feature (color) or a more complex feature (shape) of presented objects was task-relevant. We showed that pupil sizes indicate the number of stored objects and therefore can be interpreted to reflect attentional demands that are necessary to focus on presented stimuli. It could be further demonstrated that pupillary changes were independent of luminance effects of the presented stimuli. Slow potentials during retention were modulated by the type of task-relevant feature and were interpreted to reflect processing effort. The second part of this work targets the question of how objects are represented in VWM by conducting a CDT where also task-irrelevant information was manipulated. According to object-based models items are always represented as integrated objects and the number of objects limits capacity in VWM. Feature-based models assume that the number and quality of features are the capacity limiting factors. Behavioral results revealed that changes of irrelevant information affect performance when color but not when shape was task-irrelevant. Nevertheless, in ERPs an irrelevant mismatch effect was found in both conditions and this effect was apparent until the respective individual capacity maximum for color and shape was achieved. We can conclude that features of presented objects in the current task were always represented independent of their task-relevance. These results were interpreted in terms of the VWM model provided by Brady et al. (2011) suggesting that objects are represented in hierarchical feature bundles which integrates object-based and feature-based VWM models.Das visuelle Arbeitsgedächtnis (VAG) beschreibt die vorübergehende Speicherung weniger Objekte und es besteht eine umfangreiche Debatte darüber, wie Objekte im VAG repräsentiert sind. Weniger ausführlich diskutiert wird die Frage wie viel Aufwand (Effort) benötigt wird, Objekte in Abhängigkeit des aufgabenrelevanten Merkmals zu enkodieren und aufrechtzuerhalten. Im ersten Teil dieses Dissertationsprojektes wurde der Effort während des Aufrechterhaltens visueller Information in einer Change Detection Aufgabe mithilfe von Pupillenweiten und Ereigniskorrelierten Potentiale (EKPs) untersucht. Dabei wurden die Set Größe und die Komplexität der aufgabenrelevanten Merkmale variiert. Entweder Farbe als einfaches Merkmal oder Form als komplexes Merkmal waren aufgabenrelevant. Die Pupillenweite spiegelte die Anzahl der Objekte wider und kann somit als Indikator für Aufmerksamkeitsaufwand (Attentional Effort) interpretiert werden, der notwendig ist um auf die präsentierten Objekte zu fokussieren. Es konnte weiter gezeigt werden, dass die Pupillenveränderungen unabhängig von der Luminanz der präsentierten Objekte sind. Langsame Potentiale während der Retentionsphase spiegelten die Art des aufgabenrelevanten Merkmals wider und wurden als Verarbeitungsaufwand (Processing Effort) interpretiert. Der zweite Teil dieser Arbeit beschäftigt sich mit der Frage wie Objekte im visuellen Arbeitsgedächtnis repräsentiert sind, indem aufgabenirrelevante Information in einer Change Detection Aufgabe manipuliert wurde. Im Hinblick auf objektbasierte Modelle des VAG, sind Items immer als integrierte Objekte repräsentiert und die Anzahl dieser Objekte limitiert die Kapazität des VAG. Merkmalsbasierte Modelle sagen vorher, dass die Anzahl und Qualität der Merkmale die Kapazität limitierenden Faktoren sind. Es konnte gezeigt werden, dass Veränderungen irrelevanter Information die Leistung beeinflusst wenn Farbe irrelevant war, nicht jedoch wenn Form das irrelevante Merkmal war. Im Gegensatz dazu wurde in den EKPs ein mismatch Effekt für die irrelevante Information in beiden Bedingungen gefunden, der bis zur individuellen Kapazitätsgrenze für Farben bzw. Formen bestand hatte. Die Ergebnisse wurden dahingehend interpretiert, dass Merkmale der präsentierten Objekte in der gegenwärtigen Aufgabe unabhängig von ihrer Aufgabenrelevanz repräsentiert waren. Dies wurde vor dem Hintergrund des VAG Modells von Brady et al. (2011) diskutiert, in dem vorgeschlagen wird, dass Objekte in „Hierarchical Feature Bundles“ repräsentiert sind, wodurch objektbasierte und merkmalsbasierte VAG Modelle integriert werden

Metacognitive Therapy for Posttraumatic Stress Disorder in Youth: A Feasibility Study

Metacognitive therapy (MCT) is an effective treatment for posttraumatic stress disorders (PTSD) in adults. However, there is no evidence for the feasibility, acceptability, and efficacy of MCT for PTSD in youth so far. This study is the first to utilize MCT for children and adolescents with PTSD. Twenty-one children and adolescents (aged 8–19 years) who were consecutively referred to the outpatient trauma clinic were treated with MCT. In all patients, treatment was well accepted and regularly attended. At post-treatment, MCT was associated with significant and large reductions in posttraumatic stress symptoms. Depending on the outcome measure, 95 or 85% of the patients were classified as recovered after treatment. Eighteen patients were included in the calculation of the overall outcome. Effect sizes on primary PTSD measures were large (Cohen’s d = 3.42 and d = 1.92) and more than comparable to well-established treatments. Only six patients were available at follow-up, but their improvements were found to be stable. Despite the limitations of this uncontrolled study, the results suggest that MCT may be a feasible and promising treatment for traumatized children and adolescents and they justify a controlled trial evaluating the efficacy of MCT versus an already well-established intervention

Functional characterization of T2D-associated SNP effects on baseline and ER stress-responsive β cell transcriptional activation.

Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) at \u3e250 loci in the human genome to type 2 diabetes (T2D) risk. For each locus, identifying the functional variant(s) among multiple SNPs in high linkage disequilibrium is critical to understand molecular mechanisms underlying T2D genetic risk. Using massively parallel reporter assays (MPRA), we test the cis-regulatory effects of SNPs associated with T2D and altered in vivo islet chromatin accessibility in MIN6 β cells under steady state and pathophysiologic endoplasmic reticulum (ER) stress conditions. We identify 1,982/6,621 (29.9%) SNP-containing elements that activate transcription in MIN6 and 879 SNP alleles that modulate MPRA activity. Multiple T2D-associated SNPs alter the activity of short interspersed nuclear element (SINE)-containing elements that are strongly induced by ER stress. We identify 220 functional variants at 104 T2D association signals, narrowing 54 signals to a single candidate SNP. Together, this study identifies elements driving β cell steady state and ER stress-responsive transcriptional activation, nominates causal T2D SNPs, and uncovers potential roles for repetitive elements in β cell transcriptional stress response and T2D genetics

Tet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes.

β cells may participate and contribute to their own demise during Type 1 diabetes (T1D). Here we report a role of their expression of Tet2 in regulating immune killing. Tet2 is induced in murine and human β cells with inflammation but its expression is reduced in surviving β cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate β cells even though immune cells from the mice can transfer diabetes to NOD/scid recipients. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells.Tet2-KO β cells show reduced expression of IFNγ-induced inflammatory genes that are needed to activate diabetogenic T cells. Here we show that Tet2 regulates pathologic interactions between β cells and immune cells and controls damaging inflammatory pathways. Our data suggests that eliminating TET2 in β cells may reduce activating pathologic immune cells and killing of β cells

AMULET: a novel read count-based method for effective multiplet detection from single nucleus ATAC-seq data.

Detecting multiplets in single nucleus (sn)ATAC-seq data is challenging due to data sparsity and limited dynamic range. AMULET (ATAC-seq MULtiplet Estimation Tool) enumerates regions with greater than two uniquely aligned reads across the genome to effectively detect multiplets. We evaluate the method by generating snATAC-seq data in the human blood and pancreatic islet samples. AMULET has high precision, estimated via donor-based multiplexing, and high recall, estimated via simulated multiplets, compared to alternatives and identifies multiplets most effectively when a certain read depth of 25K median valid reads per nucleus is achieved

Variation in histone configurations correlates with gene expression across nine inbred strains of mice.

The diversity outbred (DO) mice and their inbred founders are widely used models of human disease. However, although the genetic diversity of these mice has been well documented, their epigenetic diversity has not. Epigenetic modifications, such as histone modifications and DNA methylation, are important regulators of gene expression, and as such are a critical mechanistic link between genotype and phenotype. Therefore, creating a map of epigenetic modifications in the DO mice and their founders is an important step toward understanding mechanisms of gene regulation and the link to disease in this widely used resource. To this end, we performed a strain survey of epigenetic modifications in hepatocytes of the DO founders. We surveyed four histone modifications (H3K4me1, H3K4me3, H3K27me3, and H3K27ac), and DNA methylation. We used ChromHMM to identify 14 chromatin states, each of which represented a distinct combination of the four histone modifications. We found that the epigenetic landscape was highly variable across the DO founders and was associated with variation in gene expression across strains. We found that epigenetic state imputed into a population of DO mice recapitulated the association with gene expression seen in the founders suggesting that both histone modifications and DNA methylation are highly heritable mechanisms of gene expression regulation. We illustrate how DO gene expression can be aligned with inbred epigenetic states to identify putative cis-regulatory regions. Finally, we provide a data resource that documents strain-specific variation in chromatin state and DNA methylation in hepatocytes across nine widely used strains of laboratory mice

Genetic regulatory signatures underlying islet gene expression and type 2 diabetes

The majority of genetic variants associated with type 2 diabetes (T2D) are located outside of genes in noncoding regions that may regulate gene expression in disease-relevant tissues, like pancreatic islets. Here, we present the largest integrated analysis to date of high-resolution, high-throughput human islet molecular profiling data to characterize the genome (DNA), epigenome (DNA packaging), and transcriptome (gene expression). We find that T2D genetic variants are enriched in regions of the genome where transcription Regulatory Factor X (RFX) is predicted to bind in an islet-specific manner. Genetic variants that increase T2D risk are predicted to disrupt RFX binding, providing a molecular mechanism to explain how the genome can influence the epigenome, modulating gene expression and ultimately T2D risk

Multiomic Profiling Identifies cis-Regulatory Networks Underlying Human Pancreatic β Cell Identity and Function.

EndoC-βH1 is emerging as a critical human β cell model to study the genetic and environmental etiologies of β cell (dys)function and diabetes. Comprehensive knowledge of its molecular landscape is lacking, yet required, for effective use of this model. Here, we report chromosomal (spectral karyotyping), genetic (genotyping), epigenomic (ChIP-seq and ATAC-seq), chromatin interaction (Hi-C and Pol2 ChIA-PET), and transcriptomic (RNA-seq and miRNA-seq) maps of EndoC-βH1. Analyses of these maps define known (e.g., PDX1 and ISL1) and putative (e.g., PCSK1 and mir-375) β cell-specific transcriptional cis-regulatory networks and identify allelic effects on cis-regulatory element use. Importantly, comparison with maps generated in primary human islets and/or β cells indicates preservation of chromatin looping but also highlights chromosomal aberrations and fetal genomic signatures in EndoC-βH1. Together, these maps, and a web application we created for their exploration, provide important tools for the design of experiments to probe and manipulate the genetic programs governing β cell identity and (dys)function in diabetes

Kosten und Korrelate des Speicherns im visuellen Arbeitsgedächtnis

Visual working memory (VWM) refers to temporary storage of only a few items and it is intensely discussed how objects are represented. A less elaborated topic is how much effort is necessary to encode and maintain objects dependent on the type of task-relevant feature. In the first part of this dissertation project pupil sizes and event-related potentials (ERPs) were used to estimate storage effort during maintenance of visual information in change detection tasks (CDT) where set size and complexity of task-relevant features was manipulated. Either an easy feature (color) or a more complex feature (shape) of presented objects was task-relevant. We showed that pupil sizes indicate the number of stored objects and therefore can be interpreted to reflect attentional demands that are necessary to focus on presented stimuli. It could be further demonstrated that pupillary changes were independent of luminance effects of the presented stimuli. Slow potentials during retention were modulated by the type of task-relevant feature and were interpreted to reflect processing effort. The second part of this work targets the question of how objects are represented in VWM by conducting a CDT where also task-irrelevant information was manipulated. According to object-based models items are always represented as integrated objects and the number of objects limits capacity in VWM. Feature-based models assume that the number and quality of features are the capacity limiting factors. Behavioral results revealed that changes of irrelevant information affect performance when color but not when shape was task-irrelevant. Nevertheless, in ERPs an irrelevant mismatch effect was found in both conditions and this effect was apparent until the respective individual capacity maximum for color and shape was achieved. We can conclude that features of presented objects in the current task were always represented independent of their task-relevance. These results were interpreted in terms of the VWM model provided by Brady et al. (2011) suggesting that objects are represented in hierarchical feature bundles which integrates object-based and feature-based VWM models.Das visuelle Arbeitsgedächtnis (VAG) beschreibt die vorübergehende Speicherung weniger Objekte und es besteht eine umfangreiche Debatte darüber, wie Objekte im VAG repräsentiert sind. Weniger ausführlich diskutiert wird die Frage wie viel Aufwand (Effort) benötigt wird, Objekte in Abhängigkeit des aufgabenrelevanten Merkmals zu enkodieren und aufrechtzuerhalten. Im ersten Teil dieses Dissertationsprojektes wurde der Effort während des Aufrechterhaltens visueller Information in einer Change Detection Aufgabe mithilfe von Pupillenweiten und Ereigniskorrelierten Potentiale (EKPs) untersucht. Dabei wurden die Set Größe und die Komplexität der aufgabenrelevanten Merkmale variiert. Entweder Farbe als einfaches Merkmal oder Form als komplexes Merkmal waren aufgabenrelevant. Die Pupillenweite spiegelte die Anzahl der Objekte wider und kann somit als Indikator für Aufmerksamkeitsaufwand (Attentional Effort) interpretiert werden, der notwendig ist um auf die präsentierten Objekte zu fokussieren. Es konnte weiter gezeigt werden, dass die Pupillenveränderungen unabhängig von der Luminanz der präsentierten Objekte sind. Langsame Potentiale während der Retentionsphase spiegelten die Art des aufgabenrelevanten Merkmals wider und wurden als Verarbeitungsaufwand (Processing Effort) interpretiert. Der zweite Teil dieser Arbeit beschäftigt sich mit der Frage wie Objekte im visuellen Arbeitsgedächtnis repräsentiert sind, indem aufgabenirrelevante Information in einer Change Detection Aufgabe manipuliert wurde. Im Hinblick auf objektbasierte Modelle des VAG, sind Items immer als integrierte Objekte repräsentiert und die Anzahl dieser Objekte limitiert die Kapazität des VAG. Merkmalsbasierte Modelle sagen vorher, dass die Anzahl und Qualität der Merkmale die Kapazität limitierenden Faktoren sind. Es konnte gezeigt werden, dass Veränderungen irrelevanter Information die Leistung beeinflusst wenn Farbe irrelevant war, nicht jedoch wenn Form das irrelevante Merkmal war. Im Gegensatz dazu wurde in den EKPs ein mismatch Effekt für die irrelevante Information in beiden Bedingungen gefunden, der bis zur individuellen Kapazitätsgrenze für Farben bzw. Formen bestand hatte. Die Ergebnisse wurden dahingehend interpretiert, dass Merkmale der präsentierten Objekte in der gegenwärtigen Aufgabe unabhängig von ihrer Aufgabenrelevanz repräsentiert waren. Dies wurde vor dem Hintergrund des VAG Modells von Brady et al. (2011) diskutiert, in dem vorgeschlagen wird, dass Objekte in „Hierarchical Feature Bundles“ repräsentiert sind, wodurch objektbasierte und merkmalsbasierte VAG Modelle integriert werden

Metacognitive Therapy for Posttraumatic Stress Disorder in Youth : A Feasibility Study

Metacognitive therapy (MCT) is an effective treatment for posttraumatic stress disorders (PTSD) in adults. However, there is no evidence for the feasibility, acceptability, and efficacy of MCT for PTSD in youth so far. This study is the first to utilize MCT for children and adolescents with PTSD. Twenty-one children and adolescents (aged 8–19 years) who were consecutively referred to the outpatient trauma clinic were treated with MCT. In all patients, treatment was well accepted and regularly attended. At post-treatment, MCT was associated with significant and large reductions in posttraumatic stress symptoms. Depending on the outcome measure, 95 or 85% of the patients were classified as recovered after treatment. Eighteen patients were included in the calculation of the overall outcome. Effect sizes on primary PTSD measures were large (Cohen’s d = 3.42 and d = 1.92) and more than comparable to well-established treatments. Only six patients were available at follow-up, but their improvements were found to be stable. Despite the limitations of this uncontrolled study, the results suggest that MCT may be a feasible and promising treatment for traumatized children and adolescents and they justify a controlled trial evaluating the efficacy of MCT versus an already well-established intervention