Social Functioning in Children with Brain Insult

Social dysfunction is commonly reported by survivors of brain insult, and is often rated as the most debilitating of all sequelae, impacting on many areas of daily life, as well as overall quality of life. Within the early brain insult (EBI) literature, physical and cognitive domains have been of primary interest and social skills have received scant attention. As a result it remains unclear how common these problems are, and whether factors predictive of recovery (insult severity, lesion location, age at insult, environment) in other functional domains (motor, speech, cognition) also contribute to social outcome. This study compared social outcomes for children sustaining EBI at different times from gestation to late childhood to determine whether EBI was associated with an increased risk of problems. Children with focal brain insults were categorized according to timing of brain insult: (i) Congenital (n = 38): EBI: first–second trimester; (ii) Perinatal (n = 33); EBI: third trimester to 1-month post-natal; (iii) Infancy (n = 23): EBI: 2 months–2 years post-birth; (iv) Preschool (n = 19): EBI: 3–6 years; (v) Middle Childhood (n = 31): EBI: 7–9 years; and (vi) Late Childhood (n = 19): EBI: after age 10. Children's teachers completed questionnaires measuring social function (Strengths and Difficulties Questionnaire, Walker–McConnell Scale of Social Competence and School Adjustment). Results showed that children with EBI were at increased risk for social impairment compared to normative expectations. EBI before age 2 years was associated with most significant social impairment, while children with EBI in the preschool years and in late childhood recorded scores closer to normal. Lesion location and laterality were not predictive of social outcome, and nor was social risk. In contrast, presence of disability (seizures) and family function were shown to contribute to aspects of social function

A Neuropsychological Profile for Agenesis of the Corpus Callosum?: Cognitive, Academic, Executive, Social, and Behavioral Functioning in School-Age Children

Objectives: Agenesis of the corpus callosum (AgCC), characterized by developmental absence of the corpus callosum, is one of the most common congenital brain malformations. To date, there are limited data on the neuropsychological consequences of AgCC and factors that modulate different outcomes, especially in children. This study aimed to describe general intellectual, academic, executive, social and behavioral functioning in a cohort of school-aged children presenting for clinical services to a hospital and diagnosed with AgCC. The influences of age, social risk and neurological factors were examined. Methods: Twenty-eight school-aged children (8 to 17 years) diagnosed with AgCC completed tests of general intelligence (IQ) and academic functioning. Executive, social and behavioral functioning in daily life, and social risk, were estimated from parent and teacher rated questionnaires. MRI findings reviewed by a pediatric neurologist confirmed diagnosis and identified brain characteristics. Clinical details including the presence of epilepsy and diagnosed genetic condition were obtained from medical records. Results: In our cohort, ~50% of children experienced general intellectual, academic, executive, social and/or behavioral difficulties and ~20% were functioning at a level comparable to typically developing children. Social risk was important for understanding variability in neuropsychological outcomes. Brain anomalies and complete AgCC were associated with lower mathematics performance and poorer executive functioning. Conclusions: This is the first comprehensive report of general intellectual, academic, executive social and behavioral consequences of AgCC in school-aged children. The findings have important clinical implications, suggesting that support to families and targeted intervention could promote positive neuropsychological functioning in children with AgCC who come to clinical attention

Impact of hypercapnia on alveolar Na+-transport : Establishing a system for ENaC-protein detection

Acute respiratory distress syndrome is a life threatening condition triggered by a variety of pulmonary and extrapulmonary causes, that is characterized by pulmonary edema and subsequently impaired gas exchange. Due to lung protective ventilation strategies, its treatment is often associated with systemic accumulation of CO2, a condition termed permissive hypercapnia. Recent studies report a negative effect of CO2 on alveolar fluid clearance, a process mediated by its two key elements the Na+,K+-ATPase and epithelial Na+-channels (ENaCs). A reduced activity of the Na+,K+-ATPase during hypercapnia has already been demonstrated, but regulation of ENaC has never been directly linked to CO2. Many molecular signaling events that are activated during hypercapnia are known to regulate ENaC function, so the present study aimed to generate and subsequently apply techniques to investigate a possible contribution of ENaC to the reduction of alveolar epithelial fluid transport upon hypercapnia. ENaC function was studied in H441 cells by Ussing chamber experiments which revealed no significant regulation during short term hypercapnia, but a clear reduction of ENaC function during sustained hypercapnia. To identify the signaling mechanism on the molecular level, epitope-tagged human ENaC constructs for the α-, β- and γ-subunit were cloned and initially expressed in A549 cells. Exposition to hypercapnia up to 4 hours did not significantly reduce cell surface expression of the ENaC-subunits, but after 24 hours, a significant decrease of β-ENaC was observed. Since the molecular sizes of α- and γ-ENaC expressed in A549 cells were differing from previously published studies, transfection of ENaC was continued in other cells. H441 cells are commonly used for ENaC studies, so their transfection was established, yielding an efficiency of about 60 %. The molecular sizes of transfected ENaC subunits matched the pattern that was expected, but expression levels were evanescent and too low for further experiments. Since ENaC detection in these two cell lines remained problematic, a novel methodology was applied. Since the primary site of ENaC expression in the lung are epithelial cells, rat primary alveolar epithelial cells type II were used as recipients for ENaC plasmids. Non-viral transfection of ATII cells has been inefficient in the past, but during the present study a protocol was generated to efficiently deliver nucleic acids to exactly this cell type. ENaC expression was largely increased in ATII cells, compared to the cell lines used, indicating that established system might be extremely useful for further studies involving ENaC turnover. Thus, a new and highly relevant, non-viral transfection technique for primary alveolar epithelial type II cells was established, providing ground-breaking opportunities for future pulmonary research.Das Atemnotsyndrom des Erwachsenen ist eine lebensbedrohliche Erkrankung, ausgelöst durch eine Reihe von Faktoren, die direkt oder indirekt auf die Lunge einwirken . Charakteristisch für dieses Syndrom sind pulmonare Ödeme und daraus resultierend ein eingeschränkter Gasaustausch. Die daher benötigte künstliche Beatmung führt im Zuge von protektiven Beatmungsstrategien oft zu einer systemischen Anreicherung von CO2 (Hyperkapnie). Einige Studien zeigen, dass erhöhte CO2-Level den Flüssigkeitstransport der Lunge einschränken. Dieser aktive Prozess wird maßgeblich durch zwei Komponenten, die Na+,K+-ATPase und epitheliale Na+-Kanäle (ENaCs), kontrolliert. Eine Beeinträchtigung der Na+,K+-ATPase durch CO2 gezeigt, für ENaCs ist dies bislang nicht bekannt. Einige bekannte Regulatoren von ENaCs werden jedoch während Hyperkapnie aktiviert. Das Ziel der vorliegenden Arbeit war, Methoden zu etablieren und anzuwenden, die einen möglichen Einfluss von CO2 auf ENaC zeigen. Funktionelle Versuche wurden an H441-Zellen mit Ussing-Kammer-Messungen durchgeführt. Während akuter Hyperkapnie konnte keine signifikante Regulation von ENaC nachgewiesen werden, jedoch war die ENaC-Funktion bei anhaltender Hyperkapnie deutlich verringert. Um die Signalwege auf molekularer Ebene zu untersuchen, wurde die α-, β- und γ- Untereinheit des humanen ENaC kloniert, genetisch modifiziert und in A549 Zellen überexprimiert. Nach bis zu vierstündiger Hyperkapnie erfolgte keine Regulation von ENaC, jedoch wurde nach 24 Stunden eine deutlich verminderte Menge β-ENaC in der Zellmembran nachgewiesen. Da die Größen von α- und γ-ENaC von den bisher publizierten abwichen, wurden weitere Versuche in H441 Zellen durchgeführt. Die Transfektion dieser Zelllinie wurde etabliert und erreichte eine Effizienz von ungefähr 60 %. Die posttranslationale Regulation der α- und γ-Untereinheiten, insbesondere die proteolytische Aktivierung funktionierten wie in der Literatur beschrieben, jedoch waren die Expressionslevel zu gering für weitere Versuche. In der Lunge werden ENaCs überwiegend in epithelialen Zellen exprimiert. Diese Zellen konnten bisher jedoch nicht effizient transfiziert werden, ohne Viren einzusetzen. In der vorliegenden Arbeit wurde jedoch eine effiziente Methode zur Transfektion von primären epithelialen Zellen der Ratte erarbeitet. Die Expression von transfizierten ENaC-Untereinheiten war in diesen Zellen deutlich erhöht, weswegen die Etablierung dieses Systems ausschlaggebend für weitere Versuche ist. Die vorliegende Arbeit beschreibt daher zum ersten Mal die nicht-virale, effiziente Transfektion von primären alveolaren Zellen und liefert damit ein bedeutendes neues Werkzeug für die Lungenforschung

Large-scale functional network dynamics in human callosal agenesis:Increased subcortical involvement and preserved laterality

In the human brain, the corpus callosum is the major white-matter commissural tract enabling the transmission of sensory-motor, and higher level cognitive information between homotopic regions of the two cerebral hemispheres. Despite developmental absence (i.e., agenesis) of the corpus callosum (AgCC), functional connectivity is preserved, including interhemispheric connectivity. Subcortical structures have been hypothesised to provide alternative pathways to enable this preservation. To test this hypothesis, we used functional Magnetic Resonance Imaging (fMRI) recordings in children with AgCC and typically developing children, and a time-resolved approach to retrieve temporal characteristics of whole-brain functional networks. We observed an increased engagement of the cerebellum and amygdala/hippocampus networks in children with AgCC compared to typically developing children. There was little evidence that laterality of activation networks was affected in AgCC. Our findings support the hypothesis that subcortical structures play an essential role in the functional reconfiguration of the brain in the absence of a corpus callosum

Revisiting brain rewiring and plasticity in children born without corpus callosum

The corpus callosum is the largest white matter pathway connecting homologous structures of the two cerebral hemispheres. Remarkably, children and adults with developmental absence of the corpus callosum (callosal dysgenesis, CD) show typical interhemispheric integration, which is classically impaired in adult split-brain patients, for whom the corpus callosum is surgically severed. Tovar-Moll and colleagues (2014) proposed alternative neural pathways involved in the preservation of interhemispheric transfer. In a sample of six adults with CD, they revealed two homotopic bundles crossing the midline via the anterior and posterior commissures and connecting parietal cortices, and the microstructural properties of these aberrant bundles were associated with functional connectivity of these regions. The aberrant bundles were specific to CD and not visualised in healthy brains. We extended this study in a developmental cohort of 20 children with CD and 29 typically developing controls (TDC). The two anomalous white-matter bundles were visualised using tractography. Associations between structural properties of these bundles and their regional functional connectivity were explored. The proposed atypical bundles were observed in 30% of our CD cohort crossing via the anterior commissure, and in 30% crossing via the posterior commissure (also observed in 6.9% of TDC). However, the structural property measures of these bundles were not associated with parietal functional connectivity, bringing into question their role and implication for interhemispheric functional connectivity in CD. It is possible that very early disruption of embryological callosal development enhances neuroplasticity and facilitates the formation of these proposed alternative neural pathways, but further evidence is needed

DU Undergraduate Showcase: Research, Scholarship, and Creative Works: Abstracts

Abstracts from the DU Undergraduate Showcase

Working memory training and brain structure and function in extremely preterm or extremely low birth weight children.

This study in children born extremely preterm (EP; <28 weeks' gestational age) or extremely low birth weight (ELBW; <1,000 g) investigated whether adaptive working memory training using Cogmed® is associated with structural and/or functional brain changes compared with a placebo program. Ninety-one EP/ELBW children were recruited at a mean (standard deviation) age of 7.8 (0.4) years. Children were randomly allocated to Cogmed or placebo (45-min sessions, 5 days a week over 5-7 weeks). A subset had usable magnetic resonance imaging (MRI) data pretraining and 2 weeks posttraining (structural, n = 48; diffusion, n = 43; task-based functional, n = 18). Statistical analyses examined whether cortical morphometry, white matter microstructure and blood oxygenation level-dependent (BOLD) signal during an n-back working memory task changed from pretraining to posttraining in the Cogmed and placebo groups separately. Interaction analyses between time point and group were then performed. There was a significant increase in neurite density in several white matter regions from pretraining to posttraining in both the Cogmed and placebo groups. BOLD signal in the posterior cingulate and precuneus cortices during the n-back task increased from pretraining to posttraining in the Cogmed but not placebo group. Evidence for group-by-time interactions for the MRI measures was weak, suggesting that brain changes generally did not differ between Cogmed and placebo groups. Overall, while some structural and functional MRI changes between the pretraining and posttraining period in EP/ELBW children were observed, there was little evidence of training-induced neuroplasticity, with changes generally identified in both groups. Trial registration Australian New Zealand Clinical Trials Registry, anzctr.org.au; ACTRN12612000124831

The Complete Spectrum of Yeast Chromosome Instability Genes Identifies Candidate CIN Cancer Genes and Functional Roles for ASTRA Complex Components

Chromosome instability (CIN) is observed in most solid tumors and is linked to somatic mutations in genome integrity maintenance genes. The spectrum of mutations that cause CIN is only partly known and it is not possible to predict a priori all pathways whose disruption might lead to CIN. To address this issue, we generated a catalogue of CIN genes and pathways by screening ∼2,000 reduction-of-function alleles for 90% of essential genes in Saccharomyces cerevisiae. Integrating this with published CIN phenotypes for other yeast genes generated a systematic CIN gene dataset comprised of 692 genes. Enriched gene ontology terms defined cellular CIN pathways that, together with sequence orthologs, created a list of human CIN candidate genes, which we cross-referenced to published somatic mutation databases revealing hundreds of mutated CIN candidate genes. Characterization of some poorly characterized CIN genes revealed short telomeres in mutants of the ASTRA/TTT components TTI1 and ASA1. High-throughput phenotypic profiling links ASA1 to TTT (Tel2-Tti1-Tti2) complex function and to TORC1 signaling via Tor1p stability, consistent with the role of TTT in PI3-kinase related kinase biogenesis. The comprehensive CIN gene list presented here in principle comprises all conserved eukaryotic genome integrity pathways. Deriving human CIN candidate genes from the list allows direct cross-referencing with tumor mutational data and thus candidate mutations potentially driving CIN in tumors. Overall, the CIN gene spectrum reveals new chromosome biology and will help us to understand CIN phenotypes in human disease

Was ist "Populäre Musik"? : Überlegungen in eigener Sache

Many common disorders across the lifespan feature impaired working memory (WM). Reported benefits of a WM training program include improving inattention in daily life, but this has not been evaluated in a meta-analysis. This study aimed to evaluate whether one WM training method has benefits for inattention in daily life by conducting a systematic review and meta-analysis.We searched Medline and PsycINFO, relevant journals and contacted authors for studies with an intervention and control group reporting post-training estimates of inattention in daily life. To reduce the influence of different WM training methods on the findings, the review was restricted to trials evaluating the Cogmed method. A meta-analysis calculated the pooled standardised difference in means (SMD) between intervention and control groups.A total of 622 studies were identified and 12 studies with 13 group comparisons met inclusion criteria. The meta-analysis showed a significant training effect on inattention in daily life, SMD=-0.47, 95% CI -0.65, -0.29, p<.00001. Subgroup analyses showed this significant effect was observed in groups of children and adults as well as users with and without ADHD, and in studies using control groups that were active and non-adaptive, wait-list and passive as well as studies using specific or general measures. Seven of the studies reported follow-up assessment and a meta-analysis showed persisting training benefits for inattention in daily life, SMD=-0.33, 95% CI -0.57 -0.09, p=.006. Additional meta-analyses confirmed improvements after training on visuospatial WM, SMD=0.66, 95% CI 0.43, 0.89, p<.00001, and verbal WM tasks, SMD=0.40, 95% CI 0.18, 0.62, p=.0004.Benefits of a WM training program generalise to improvements in everyday functioning. Initial evidence shows that the Cogmed method has significant benefits for inattention in daily life with a clinically relevant effect size