Pediatric ADHD symptom burden relates to distinct neural activity across executive function domains

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent childhood disorder marked by inattention and/or hyperactivity symptoms. ADHD may also relate to impaired executive function (EF), but is often studied in a single EF task per sample. The current study addresses the question of unique vs. overlapping relations in brain activity across multiple EF tasks and ADHD symptom burden. Three in-scanner tasks drawn from distinct EF domains (cognitive flexibility, working memory, and inhibition) were collected from children with and without an ADHD diagnosis (N = 63). Whole-brain activity and 11 regions of interest were correlated with parent reports of inattention and hyperactivity symptoms. Across the three EF domains, brain activity related to ADHD symptom burden, but the direction and location of these associations differed across tasks. Overall, activity in sensory and default mode network regions related to ADHD, and these relations did not consistently overlap across EF domains. We observed both distinct and overlapping patterns for inattention and hyperactivity symptoms. By studying multiple EF tasks in the same sample, we identified a heterogenous neural profile related to attention symptom burden in children. Our results inform ADHD characterization and treatment and explain some of the variable brain results related to EF and ADHD reported in the literature

Resting-state cortical hubs in youth organize into four categories

During childhood, neural systems supporting high-level cognitive processes undergo periods of rapid growth and refinement, which rely on the successful coordination of activation across the brain. Some coordination occurs via cortical hubs-brain regions that coactivate with functional networks other than their own. Adult cortical hubs map into three distinct profiles, but less is known about hub categories during development, when critical improvement in cognition occurs. We identify four distinct hub categories in a large youth sample (n = 567, ages 8.5-17.2), each exhibiting more diverse connectivity profiles than adults. Youth hubs integrating control-sensory processing split into two distinct categories (visual control and auditory/motor control), whereas adult hubs unite under one. This split suggests a need for segregating sensory stimuli while functional networks are experiencing rapid development. Functional coactivation strength for youth control-processing hubs are associated with task performance, suggesting a specialized role in routing sensory information to and from the brain\u27s control system

Cognitive control and developmental difficulties

Carrying out daily goals, such as getting ready for school, require a complex orchestration of attention, self-regulation, and task-specific actions facilitated by higher-order cognitive processes we term cognitive control. Cognitive control matures throughout childhood and adolescence, and impaired cognitive control is thought to be a transdiagnostic feature of groups with developmental difficulties, such as learning difficulties or attention-deficit/hyperactivity disorder (ADHD). The work in this dissertation builds towards understanding the neurobiological underpinnings of variability in cognitive control in children with developmental difficulties. The first study tests for overlapping relationships between ADHD symptom burden and brain activity across three control demanding tasks. We found brain activity in motor and default mode network regions related to ADHD symptom burden, but these relations did not overlap across tasks. We also observed distinct patterns for inattention and hyperactivity symptoms, suggesting diverse impacts of ADHD burden on executive functions. For studies two and three we focus on groups of students with diverse learning difficulties. Study Two examined whether before reading intervention, there were distinct neurobiological profiles of struggling readers in 4th grade who would go on to gain in their reading skills post-remediation compared to those who do not. We found that before intervention, brain activity in reading, cognitive control and default mode network regions predicted who would see gains in their reading skill after intervention. While pre-intervention brain activity separated responders from non-responders, there were no behavioral or demographic variables that separated the groups. The third study focused on another group with learning challenges, Hispanic middle schoolers with limited English proficiency. Here we tested whether individual differences in functional connectivity of brain systems underlying reading, math and cognitive control were related to academic skills. Using a novel method of localizing functional brain regions at the individual level, we found that measures of functional connectivity of these three systems were related to multiple measures of reading skills in this group with unique learning circumstances. Together, these three studies interrogate the complex role of cognitive control in development and characterize brain and behavioral heterogeneity in groups with developmental difficulties.Psycholog

Stereocontrolled second generation synthesis of the ABC and FG ring systems of brevetoxin B. New methodology for the construction of oxepanes and bis-oxepanes. Approaches to the total synthesis of brevetoxin B

Second generation syntheses of the ABC and FG ring systems of brevetoxin B (1) were carried out in a stereocontrolled manner. The two key intermediates, 2 and 3, representing the ABC and FG ring frameworks, were prepared from 2-deoxy-D-ribose via short and efficient sequences. The synthesis of 2 proceeds in 3.6% overall yield and the synthesis of 3 proceeds in 11.5% overall yield. Both syntheses represent improvements over the previous procedures.(DIAGRAM, TABLE OR GRAPHIC OMITTED...PLEASE SEE DAI) Two new approaches for constructing oxepanes are described. The first is based on a photolytic bridging reaction of dithionoesters that gives the corresponding oxepene system. Regioselective hydrolysis provides the highly functionalized oxepane in good yield. The second approach is based on an intramolecular hydroxy ketone condensation reaction. This is a general reaction for both cyclic and acyclic systems and proceeds under mild reaction conditions with high yield. By combining these two new reactions in tandem, several complex bis-oxepane systems were prepared. Application of this new methodology to the total synthesis of brevetoxin B (1), provided some unexpected results. Several approaches are presented and a novel rearrangement of the pyran framework was uncovered

Brain engagement during a cognitive flexibility task relates to academic performance in English learners

English Learners (ELs), students from non-English speaking backgrounds, are a fast-growing, understudied, group of students in the U.S. with unique learning challenges. Cognitive flexibility - the ability to switch between task demands with ease - may be an important factor in learning for ELs as they have to manage learning in their non-dominant language and access knowledge in multiple languages. We used functional MRI to measure cognitive flexibility brain activity in a group of Hispanic middle school ELs (N = 63) and related it to their academic skills. We found that brain engagement during the cognitive flexibility task was related to both out-of-scanner reading and math measures. These relationships were observed across the brain including in cognitive control, attention, and default mode networks. This work suggests the real-world importance of cognitive flexibility for adolescent ELs, where individual differences in brain engagement were associated with educational outcomes

Total Synthesis of Brevetoxin-B .1. First Generation Strategies and New Approaches to Oxepane Systems

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