Cognitive Flexibility: A Default Mode Perspective

The intra/extradimensional set-shifting task (IED) provides a reliable assessment of cognitive flexibility, the shifting of attention to select behaviorally relevant stimuli in a given context. Impairments in this domain were previously reported in patients with altered neurotransmitter systems such as schizophrenia and Parkinson's disease. Consequently, corticostriatal connections were implicated in the mediation of this function. In addition, parts of the default mode network (DMN), namely the medial prefrontal and posterior cingulate/precuneus cortices, are also being progressively described in association with set-shifting paradigms. Nevertheless, a definitive link between cognitive flexibility and DMN connectivity remains to be established. To this end, we related resting state functional magnetic resonance imaging (fMRI)-based functional connectivity of DMN with IED task performance in a healthy population, measured outside the scanner. The results demonstrated that greater posterior cingulate cortex/precuneus (DMN) connectivity with the ventromedial striatopallidum at rest correlated with fewer total adjusted errors on the IED task. This finding points to a relationship between DMN and basal ganglia connectivity for cognitive flexibility, further highlighting this network's potential role in adaptive human cognition.The Evelyn Trust (RUAG/018) supported this research. Additionally, DV received funding from the Yousef Jameel Academic Program; DKM is funded by the NIHR Cambridge Biomedical Centre (RCZB/004), and an NIHR Senior Investigator Award (RCZB/014), and EAS is supported by the Stephen Erskine Fellowship Queens’ College, Cambridge. We would also like to thank Dr. Guy Williams and Victoria Lupson and the rest of the staff in the Wolfson Brain Imaging Centre (WBIC) at Addenbrooke’s Hospital for their assistance in scanning. Finally, we thank all the participants for their contribution to this studyThis is the author accepted manuscript. The final version is available from Mary Ann Liebert via http://dx.doi.org/10.1089/brain.2015.038

Default Mode Dynamics for Global Functional Integration.

UNLABELLED: The default mode network (DMN) has been traditionally assumed to hinder behavioral performance in externally focused, goal-directed paradigms and to provide no active contribution to human cognition. However, recent evidence suggests greater DMN activity in an array of tasks, especially those that involve self-referential and memory-based processing. Although data that robustly demonstrate a comprehensive functional role for DMN remains relatively scarce, the global workspace framework, which implicates the DMN in global information integration for conscious processing, can potentially provide an explanation for the broad range of higher-order paradigms that report DMN involvement. We used graph theoretical measures to assess the contribution of the DMN to global functional connectivity dynamics in 22 healthy volunteers during an fMRI-based n-back working-memory paradigm with parametric increases in difficulty. Our predominant finding is that brain modularity decreases with greater task demands, thus adapting a more global workspace configuration, in direct relation to increases in reaction times to correct responses. Flexible default mode regions dynamically switch community memberships and display significant changes in their nodal participation coefficient and strength, which may reflect the observed whole-brain changes in functional connectivity architecture. These findings have important implications for our understanding of healthy brain function, as they suggest a central role for the DMN in higher cognitive processing. SIGNIFICANCE STATEMENT: The default mode network (DMN) has been shown to increase its activity during the absence of external stimulation, and hence was historically assumed to disengage during goal-directed tasks. Recent evidence, however, implicates the DMN in self-referential and memory-based processing. We provide robust evidence for this network's active contribution to working memory by revealing dynamic reconfiguration in its interactions with other networks and offer an explanation within the global workspace theoretical framework. These promising findings may help redefine our understanding of the exact DMN role in human cognition.This research was supported by the Evelyn Trust (RUAG/018). In addition, DV received funding from the Yousef Jameel Academic Program; DKM is supported by the NIHR Cambridge Biomedical Centre (RCZB/004), and an NIHR Senior Investigator Award (RCZB/014), and EAS is funded by the Stephen Erskine Fellowship Queens’ College Cambridge.This is the author accepted manuscript. The final version is available from Society for Neuroscience via http://dx.doi.org/10.1523/JNEUROSCI.2135-15.201

Spectral Diversity in Default Mode Network Connectivity Reflects Behavioral State.

Default mode network (DMN) functional connectivity is thought to occur primarily in low frequencies (<0.1 Hz), resulting in most studies removing high frequencies during data preprocessing. In contrast, subtractive task analyses include high frequencies, as these are thought to be task relevant. An emerging line of research explores resting fMRI data at higher-frequency bands, examining the possibility that functional connectivity is a multiband phenomenon. Furthermore, recent studies suggest DMN involvement in cognitive processing; however, without a systematic investigation of DMN connectivity during tasks, its functional contribution to cognition cannot be fully understood. We bridged these concurrent lines of research by examining the contribution of high frequencies in the relationship between DMN and dorsal attention network at rest and during task execution. Our findings revealed that the inclusion of high frequencies alters between network connectivity, resulting in reduced anticorrelation and increased positive connectivity between DMN and dorsal attention network. Critically, increased positive connectivity was observed only during tasks, suggesting an important role for high-frequency fluctuations in functional integration. Moreover, within-DMN connectivity during task execution correlated with RT only when high frequencies were included. These results show that DMN does not simply deactivate during task execution and suggest active recruitment while performing cognitively demanding paradigms

Pragmatic factors of deontic reasoning

This thesis is concerned with pragmatic factors of deontic reasoning, namely scale of violation, aggravating and mitigating circumstances and power of source. Nine experiments are reported investigating deontic reasoning and judgement revision. Experiment 1 established scale of violation as a modifying factor of a working rule with an inferential reasoning task, however, the effects were not transferred to a deductive reasoning task in Experiment 2. Scale of violation and circumstances were found to influence the reasoning of motoring violations with a major offence and aggravating circumstances being rated as more serious and receiving greater fines than a minor offence or mitigating circumstances (Experiments 3 &amp; 4). These effects were also observed with a judgement revision task (Experiment 5). Power of source was included as an additional pragmatic factor and was found to influence the reasoning of conditional statements (Experiment 6), inducements (Experiment 7) and ratings of credibility and probability of outcomes (Experiment 8). The final study (Experiment 9) found significant effects for scale of violation / compliance and power of source within a judgement revision task. However, no difference was observed in the reasoning of superordinate and non-superordinate statements. The findings are explained in terms of the conditional probability hypothesis.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Strong environment X genotype interactions determine the fitness costs of antibiotic resistance in vitro and in an insect model of infection (article)

This is the author accepted manuscript. The final version is available from the American Society for Microbiology via the DOI in this record.The dataset associated with this article is located in ORE at: https://doi.org/10.24378/exe.2503The acquisition of antibiotic resistance commonly imposes fitness costs, a reduction in the fitness of bacteria in the absence of drugs. These costs have been primarily quantified using in vitro experiments and a small number of in vivo studies in mice, and it is commonly assumed that these diverse methods are consistent. Here, we used an insect model of infection to compare the fitness costs of antibiotic resistance in vivo relative to in vitro conditions. Experiments explored diverse mechanisms of resistance in a Gram-positive pathogen, Bacillus thuringiensis, and a Gram-negative intestinal symbiont, Enterobacter cloacae. Rifampicin resistance in B. thuringiensis showed fitness costs that were typically elevated in vivo, although these were modulated by genotype-environment interactions. In contrast, resistance to cefotaxime via de-repression of AmpC β-lactamase in E. cloacae resulted in undetectable costs in vivo or in vitro, while spontaneous resistance to nalidixic acid, and carriage of the IncP plasmid RP4, imposed costs that increased in vivo. Overall, fitness costs in vitro were a poor predictor of fitness costs in vivo because of strong genotype environment interactions throughout this study. Insect infections provide a cheap and accessible means of assessing fitness consequences of resistance mutations, data that is important to understand the evolution and spread of resistance. This study emphasizes that the fitness costs imposed by particular mutations or different modes of resistance are extremely variable, and that only a subset of these mutations are likely to be prevalent outside of the laboratory.Medical Research Council (MRC

Methylphenidate-mediated motor control network enhancement in patients with traumatic brain injury.

PRIMARY OBJECTIVE: To investigate functional improvement late (>6 months) after traumatic brain injury (TBI). To this end, we conducted a double-blind, placebo-controlled experimental medicine study to test the hypothesis that a widely used cognitive enhancer would benefit patients with TBI. RESEARCH DESIGN: We focused on motor control function using a sequential finger opposition fMRI paradigm in both patients and age-matched controls. METHODS AND PROCEDURES: Patients' fMRI and DTI scans were obtained after randomised administration of methylphenidate or placebo. Controls were scanned without intervention. To assess differences in motor speed, we compared reaction times from the baseline condition of a sustained attention task. MAIN OUTCOMES AND RESULTS: Patients' reaction times correlated with wide-spread motor-related white matter abnormalities. Administration of methylphenidate resulted in faster reaction times in patients, which were not significantly different from those achieved by controls. This was also reflected in the fMRI findings in that patients on methylphenidate activated the left inferior frontal gyrus significantly more than when on placebo. Furthermore, stronger functional connections between pre-/post-central cortices and cerebellum were noted for patients on methylphenidate. CONCLUSIONS: Our findings suggest that residual functionality in patients with TBI may be enhanced by a single dose of methylphenidate.The study was funded by the Evelyn Trust- grant number 06/20. C.D. was funded by the Clinical Academic Research Awards organized by the East of England Multi Professional Deanery. B.J.S. consults for Cambridge Cognition, Otsuka, Servier and Lundbeck. She holds a grant from Janssen/J&J and has share options in Cambridge Cognition. D.K.M. is supported by the Neuroscience Theme of the NIHR Cambridge Biomedical Research Centre and NIHR Senior Investigator awards, and by Framework Program 7 funding from the European Commission (TBIcare). He has received lecture and consultancy fees and support for research from Glaxo SmithKline, Solvay and Linde. E.A.S. is funded by the Stephen Erskine Fellowship, Queens' College, Cambridge, UK

Description and evaluation of GLOMAP-mode: a modal global aerosol microphysics model for the UKCA composition-climate model

A new version of the Global Model of Aerosol Processes (GLOMAP) is described, which uses a two-moment pseudo-modal aerosol dynamics approach rather than the original two-moment bin scheme. GLOMAP-mode simulates the multi-component global aerosol, resolving sulfate, sea-salt, dust, black carbon (BC) and particulate organic matter (POM), the latter including primary and biogenic secondary POM. Aerosol processes are simulated in a size-resolved manner including primary emissions, secondary particle formation by binary homogeneous nucleation of sulfuric acid and water, particle growth by coagulation, condensation and cloud-processing and removal by dry deposition, in-cloud and below-cloud scavenging. A series of benchmark observational datasets are assembled against which the skill of the model is assessed in terms of normalised mean bias (&lt;i&gt;b&lt;/i&gt;) and correlation coefficient (&lt;i&gt;R&lt;/i&gt;). Overall, the model performs well against the datasets in simulating concentrations of aerosol precursor gases, chemically speciated particle mass, condensation nuclei (CN) and cloud condensation nuclei (CCN). Surface sulfate, sea-salt and dust mass concentrations are all captured well, while BC and POM are biased low (but correlate well). Surface CN concentrations compare reasonably well in free troposphere and marine sites, but are underestimated at continental and coastal sites related to underestimation of either primary particle emissions or new particle formation. The model compares well against a compilation of CCN observations covering a range of environments and against vertical profiles of size-resolved particle concentrations over Europe. The simulated global burden, lifetime and wet removal of each of the simulated aerosol components is also examined and each lies close to multi-model medians from the AEROCOM model intercomparison exercise

Physicochemical analysis of rotavirus segment 11 supports a 'modified panhandle' structure and not the predicted alternative tRNA-like structure (TRLS)

.Rotaviruses are a major cause of acute gastroenteritis, which is often fatal in infants. The viral genome consists of 11 double-stranded RNA segments, but little is known about their cis-acting sequences and structural elements. Covariation studies and phylogenetic analysis exploring the potential structure of RNA11 of rotaviruses suggested that, besides the previously predicted "modified panhandle" structure, the 5' and 3' termini of one of the isoforms of the bovine rotavirus UKtc strain may interact to form a tRNA-like structure (TRLS). Such TRLSs have been identified in RNAs of plant viruses, where they are important for enhancing replication and packaging. However, using tRNA mimicry assays (in vitro aminoacylation and 3'- adenylation), we found no biochemical evidence for tRNA-like functions of RNA11. Capping, synthetic 3' adenylation and manipulation of divalent cation concentrations did not change this finding. NMR studies on a 5'- and 3'-deletion construct of RNA11 containing the putative intra-strand complementary sequences supported a predominant panhandle structure and did not conform to a cloverleaf fold despite the strong evidence for a predicted structure in this conserved region of the viral RNA. Additional viral or cellular factors may be needed to stabilise it into a form with tRNA-like properties