A circuit mechanism for irrationalities in decision-making and NMDA receptor hypofunction: behaviour, computational modelling, and pharmacology

Decision-making biases can be systematic features of normal behaviour, or deficits underlying neuropsychiatric symptoms. We used behavioural psychophysics, spiking-circuit modelling and pharmacological manipulations to explore decision-making biases in health and disease. Monkeys performed an evidence integration task in which they showed a pro-variance bias (PVB): a preference to choose options with more variable evidence. The PVB was also present in a spiking circuit model, revealing a neural mechanism for this behaviour. Because NMDA receptor (NMDA-R) hypofunction is a leading hypothesis for neuropathology in schizophrenia, we simulated behavioural effects of NMDA-R hypofunction onto either excitatory or inhibitory neurons in the model. These were tested experimentally using the NMDA-R antagonist ketamine, yielding changes in decision-making consistent with lowered cortical excitation/inhibition balance from NMDA-R hypofunction onto excitatory neurons. These results provide a circuit-level mechanism that bridges across explanatory scales, from the synaptic to the behavioural, in neuropsychiatric disorders where decision-making biases are prominent. Significance People can make apparently irrational decisions because of underlying features in their decision circuitry. Deficits in the same neural circuits may also underlie debilitating cognitive symptoms of neuropsychiatric patients. Here, we reveal a neural circuit mechanism explaining an irrationality frequently observed in healthy humans making binary choices – the pro-variance bias. Our circuit model could be perturbed by introducing deficits in either excitatory or inhibitory neuron function. These two perturbations made specific, dissociable predictions for the types of irrational decisionmaking behaviour produced. We used the NMDA-R antagonist ketamine, an experimental model for schizophrenia, to test if these predictions were relevant to neuropsychiatric pathophysiology. The results were consistent with impaired excitatory neuron function, providing important new insights into the pathophysiology of schizophrenia

A circuit mechanism for decision-making biases and NMDA receptor hypofunction

Decision-making biases can be features of normal behaviour, or deficits underlying neuropsychiatric symptoms. We used behavioural psychophysics, spiking-circuit modelling and pharmacological manipulations to explore decision-making biases during evidence integration. Monkeys showed a pro-variance bias (PVB): a preference to choose options with more variable evidence. The PVB was also present in a spiking circuit model, revealing a potential neural mechanism for this behaviour. To model possible effects of NMDA receptor (NMDA-R) antagonism on this behaviour, we simulated the effects of NMDA-R hypofunction onto either excitatory or inhibitory neurons in the model. These were then tested experimentally using the NMDA-R antagonist ketamine, a pharmacological model of schizophrenia. Ketamine yielded an increase in subjects' PVB, consistent with lowered cortical excitation/inhibition balance from NMDA-R hypofunction predominantly onto excitatory neurons. These results provide a circuit-level mechanism that bridges across explanatory scales, from the synaptic to the behavioural, in neuropsychiatric disorders where decision-making biases are prominent

Policy mapping for establishing a national emergency health policy for Nigeria

BACKGROUND: The number of potential life years lost due to accidents and injuries though poorly studied has resulted in tremendous economic and social loss to Nigeria. Numerous socio-cultural, economic and political factors including the current epidemic of ethnic and religious conflicts act in concert in predisposing to and enabling the ongoing catastrophe of accident and injuries in Nigeria. METHODS: Using the "policymaker", Microsoft-Windows(®) based software, the information generated on accidents and injuries and emergency health care in Nigeria from literature review, content analysis of relevant documents, expert interviewing and consensus opinion, a model National Emergency Health Policy was designed and analyzed. A major point of analysis for the policy is the current political feasibility of the policy including its opportunities and obstacles in the country. RESULTS: A model National Emergency Health Policy with policy goals, objectives, programs and evaluation benchmarks was generated. Critical analyses of potential policy problems, associated multiple players, diverging interests and implementation guidelines were developed. CONCLUSIONS: "Political health modeling" a term proposed here would be invaluable to policy makers and scholars in developing countries in assessing the political feasibility of policy managing. Political modeling applied to the development of a NEHP in Nigeria would empower policy makers and the policy making process and would ensure a sustainable emergency health policy in Nigeria

Development and initial validation of the bronchiectasis exacerbation and symptom tool (BEST)

BACKGROUND: Recurrent bronchiectasis exacerbations are related to deterioration of lung function, progression of the disease, impairment of quality of life, and to an increased mortality. Improved detection of exacerbations has been accomplished in chronic obstructive pulmonary disease through the use of patient completed diaries. These tools may enhance exacerbation reporting and identification. The aim of this study was to develop a novel symptom diary for bronchiectasis symptom burden and detection of exacerbations, named the BEST diary. METHODS: Prospective observational study of patients with bronchiectasis conducted at Ninewells Hospital, Dundee. We included patients with confirmed bronchiectasis by computed tomography, who were symptomatic and had at least 1 documented exacerbation of bronchiectasis in the previous 12\u2009months to participate. Symptoms were recorded daily in a diary incorporating cough, sputum volume, sputum colour, dyspnoea, fatigue and systemic disturbance scored from 0 to 26. RESULTS: Twenty-one patients were included in the study. We identified 29 reported (treated exacerbations) and 23 unreported (untreated) exacerbations over 6-month follow-up. The BEST diary score showed a good correlation with the established and validated questionnaires and measures of health status (COPD Assessment Test, r =\u20090.61, p =\u20090.0037, Leicester Cough Questionnaire, r =\u2009-\u20090.52,p =\u20090.0015, St Georges Respiratory Questionnaire, r =\u20090.61,p <\u20090.0001 and 6\u2009min walk test, r =\u2009-\u20090.46,p =\u20090.037). The mean BEST score at baseline was 7.1 points (SD 2.2). The peak symptom score during exacerbation was a mean of 16.4 (3.1), and the change from baseline to exacerbation was a mean of 9.1 points (SD 2.5). Mean duration of exacerbations based on time for a return to baseline symptoms was 15.3\u2009days (SD 5.7). A minimum clinically important difference of 4 points is proposed. CONCLUSIONS: The BEST symptom diary has shown concurrent validity with current health questionnaires and is responsive at onset and recovery from exacerbation. The BEST diary may be useful to detect and characterise exacerbations in bronchiectasis clinical trials

Lack of Support for the Genes by Early Environment Interaction Hypothesis in the Pathogenesis of Schizophrenia

Ursini et al reported recently that the liability of schizophrenia explained by a polygenic risk score (PRS) derived from the variants most associated with schizophrenia was increased 5-fold in individuals who experienced complications during pregnancy or birth. Follow-up gene expression analysis showed that the genes mapping to the most associated genetic variants are highly expressed in placental tissues. If confirmed, these findings will have major implications in our understanding of the joint effect of genes and environment in the pathogenesis of schizophrenia. We examined the interplay between PRS and obstetric complications (OCs) in 5 independent samples (effective N = 2110). OCs were assessed with the full or modified Lewis-Murray scale, or with birth weight < 2.5 kg as a proxy. In a large cohort we tested whether the pathways from placenta-relevant variants in the original report were associated with case-control status. Unlike in the original study, we did not find significant effect of PRS on the presence of OCs in cases, nor a substantial difference in the association of PRS with case-control status in samples stratified by the presence of OCs. Furthermore, none of the PRS by OCs interactions were significant, nor were any of the biological pathways, examined in the Swedish cohort. Our study could not support the hypothesis of a mediating effect of placenta biology in the pathway from genes to schizophrenia. Methodology differences, in particular the different scales measuring OCs, as well as power constraints for interaction analyses in both studies, may explain this discrepancy

Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations

The final published article can be found here: http://dx.doi.org/10.1038/ncomms5654This work was supported by KKL632 grant from the Kay Kendall Leukaemia Fund, Jerome Lejeune Foundation project grant 2011B-960, the Wellcome Trust Strategic Award WT 098330/Z/12/Z (The LonDownS Consortium) and the Lee Kong Chian School of Medicine, Nanyang Technological University-Singapore start-up funding grant M4230024 to D.N.; Swiss Cancer League (LSCC 2939-02-2012) and Dinu Lipatti 2014 grants to S.I.N.; SNF 144082, ERC 249968 and Foundation ‘ChildCare’ grants to S.E.A.; and by Cariparo bando ricerca pediatrica and by European commission (FP7 ENCCA, 261474, Trancan PER-2011-2353841) to G.B

Understanding Needs, Identifying Opportunities: ICT in the View of Universal Design

This article provides food for thoughts elaborated by peer researchers who, basing on their studies and on current literature on relationships between Universal Design (UD) and Information and Communication Technologies (ICT), wish to share few key issues related to the challenges offered by the involvement of final users in designing product and services. Referring to approaches from different disciplines, key questions will be highlighted on which a debate could start, focused on the issue of promoting inclusion and how a close relationship among these different areas of knowledge can contribute to bridge the gap between the potential of new technologies and the real and diversified need by persons. Thus, actively contributing toward the empowerment of the community of belonging

Generation of Nitric Oxide in the Opossum Lower Esophageal Sphincter during Physiological Experimentation

Lipopolysaccharide (LPS), given in vivo, modulates opossum esophageal motor functions by inducing the inducible nitric oxide synthase (iNOS), which increases nitric oxide (NO) production. Superoxide, a NO scavenger, is generated during this endotoxemia. Superoxide is cleared by superoxide dismutase (SOD) and catalase (CAT) to protect the physiological function of NO. This study examined whether lower esophageal sphincter (LES) motility, NO release, and iNOS and nitrotyrosine accumulation in the LES are affected by LPS in vitro. Muscle strips from the opossum LES were placed in tissue baths containing oxygenated Krebs buffer. NO release was measured with a chemiluminescence NOx analyzer, and Western blots were performed to analyze iNOS and nitrotyrosine production. The percent change in resting LES tone after a 6-hour exposure to LPS was significantly increased compared to pretreatment values. The percent LES relaxation upon electrical stimulation was significantly decreased in the control group at 6 hours, indicating that the LPS treatment had an effect. The NO concentration in the tissue bath of LPS-treated muscle without nerve stimulation was significantly less than that of LPS treatment combined with SOD/CAT or SOD/CAT alone. iNOS and nitrotyrosine were detectable and increased over time in the LES muscle of both the control and LPS-treated groups. Antioxidant enzymes may play a role in regulating NO-mediated neuromuscular functions in the LES

Subjective cognitive complaints at age 70: associations with amyloid and mental health.

OBJECTIVE: To investigate subjective cognitive decline (SCD) in relation to β-amyloid pathology and to test for associations with anxiety, depression, objective cognition and family history of dementia in the Insight 46 study. METHODS: Cognitively unimpaired ~70-year-old participants, all born in the same week in 1946 (n=460, 49% female, 18% amyloid-positive), underwent assessments including the SCD-Questionnaire (MyCog). MyCog scores were evaluated with respect to 18F-Florbetapir-PET amyloid status (positive/negative). Associations with anxiety, depression, objective cognition (measured by the Preclinical Alzheimer Cognitive Composite, PACC) and family history of dementia were also investigated. The informant's perspective on SCD was evaluated in relation to MyCog score. RESULTS: Anxiety (mean (SD) trait anxiety score: 4.4 (3.9)) was associated with higher MyCog scores, especially in women. MyCog scores were higher in amyloid-positive compared with amyloid-negative individuals (adjusted means (95% CIs): 5.3 (4.4 to 6.1) vs 4.3 (3.9 to 4.7), p=0.044), after accounting for differences in anxiety. PACC (mean (SD) -0.05 (0.68)) and family history of dementia (prevalence: 23.9%) were not independently associated with MyCog scores. The informant's perception of SCD was generally in accordance with that of the participant. CONCLUSIONS: This cross-sectional study demonstrates that symptoms of SCD are associated with both β-amyloid pathology, and more consistently, trait anxiety in a population-based cohort of older adults, at an age when those who are destined to develop dementia are still likely to be some years away from symptoms. This highlights the necessity of considering anxiety symptoms when assessing Alzheimer's disease pathology and SCD