Dimensionality of Cognitions in Behavioral Addiction.

Cognitive constructs provide conceptual frameworks for transpathological characterization and improved phenotyping of apparently disparate psychiatric groups. This dimensional approach can be applied to the examination of individuals with behavioral addictions, for example, towards gambling, video-games, the internet, food, and sex, allowing operationalization of core deficits. We use this approach to review constructs such as impulsivity, compulsivity, and attention regulation, which may be most relevant, applicable, and successful for the understanding and subsequent treatment of the addictions.This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s40473-016-0068-

Disrupted avoidance learning in functional neurological disorder: Implications for harm avoidance theories

BACKGROUND: Functional neurological disorder (FND) is an elusive disorder characterized by unexplained neurological symptoms alongside aberrant cognitive processing and negative affect, often associated with amygdala reactivity. METHODS: We examined the effect of negative conditioning on cognitive function and amygdala reactivity in 25 FND patients and 20 healthy volunteers (HV). Participants were first conditioned to stimuli paired with negative affective or neutral (CS +/CS −) information. During functional MRI, subjects then performed an instrumental associative learning task to avoid monetary losses in the context of the previously conditioned stimuli. We expected that FND patients would be better at learning to avoid losses when faced with negatively conditioned stimuli (increased harm avoidance). Multi-echo resting state fMRI was also collected from the same subjects and a robust denoising method was employed, important for removing motion and physiological artifacts. RESULTS: FND subjects were more sensitive to the negative CS + compared to HV, demonstrated by a reinforcement learning model. Contrary to expectation, FND patients were generally more impaired at learning to avoid losses under both contexts (CS +/CS −), persisting to choose the option that resulted in a negative outcome demonstrated by both behavioural and computational analyses. FND patients showed enhanced amygdala but reduced dorsolateral prefrontal cortex responses when they received negative feedback. Patients also had increased resting state functional connectivity between these two regions. CONCLUSIONS: FND patients had impaired instrumental avoidance learning, findings that parallel previous observations of impaired action-outcome binding. FND patients further show enhanced behavioural and neural sensitivity to negative information. However, this did not translate to improved avoidance learning. Put together, our findings do not support the theory of harm avoidance in FND. We highlight a potential mechanism by which negative contexts interfere with adaptive behaviours in this under-explored disorder.The authors declare no competing financial disclosures. VV is a Medical Research Council Senior Clinical Fellow (MR/P008747/1). This work is supported by the NIHR Biomedical Research Centre Funding at the University of Cambridge

Disrupted resting-state brain network properties in obesity: decreased global and putaminal cortico-striatal network efficiency.

BACKGROUND: The efficient organization and communication of brain networks underlie cognitive processing and their disruption can lead to pathological behaviours. Few studies have focused on whole-brain networks in obesity and binge eating disorder (BED). Here we used multi-echo resting-state functional magnetic resonance imaging (rsfMRI) along with a data-driven graph theory approach to assess brain network characteristics in obesity and BED. METHOD: Multi-echo rsfMRI scans were collected from 40 obese subjects (including 20 BED patients) and 40 healthy controls and denoised using multi-echo independent component analysis (ME-ICA). We constructed a whole-brain functional connectivity matrix with normalized correlation coefficients between regional mean blood oxygenation level-dependent (BOLD) signals from 90 brain regions in the Automated Anatomical Labeling atlas. We computed global and regional network properties in the binarized connectivity matrices with an edge density of 5%-25%. We also verified our findings using a separate parcellation, the Harvard-Oxford atlas parcellated into 470 regions. RESULTS: Obese subjects exhibited significantly reduced global and local network efficiency as well as decreased modularity compared with healthy controls, showing disruption in small-world and modular network structures. In regional metrics, the putamen, pallidum and thalamus exhibited significantly decreased nodal degree and efficiency in obese subjects. Obese subjects also showed decreased connectivity of cortico-striatal/cortico-thalamic networks associated with putaminal and cortical motor regions. These findings were significant with ME-ICA with limited group differences observed with conventional denoising or single-echo analysis. CONCLUSIONS: Using this data-driven analysis of multi-echo rsfMRI data, we found disruption in global network properties and motor cortico-striatal networks in obesity consistent with habit formation theories. Our findings highlight the role of network properties in pathological food misuse as possible biomarkers and therapeutic targets.The study was funded by the Wellcome Trust Fellowship grant for V.V. (093705/Z/10/Z) and the Cambridge National Institute for Health Research (NIHR) Biomedical Research Centre. We thank Dr Ameera Patel for providing the H-O470 brain parcellation atlas in the present study.This is the final version of the article. It first appeared from Cambridge University Press via https://doi.org/10.1017/S003329171600264

Evidence for ecosystem state shifts in Alaskan continuous permafrost peatlands in response to recent warming

Peatlands in continuous permafrost regions represent a globally-important store of organic carbon, the stability of which is thought to be at risk under future climatic warming. To better understand how these ecosystems may change in a warmer future, we use a palaeoenvironmental approach to reconstruct changes in two peatlands near Toolik Lake on Alaska's North Slope (TFS1 and TFS2). We present the first testate amoeba-based reconstructions from peatlands in continuous permafrost, which we use to infer changes in water-table depth and porewater electrical conductivity during the past two millennia. TFS1 likely initiated during a warm period between 0 and 300 CE. Throughout the late-Holocene, both peatlands were minerotrophic fens with low carbon accumulation rates (means of 18.4 and 14.2 g C m−2 yr−1 for cores TFS1 and TFS2 respectively). However, since the end of the Little Ice Age, both fens have undergone a rapid transition towards oligotrophic peatlands, with deeper water tables and increased carbon accumulation rates (means of 59.5 and 48.2 g C m−2 yr−1 for TFS1 and TFS2 respectively). We identify that recent warming has led to these two Alaskan rich fens to transition into poor fens, with greatly enhanced carbon accumulation rates. Our work demonstrates that some Arctic peatlands may become more productive with future regional warming, subsequently increasing their ability to sequester carbon

Time and travel costs incurred by women attending antenatal tests: A costing study

OBJECTIVE: to estimate the costs to women, their friends and family for different antenatal tests in the Down's syndrome (DS) screening pathway. DESIGN: questionnaire-based costing study. SETTING: eight maternity clinics across the UK. PARTICIPANTS: pregnant women (n=574) attending an appointment for DS screening, NIPT or invasive testing between December 2013 and September 2014. MEASUREMENTS: using data collected from the questionnaires we calculated the total costs to women by multiplying the time spent at the hospital and travelling to and from it by the opportunity costs of the women and accompanying person and adding travel and childcare costs. Assumptions about the value of opportunity costs were tested in one-way sensitivity analyses. The main outcome measure was the mean cost to the women and friends/family for each test (DS screening, NIPT, and invasive testing). FINDINGS: mean costs to women and their family/friend were £33.96 per visit, of which £22.47 were time costs, £9.15 were travel costs and £2.34 were childcare costs. Costs were lowest for NIPT (£22), £32 for DS screening (£44 if combined with NIPT), and highest for invasive testing (£60). Sensitivity analysis revealed that variations around the value of leisure time opportunity costs had the largest influence on the results. KEY CONCLUSIONS: there are considerable costs to women, their friends and family when attending different tests in the DS screening pathway. IMPLICATIONS FOR PRACTICE: when assessing the cost-effectiveness of changes to this pathway, costs to women should be considered

Preferences for prenatal diagnosis of sickle-cell disorder: A discrete choice experiment comparing potential service users and health-care providers

BACKGROUND: Non-invasive prenatal diagnosis (NIPD) for sickle-cell disorder (SCD) is moving closer to implementation and studies considering stakeholder preferences are required to underpin strategies for offering NIPD in clinical practice. OBJECTIVE: Determine service user and provider preferences for key attributes of prenatal diagnostic tests for SCD and examine views on NIPD. METHOD: A questionnaire that includes a discrete choice experiment was used to determine the preferences of service users and providers for prenatal tests that varied across three attributes: accuracy, time of test and risk of miscarriage. RESULTS: Adults who were carriers of SCD or affected with the condition (N=67) were recruited from haemoglobinopathy clinics at two maternity units. Health professionals, predominately midwives, who offer antenatal care (N=62) were recruited from one maternity unit. No miscarriage risk was a key driver of decision making for both service users and providers. Service providers placed greater emphasis on accuracy than service users. Current uptake of invasive tests was 63%, whilst predicted uptake of NIPD was 93.8%. Many service users (55.4%) and providers (52.5%) think pressure to have prenatal testing will increase when NIPD for SCD becomes available. CONCLUSIONS: There are clear differences between service users and health professionals' preferences for prenatal tests for sickle-cell disorder. The safety of NIPD is welcomed by parents and uptake is likely to be high. To promote informed choice, pretest counselling should be balanced and not exclusively focused on test safety. Counselling strategies that are sensitive to feelings of pressure to test will be essential

Non-invasive prenatal diagnosis (NIPD) for single gene disorders: cost analysis of NIPD and invasive testing pathways

OBJECTIVE: Evaluate the costs of offering non-invasive prenatal diagnosis (NIPD) for single gene disorders compared to traditional invasive testing to inform NIPD implementation into clinical practice. METHOD: Total costs of diagnosis using NIPD or invasive testing pathways were compared for a representative set of single gene disorders. RESULTS: For autosomal dominant conditions, where NIPD molecular techniques are straightforward, NIPD cost £314 less than invasive testing. NIPD for autosomal recessive and X-linked conditions requires more complicated technical approaches and total costs were more than invasive testing, e.g. NIPD for spinal muscular atrophy was £1090 more than invasive testing. Impact of test uptake on costs was assessed using sickle cell disorder as an example. Anticipated high uptake of NIPD resulted in an incremental cost of NIPD over invasive testing of £48 635 per 100 pregnancies at risk of sickle cell disorder. CONCLUSIONS: Total costs of NIPD are dependent upon the complexity of the testing technique required. Anticipated increased demand for testing may have economic implications for prenatal diagnostic services. Ethical issues requiring further consideration are highlighted including directing resources to NIPD when used for information only and restricting access to safe tests if it is not cost-effective to develop NIPD for rare conditions

Distinct cortico-striatal connections with subthalamic nucleus underlie facets of compulsivity

The capacity to flexibly respond to contextual changes is crucial to adapting to a dynamic environment. Compulsivity, or behavioural inflexibility, consists of heterogeneous subtypes with overlapping yet discrete neural substrates. The subthalamic nucleus (STN) mediates the switch from automatic to controlled processing to slow, break or stop behaviour when necessary. Rodent STN lesions or inactivation are linked with perseveration or repetitive, compulsive responding. However, there are few studies examining the role of latent STN-centric neural networks and compulsive behaviour in healthy individuals. We therefore aimed to characterize the relationship between measures of compulsivity (goal-directed and habit learning, perseveration, and self-reported obsessive - compulsive symptoms) and the intrinsic resting state network of the STN. We scanned 77 healthy controls using a multi-echo resting state functional MRI sequence analyzed using independent components analysis (ME-ICA) with enhanced signal-to-noise ratio to examine small subcortical structures. Goal directed model-based behaviour was associated with higher connectivity of STN with medial orbitofrontal cortex (mOFC) and ventral striatum (VS) and more habitual model-free learning was associated with STN connectivity with hippocampus and dorsal anterior cingulate cortex (ACC). Perseveration was associated with reduced connectivity between STN and premotor cortex and finally, higher obsessive -compulsive inventory scores were associated with reduced STN connectivity with dorsolateral prefrontal cortex (PF). We highlight unique contributions of diffuse cortico-striatal functional connections with STN in dissociable measures of compulsivity. These findings are relevant to the development of potential biomarkers of treatment response in neurosurgical procedures targeting the STN for neurological and psychiatric disorders.This study was funded by the Wellcome Trust Fellowship grant for VV (093705/Z/10/Z)

In Vitro Evaluation and Characterization of Newly Designed Alkylamidophospholipid Analogues as Anti-Human Immunodeficiency Virus Type 1 Agents

Our laboratories first reported two novel classes of complex synthetic lipids, including alkylamidophosphocholines (PC lipid; CP-51) and alkylamidophosphate ester-linked lipid-AZT conjugates (lipid-AZT conjugates; CP-92), with selective and potent activity against human immunodeficiency virus type 1 (HIV-1). To extend these observations, we synthesized additional PC lipids and lipid-AZT conjugates (INK and INK-AZT conjugate) to evaluate their structure-activity relationships by testing for selectivity against infectious wild-type (wt) and drug-resistant HIV-1 replication, virus fusogenic activity and toxicity for mouse bone marrow cells. PC lipid compounds with medium chain lengths at positions 1 and 2 gave an improved selective index (SI). INK-3, with 12 and 8 carbons and INK-15, with 10 and 12 carbons were among the most selective when evaluated in CEM-SS cells. INK-14, a lipid-AZT conjugate where AZT replaced the choline in PC lipid INK-3, gave the highest SI of > 1250 against both infectious wt HIV-1 replication in CEM-SS cells and a clinical isolate in peripheral blood leukocytes. Notably, the PC lipid compounds INK-3 and INK-15, but not the lipid-AZT conjugate INK-14, were potent inhibitors of matched pairs of AZT-sensitive and AZT-resistant HIV-1 clinical isolates. INK-3 also inhibited replication of HIV-2 and TIBO-resistant HIV-1, and inhibited HIV-1-mediated fusogenic activity by 78, 41 and 9% in a dose-dependent manner. The TC50 for mouse bone marrow cells was > 100 micrograms/ml for INK-3 compared to 9.15-14.17 micrograms/ml for CP-51 and 0.142-0.259 microgram/ml for AZT. These data suggest that optimum PC lipid compounds are significantly less toxic than AZT and have high potential as novel therapeutic agents for AIDS