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3.  Acquisition of internal models of motor tasks in children with autism 
Brain  2008;131(11):2894-2903.
Children with autism exhibit a host of motor disorders including poor coordination, poor tool use and delayed learning of complex motor skills like riding a tricycle. Theory suggests that one of the crucial steps in motor learning is the ability to form internal models: to predict the sensory consequences of motor commands and learn from errors to improve performance on the next attempt. The cerebellum appears to be an important site for acquisition of internal models, and indeed the development of the cerebellum is abnormal in autism. Here, we examined autistic children on a range of tasks that required a change in the motor output in response to a change in the environment. We first considered a prism adaptation task in which the visual map of the environment was shifted. The children were asked to throw balls to visual targets with and without the prism goggles. We next considered a reaching task that required moving the handle of a novel tool (a robotic arm). The tool either imposed forces on the hand or displaced the cursor associated with the handle position. In all tasks, the children with autism adapted their motor output by forming a predictive internal model, as exhibited through after-effects. Surprisingly, the rates of acquisition and washout were indistinguishable from normally developing children. Therefore, the mechanisms of acquisition and adaptation of internal models in self-generated movements appeared normal in autism. Sparing of adaptation suggests that alternative mechanisms contribute to impaired motor skill development in autism. Furthermore, the findings may have therapeutic implications, highlighting a reliable mechanism by which children with autism can most effectively alter their behaviour.
doi:10.1093/brain/awn226
PMCID: PMC2577807  PMID: 18819989
reach adaptation; prism adaptation; motor control; autism
4.  Depression after status epilepticus: behavioural and biochemical deficits and effects of fluoxetine 
Brain  2008;131(8):2071-2083.
Depression represents one of the most common comorbidities in patients with epilepsy. However, the mechanisms of depression in epilepsy patients are poorly understood. Establishment of animal models of this comorbidity is critical for both understanding the mechanisms of the condition, and for preclinical development of effective therapies. The current study examined whether a commonly used animal model of temporal lobe epilepsy (TLE) is characterized by behavioural and biochemical alterations involved in depression. Male Wistar rats were subjected to LiCl and pilocarpine status epilepticus (SE). The development of chronic epileptic state was confirmed by the presence of spontaneous seizures and by enhanced brain excitability. Post-SE animals exhibited increase in immobility time under conditions of forced swim test (FST) which was indicative of despair-like state, and loss of taste preference in saccharin solution consumption test which pointed to the symptomatic equivalence of anhedonia. Biochemical studies revealed compromised serotonergic transmission in the raphe-hippocampal serotonergic pathway: decrease of serotonin (5-HT) concentration and turnover in the hippocampus, measured by high performance liquid chromatography, and decrease of 5-HT release from the hippocampus in response to raphe stimulation, measured by fast cyclic voltammetry. Administration of fluoxetine (FLX, 20 mg/kg/day for 10 days) to naive animals significantly shortened immobility time under conditions of FST, and inhibited 5-HT turnover in the hippocampus. In post-SE rats FLX treatment led to a further decrease of hippocampal 5-HT turnover; however, performance in FST was not improved. At the same time, FLX reversed SE-induced increase in brain excitability. In summary, our studies provide initial evidence that post-SE model of TLE might serve as a model of the comorbidity of epilepsy and depression. The finding that behavioural equivalents of depression were resistant to an antidepressant medication suggested that depression in epilepsy might have distinct underlying mechanisms beyond alterations in serotonergic pathways.
doi:10.1093/brain/awn117
PMCID: PMC2587254  PMID: 18559371
comorbidity; depression; epilepsy; hippocampus; serotonin
5.  Depression after status epilepticus: behavioral and biochemical deficits, and effects of fluoxetine 
Brain : a journal of neurology  2008;131(Pt 8):2071-2083.
Summary
Depression represents one of the most common comorbidities in patients with epilepsy. However, the mechanisms of depression in epilepsy patients are poorly understood. Establishment of animal models of this comorbidity is critical for both understanding the mechanisms of the condition, and for preclinical development of effective therapies. The current study examined whether a commonly used animal model of temporal lobe epilepsy (TLE) is characterized by behavioral and biochemical alterations involved in depression. Male Wistar rats were subjected to LiCl and pilocarpine status epilepticus (SE). The development of chronic epileptic state was confirmed by the presence of spontaneous seizures and by enhanced brain excitability. Post-SE animals exhibited increase in immobility time under conditions of forced swim test (FST) which was indicative of despair-like state, and loss of taste preference in saccharin solution consumption test which pointed to the symptomatic equivalence of anhedonia. Biochemical studies revealed compromised serotonergic transmission in the raphe-hippocampal serotonergic pathway: decrease of serotonin (5-HT) concentration and turnover in the hippocampus, measured by high performance liquid chromatography, and decrease of 5-HT release from the hippocampus in response to raphe stimulation, measured by fast cyclic voltammetry. Administration of fluoxetine (FLX, 20 mg/kg/day for 10 days) to naïve animals significantly shortened immobility time under conditions of FST, and inhibited 5-HT turnover in the hippocampus. In post-SE rats FLX treatment led to a further decrease of hippocampal 5-HT turnover; however, performance in FST was not improved. At the same time, FLX reversed SE-induced increase in brain excitability. In summary, our studies provide initial evidence that post-SE model of TLE might serve as a model of the comorbidity of epilepsy and depression. The finding that behavioral equivalents of depression were resistant to an antidepressant medication suggested that depression in epilepsy might have distinct underlying mechanisms beyond alterations in serotonergic pathways.
doi:10.1093/brain/awn117
PMCID: PMC2587254  PMID: 18559371
Comorbidity; depression; epilepsy; hippocampus; serotonin
6.  Acquisition of internal models of motor tasks in children with autism 
Brain : a journal of neurology  2008;131(Pt 11):2894-2903.
Children with autism exhibit a host of motor disorders including poor coordination, poor tool use, and delayed learning of complex motor skills like riding a tricycle. Theory suggests that one of the crucial steps in motor learning is the ability to form internal models: to predict the sensory consequences of motor commands and learn from errors to improve performance on the next attempt. The cerebellum appears to be an important site for acquisition of internal models, and indeed the development of the cerebellum is abnormal in autism. Here, we examined autistic children on a range of tasks that required a change in the motor output in response to a change in the environment. We first considered a prism adaptation task in which the visual map of the environment was shifted. The children were asked to throw balls to visual targets with and without the prism goggles. We next considered a reaching task that required moving the handle of a novel tool (a robotic arm). The tool either imposed forces on the hand or displaced the cursor associated with the handle position. In all tasks, the children with autism adapted their motor output by forming a predictive internal model, as exhibited through after-effects. Surprisingly, the rates of acquisition and washout were indistinguishable from normally developing children. Therefore, the mechanisms of acquisition and adaptation of internal models in self-generated movements appeared normal in autism. Sparing of adaptation suggests that alternative mechanisms contribute to impaired motor skill development in autism. Furthermore, the findings may have therapeutic implications, highlighting a reliable mechanism by which children with autism can most effectively alter their behavior.
doi:10.1093/brain/awn226
PMCID: PMC2577807  PMID: 18819989
reach adaptation; prism adaptation; motor control; autism
7.  EBSJ Evidence Assessment 
Global Spine Journal  2016;6(8):842.
doi:10.1055/s-0036-1597140
PMCID: PMC5110425  PMID: 27904834
8.  Is the cardiac monitoring function related to the self in both the default network and right anterior insula? 
The self has been proposed to be rooted in the neural monitoring of internal bodily signals and might thus involve interoceptive areas, notably the right anterior insula (rAI). However, studies on the self consistently showed the involvement of midline default network (DN) nodes, without referring to visceral monitoring. Here, we investigate this apparent discrepancy. We previously showed that neural responses to heartbeats in the DN encode two different self-dimensions, the agentive ‘I’ and the introspective ‘Me’, in a whole-brain analysis of magnetoencephalography (MEG) data. Here, we confirm and anatomically refine this result with intracranial recordings (intracranial electroencephalography, iEEG). In two patients, we show a parametric modulation of neural responses to heartbeats by the self-relatedness of thoughts, at the single trial level. A region-of-interest analysis of the insula reveals that MEG responses to heartbeats in the rAI encode the ‘I’ self-dimension. The effect in rAI was weaker than in the DN and was replicated in iEEG data in one patient out of two. We propose that a common mechanism, the neural monitoring of cardiac signals, underlies the self in both the DN and rAI. This might reconcile studies on the self highlighting the DN, with studies on interoception focusing on the insula.
This article is part of the themed issue ‘Interoception beyond homeostasis: affect, cognition and mental health’.
doi:10.1098/rstb.2016.0004
PMCID: PMC5062094
intracranial electroencephalography; magnetoencephalography; neural responses to heartbeats; heartbeat-evoked responses; interoception; spontaneous cognition
9.  Prospective memory mediated by interoceptive accuracy: a psychophysiological approach 
Previous studies on prospective memory (PM), defined as memory for future intentions, suggest that psychological stress enhances successful PM retrieval. However, the mechanisms underlying this notion remain poorly understood. We hypothesized that PM retrieval is achieved through interaction with autonomic nervous activity, which is mediated by the individual accuracy of interoceptive awareness, as measured by the heartbeat detection task. In this study, the relationship between cardiac reactivity and retrieval of delayed intentions was evaluated using the event-based PM task. Participants were required to detect PM target letters while engaged in an ongoing 2-back working memory task. The results demonstrated that individuals with higher PM task performance had a greater increase in heart rate on PM target presentation. Also, higher interoceptive perceivers showed better PM task performance. This pattern was not observed for working memory task performance. These findings suggest that cardiac afferent signals enhance PM retrieval, which is mediated by individual levels of interoceptive accuracy.
This article is part of the themed issue ‘Interoception beyond homeostasis: affect, cognition and mental health’.
doi:10.1098/rstb.2016.0005
PMCID: PMC5062095
prospective memory; interoception; cardiac reactivity; autonomic nervous activity
10.  Leprosy Post-Exposure Prophylaxis (LPEP) programme: study protocol for evaluating the feasibility and impact on case detection rates of contact tracing and single dose rifampicin 
BMJ Open  2016;6(11):e013633.
Introduction
The reported number of new leprosy patients has barely changed in recent years. Thus, additional approaches or modifications to the current standard of passive case detection are needed to interrupt leprosy transmission. Large-scale clinical trials with single dose rifampicin (SDR) given as post-exposure prophylaxis (PEP) to contacts of newly diagnosed patients with leprosy have shown a 50–60% reduction of the risk of developing leprosy over the following 2 years. To accelerate the uptake of this evidence and introduction of PEP into national leprosy programmes, data on the effectiveness, impact and feasibility of contact tracing and PEP for leprosy are required. The leprosy post-exposure prophylaxis (LPEP) programme was designed to obtain those data.
Methods and analysis
The LPEP programme evaluates feasibility, effectiveness and impact of PEP with SDR in pilot areas situated in several leprosy endemic countries: India, Indonesia, Myanmar, Nepal, Sri Lanka and Tanzania. Complementary sites are located in Brazil and Cambodia. From 2015 to 2018, contact persons of patients with leprosy are traced, screened for symptoms and assessed for eligibility to receive SDR. The intervention is implemented by the national leprosy programmes, tailored to local conditions and capacities, and relying on available human and material resources. It is coordinated on the ground with the help of the in-country partners of the International Federation of Anti-Leprosy Associations (ILEP). A robust data collection and reporting system is established in the pilot areas with regular monitoring and quality control, contributing to the strengthening of the national surveillance systems to become more action-oriented.
Ethics and dissemination
Ethical approval has been obtained from the relevant ethics committees in the countries. Results and lessons learnt from the LPEP programme will be published in peer-reviewed journals and should provide important evidence and guidance for national and global policymakers to strengthen current leprosy elimination strategies.
doi:10.1136/bmjopen-2016-013633
PMCID: PMC5128948  PMID: 27856484
leprosy transmission; post-exposure prophylaxis; contact tracing; contact screening; rifampicin
11.  Validation and Application of a Commercial Quantitative Real-Time Reverse Transcriptase-PCR Assay in Investigation of a Large Dengue Virus Outbreak in Southern Taiwan 
PLoS Neglected Tropical Diseases  2016;10(10):e0005036.
Background
Accurate, rapid, and early diagnosis of dengue virus (DENV) infections is essential for optimal clinical care. Here, we evaluated the efficacy of the quantitative real-time PCR (qRT-PCR)-LightMix dengue virus EC kit for DENV detection using samples from a dengue outbreak in Taiwan in 2015.
Methods
Sera from patients with suspected DENV infection were analyzed and compared using the LightMix kit, a Dengue NS1 Ag + Ab Combo kit for detection of NS1 antigen and DENV-specific IgM and IgG antibodies, and an “in-house” qualitative DENV-specific RT-PCR assay.
Results
A total of 8,989, 8,954, and 1581 samples were subjected to NS1 antigen detection, IgM and IgG detection, and LightMix assays, respectively. The LightMix assay yielded a linear curve for viral loads (VL) between 102 and 106 copies/reaction, and the minimum detection limits for DENV serotype 1 (DENV1) and DENV2, DENV3, and DENV4 were 1, 10, and 100 focus forming units (FFU)/mL, respectively. There was 88.9% concordance between the results obtained using the NS1 antigen combo kit and by LightMix analysis, and the diagnostic sensitivity and specificity of the two methods were 89.4 and 100%, and 84.7 and 100%, respectively. Notably, fatal cases were attributed to DENV2 infection, and 79.5% (27/34) of these cases occurred in patients ≥ 71 years of age. Among these older patients, 82.3% (14/17) were NS1/IgM/IgG (+/-/-), exhibiting VLs between 106–109 copies/mL, which was markedly higher than the rate observed in the other age groups.
Conclusions
The LightMix assay was effective for early diagnosis of DENV infection. Our data indicate that high VLs during primary infection in elderly patients may be a positive predictor for severe illness, and may contribute to high mortality rates.
Author Summary
The LightMix dengue virus EC qRT-PCR assay is effective for early diagnosis of DENV infection. High viral loads during primary infection in elderly patients may comprise a positive predictor for severe illness, and may contribute to high mortality rates.
doi:10.1371/journal.pntd.0005036
PMCID: PMC5061319  PMID: 27732593
12.  Spatial Distribution of Flower Color Induced by Interspecific Sexual Interaction 
PLoS ONE  2016;11(10):e0164381.
Understanding the mechanisms shaping the spatiotemporal distribution of species has long been a central concern of ecology and evolutionary biology. Contemporary patterns of plant assemblies suggest that sexual interactions among species, i.e., reproductive interference, lead to the exclusive distributions of closely related species that share pollinators. However, the fitness consequences and the initial ecological/evolutionary responses to reproductive interference remain unclear in nature, since reproductive isolation or allopatric distribution has already been achieved in the natural community. In Japan, three species of blue-eyed grasses (Sisyrinchium) with incomplete reproductive isolation have recently colonized and occur sympatrically. Two of them are monomorphic with white flowers, whereas the other exhibits heritable color polymorphism (white and purple morphs). Here we investigated the effects of the presence of two monomorphic species on the distribution and reproductive success of color morphs. The frequency and reproductive success of white morphs decreased in area where monomorphic species were abundant, while those of purple morphs did not. The rate of hybridization between species was higher in white morphs than in the purple ones. Resource competition and habitat preference seemed not to contribute to the spatial distribution and reproductive success of two morphs. Our results supported that color-dependent reproductive interference determines the distribution of flower color polymorphism in a habitat, implying ecological sorting promoted by pollinator-mediated reproductive interference. Our study helps us to understand the evolution and spatial structure of flower color in a community.
doi:10.1371/journal.pone.0164381
PMCID: PMC5056732  PMID: 27723785
13.  A Complete Fossil-Calibrated Phylogeny of Seed Plant Families as a Tool for Comparative Analyses: Testing the ‘Time for Speciation’ Hypothesis 
PLoS ONE  2016;11(10):e0162907.
Explaining the uneven distribution of species richness across the branches of the tree of life has been a major challenge for evolutionary biologists. Advances in phylogenetic reconstruction, allowing the generation of large, well-sampled, phylogenetic trees have provided an opportunity to contrast competing hypotheses. Here, we present a new time-calibrated phylogeny of seed plant families using Bayesian methods and 26 fossil calibrations. While there are various published phylogenetic trees for plants which have a greater density of species sampling, we are still a long way from generating a complete phylogeny for all ~300,000+ plants. Our phylogeny samples all seed plant families and is a useful tool for comparative analyses. We use this new phylogenetic hypothesis to contrast two alternative explanations for differences in species richness among higher taxa: time for speciation versus ecological limits. We calculated net diversification rate for each clade in the phylogeny and assessed the relationship between clade age and species richness. We then fit models of speciation and extinction to individual branches in the tree to identify major rate-shifts. Our data suggest that the majority of lineages are diversifying very slowly while a few lineages, distributed throughout the tree, are diversifying rapidly. Diversification is unrelated to clade age, no matter the age range of the clades being examined, contrary to both the assumption of an unbounded lineage increase through time, and the paradigm of fixed ecological limits. These findings are consistent with the idea that ecology plays a role in diversification, but rather than imposing a fixed limit, it may have variable effects on per lineage diversification rates through time.
doi:10.1371/journal.pone.0162907
PMCID: PMC5051821  PMID: 27706173
14.  Influence of Different Levels of Lipoic Acid Synthase Gene Expression on Diabetic Nephropathy 
PLoS ONE  2016;11(10):e0163208.
Oxidative stress is implicated in the pathogenesis of diabetic nephropathy (DN) but outcomes of many clinical trials are controversial. To define the role of antioxidants in kidney protection during the development of diabetic nephropathy, we have generated a novel genetic antioxidant mouse model with over- or under-expression of lipoic acid synthase gene (Lias). These models have been mated with Ins2Akita/+ mice, a type I diabetic mouse model. We compare the major pathologic changes and oxidative stress status in two new strains of the mice with controls. Our results show that Ins2Akita/+ mice with under-expressed Lias gene, exhibit higher oxidative stress and more severe DN features (albuminuria, glomerular basement membrane thickening and mesangial matrix expansion). In contrast, Ins2Akita/+ mice with highly-expressed Lias gene display lower oxidative stress and less DN pathologic changes. Our study demonstrates that strengthening endogenous antioxidant capacity could be an effective strategy for prevention and treatment of DN.
doi:10.1371/journal.pone.0163208
PMCID: PMC5051822  PMID: 27706190
15.  SeqKit: A Cross-Platform and Ultrafast Toolkit for FASTA/Q File Manipulation 
PLoS ONE  2016;11(10):e0163962.
FASTA and FASTQ are basic and ubiquitous formats for storing nucleotide and protein sequences. Common manipulations of FASTA/Q file include converting, searching, filtering, deduplication, splitting, shuffling, and sampling. Existing tools only implement some of these manipulations, and not particularly efficiently, and some are only available for certain operating systems. Furthermore, the complicated installation process of required packages and running environments can render these programs less user friendly. This paper describes a cross-platform ultrafast comprehensive toolkit for FASTA/Q processing. SeqKit provides executable binary files for all major operating systems, including Windows, Linux, and Mac OSX, and can be directly used without any dependencies or pre-configurations. SeqKit demonstrates competitive performance in execution time and memory usage compared to similar tools. The efficiency and usability of SeqKit enable researchers to rapidly accomplish common FASTA/Q file manipulations. SeqKit is open source and available on Github at https://github.com/shenwei356/seqkit.
doi:10.1371/journal.pone.0163962
PMCID: PMC5051824  PMID: 27706213
16.  Outstanding Symptoms of Poststroke Depression during the Acute Phase of Stroke 
PLoS ONE  2016;11(10):e0163038.
Poststroke depression (PSD) is a critical complication which might lead to unfavorable outcomes. However, most cases of PSD in the acute phase, during the 2 or 3 weeks following a stroke, are neglected because of the variable comorbid conditions. In this study, aimed at revealing the outstanding symptoms of PSD during the acute phase, consecutive patients with intracranial hemorrhage (ICH) or brain infarction (BI) were asked to fill out a depression questionnaire (Quick Inventory of Depressive Symptomatology Self-Report: QIDS-SR) at 1 week and 1 month following stroke onset. Patients with disturbed consciousness or aphasia were excluded from this study. Forty-nine ICH patients and 222 BI patients completed the QIDS-SR at 1 week and 27 of ICH and 62 of BI at 1 month. The PSD rate was 67% and 46% at 1 week in ICH and BI, respectively. Although sleep disturbance was the most frequent symptom of PSD, psychomotor agitation and appetite disturbance were the most distinguishing symptoms in ICH at 1 week and fatigue at 1 month. On the other hand, most of the depressive symptoms addressed in QIDS-SR were observed in PSD of BI patients both at 1 week and 1 month. In conclusion, while sleep disturbance was a frequent but non-specific symptom, appetite disturbance and fatigue might be critical symptoms to suggest PSD during the acute phase of stroke.
doi:10.1371/journal.pone.0163038
PMCID: PMC5051825  PMID: 27706193
17.  Adipose-Derived Stem Cells Respond to Increased Osmolarities 
PLoS ONE  2016;11(10):e0163870.
Cell therapies present a feasible option for the treatment of degenerated cartilaginous and intervertebral disc (IVD) tissues. Microenvironments of these tissues are specific and often differ from the microenvironment of cells that, could be potentially used for therapy, e.g. human adipose-derived stem cells (hASC). To ensure safe and efficient implantation of hASC, it is important to evaluate how microenvironmental conditions at the site of implantation affect the implanted cells. This study has demonstrated that cartilaginous tissue-specific osmolarities ranging from 400–600 mOsm/L affected hASC in a dose- and time-dependent fashion in comparison to 300 mOsm/L. Increased osmolarities resulted in transient (nuclear DNA and actin reorganisation) and non-transient, long-term morphological changes (vesicle formation, increase in cell area, and culture morphology), as well as reduced proliferation in monolayer cultures. Increased osmolarities diminished acid proteoglycan production and compactness of chondrogenically induced pellet cultures, indicating decreased chondrogenic potential. Viability of hASC was strongly dependent on the type of culture, with hASC in monolayer culture being more tolerant to increased osmolarity compared to hASC in suspension, alginate-agarose hydrogel, and pellet cultures, thus emphasizing the importance of choosing relevant in vitro conditions according to the specifics of clinical application.
doi:10.1371/journal.pone.0163870
PMCID: PMC5051864  PMID: 27706209
18.  The Effect of Albumin on MRP2 and BCRP in the Vesicular Transport Assay 
PLoS ONE  2016;11(10):e0163886.
The ABC transporters multidrug resistance associated protein 2 (MRP2) and breast cancer resistance protein (BCRP) are of interest in drug development, since they affect the pharmacokinetics of several drugs. Membrane vesicle transport assays are widely used to study interactions with these proteins. Since albumin has been found to affect the kinetics of metabolic enzymes in similar membrane preparations, we investigated whether albumin affects the kinetic parameters of efflux transport. We found that albumin increased the Vmax of 5(6)-carboxy-2’,7’-dichlorofluorescein (CDCF) and estradiol-17-β-D-glucuronide uptake into MRP2 vesicles in the presence of 0.1% bovine serum albumin (BSA) by 2 and 1.5-fold, respectively, while BSA increased Lucifer yellow uptake by 30% in BCRP vesicles. Km values increased slightly, but the change was not statistically significant. The effect of BSA on substrate uptake was dependent on the vesicle amount, while increasing BSA concentration did not significantly improve substrate uptake. These results indicate a minor effect of albumin on MRP2 and BCRP, but it should be considered if albumin is added to transporter assays for example as a solubilizer, since the effect may be substrate or transporter specific.
doi:10.1371/journal.pone.0163886
PMCID: PMC5051865  PMID: 27706255
19.  Netrin 1 regulates blood–brain barrier function and neuroinflammation 
Brain : a journal of neurology  2015;138(Pt 6):1598-1612.
Blood–brain barrier function is driven by the influence of astrocyte-secreted factors. During neuroinflammatory responses the blood–brain barrier is compromised resulting in central nervous system damage and exacerbated pathology. Here, we identified endothelial netrin 1 induction as a vascular response to astrocyte-derived sonic hedgehog that promotes autocrine barrier properties during homeostasis and increases with inflammation. Netrin 1 supports blood–brain barrier integrity by upregulating endothelial junctional protein expression, while netrin 1 knockout mice display disorganized tight junction protein expression and barrier breakdown. Upon inflammatory conditions, blood–brain barrier endothelial cells significantly upregulated netrin 1 levels in vitro and in situ, which prevented junctional breach and endothelial cell activation. Finally, netrin 1 treatment during experimental autoimmune encephalomyelitis significantly reduced blood–brain barrier disruption and decreased clinical and pathological indices of disease severity. Our results demonstrate that netrin 1 is an important regulator of blood–brain barrier maintenance that protects the central nervous system against inflammatory conditions such as multiple sclerosis and experimental autoimmune encephalomyelitis.
doi:10.1093/brain/awv092
PMCID: PMC4614143  PMID: 25903786 CAMSID: cams4908
multiple sclerosis; experimental autoimmune encephalomyelitis; blood–brain barrier; netrin 1; neuroinflammation
20.  A Precise Annotation of Phase-Amplitude Coupling Intensity 
PLoS ONE  2016;11(10):e0163940.
Neuronal information can be coded in different temporal and spatial scales. Cross-frequency coupling of neuronal oscillations, especially phase-amplitude coupling (PAC), plays a critical functional role in neuronal communication and large scale neuronal encoding. Several approaches have been developed to assess PAC intensity. It is generally agreed that the PAC intensity relates to the uneven distribution of the fast oscillation amplitude conditioned on the slow oscillation phase. However, it is still not clear what the PAC intensity exactly means. In the present study, it was found that there were three types of interferential signals taking part in PAC phenomenon. Based on the classification of interferential signals, the conception of PAC intensity is theoretically annotated as the proportion of slow or fast oscillation that is involved in a related PAC phenomenon. In order to make sure that the annotation is proper to some content, simulation data are constructed and then analyzed by three PAC approaches. These approaches are the mean vector length (MVL), the modulation index (MI), and a new permutation mutual information (PMI) method in which the permutation entropy and the information theory are applied. Results show positive correlations between PAC values derived from all three methods and the suggested intensity. Finally, the amplitude distributions, i.e. the phase-amplitude plots, obtained from different PAC intensities show that the annotation proposed in the study is in line with the previous understandings.
doi:10.1371/journal.pone.0163940
PMCID: PMC5049761  PMID: 27701458
21.  Asymmetric Power Boosts Extortion in an Economic Experiment 
PLoS ONE  2016;11(10):e0163867.
Direct reciprocity is a major mechanism for the evolution of cooperation. Several classical studies have suggested that humans should quickly learn to adopt reciprocal strategies to establish mutual cooperation in repeated interactions. On the other hand, the recently discovered theory of ZD strategies has found that subjects who use extortionate strategies are able to exploit and subdue cooperators. Although such extortioners have been predicted to succeed in any population of adaptive opponents, theoretical follow-up studies questioned whether extortion can evolve in reality. However, most of these studies presumed that individuals have similar strategic possibilities and comparable outside options, whereas asymmetries are ubiquitous in real world applications. Here we show with a model and an economic experiment that extortionate strategies readily emerge once subjects differ in their strategic power. Our experiment combines a repeated social dilemma with asymmetric partner choice. In our main treatment there is one randomly chosen group member who is unilaterally allowed to exchange one of the other group members after every ten rounds of the social dilemma. We find that this asymmetric replacement opportunity generally promotes cooperation, but often the resulting payoff distribution reflects the underlying power structure. Almost half of the subjects in a better strategic position turn into extortioners, who quickly proceed to exploit their peers. By adapting their cooperation probabilities consistent with ZD theory, extortioners force their co-players to cooperate without being similarly cooperative themselves. Comparison to non-extortionate players under the same conditions indicates a substantial net gain to extortion. Our results thus highlight how power asymmetries can endanger mutually beneficial interactions, and transform them into exploitative relationships. In particular, our results indicate that the extortionate strategies predicted from ZD theory could play a more prominent role in our daily interactions than previously thought.
doi:10.1371/journal.pone.0163867
PMCID: PMC5049762  PMID: 27701427
22.  Opioid Therapy and Sleep Disorders: Risks and Mitigation Strategies 
Pain medicine (Malden, Mass.)  2015;16(0 1):S22-S26.
Objective
Patients with chronic pain frequently experience concomitant sleep disorders. There has been controversy on whether opioids have a beneficial or deleterious effect on sleep quality, duration and efficiency. There is also concern regarding the association between chronic opioid therapy and sleep disordered breathing and the increased risk for unintentional opioid related overdose. This article provides a narrative review of the literature on the effect of opioids on sleep disorders and discusses risk assessment and mitigation strategies.
Design
A narrative review of the current literature on the effect of prescription opioids on sleep quality and efficiency, the relationship between opioids and sleep disorders and potential risk factors in patients with chronic pain.
Results
There is conflicting evidence regarding the benefit of opioids in improving sleep quality, duration and efficiency with several studies and reviews suggesting a beneficial effect of opioids on sleep and other studies demonstrating the opioids can cause sleep disturbance leading to hyperalgesia. There was credible evidence of a strong relationship between opioids and sleep disordered breathing with noted risk factors including use of methadone, high opioid dosing (> 200 mg MED) and combining opioids with benzodiazepines.
Conclusions
Further research is required to elucidate the effect of prescription opioids on sleep quality and pain intensity and the risks associated with opioids and sleep disordered breathing. The risk of sleep disordered breathing should be routinely assessed in patients on chronic opioid therapy.
doi:10.1111/pme.12910
PMCID: PMC4608386  PMID: 26461072
Opioid therapy; chronic pain; sleep disordered breathing; methadone
23.  Investigating the Phenomenological Matrix of Mindfulness-related Practices from a Neurocognitive Perspective 
The American psychologist  2015;70(7):632-658.
There has been a great increase in literature concerned with the effects of a variety of mental training regimes that generally fall within what might be called contemplative practices, and a majority of these studies have focused on mindfulness. Mindfulness meditation practices can be conceptualized as a set of attention-based, regulatory and self-inquiry training regimes cultivated for various ends, including well-being and psychological health. This article examines the construct of mindfulness in psychological research and reviews recent, non-clinical work in this area. Instead of proposing a single definition of mindfulness, we interpret it as a continuum of practices involving states that can be mapped into a multidimensional phenomenological matrix which itself can be expressed in a neurocognitive framework. This phenomenological matrix of mindfulness is presented as a heuristic to guide formulation of next-generation research hypotheses from both cognitive/behavioral and neuroscientific perspectives. In relation to this framework, we review selected findings on mindfulness cultivated through practices in both traditional and research settings, and we conclude by identifying significant gaps in the literature and outlining new directions for research.
doi:10.1037/a0039585
PMCID: PMC4608430  PMID: 26436313
Mindfulness meditation; dispositional mindfulness; MBSR; MBCT; focused-attention meditation; open monitoring meditation; neuroimaging; meta-awareness; dereification; decentering; attention regulation
24.  What Can DuchenneConnect Teach Us About Treating Duchenne Muscular Dystrophy? 
Current opinion in neurology  2015;28(5):535-541.
Purpose of Review
This review aims to describe the benefits and limitations of using the DuchenneConnect patient registry to provide information particularly in regard to active treatment choices in Duchenne muscular dystrophy and their impact on disease progression.
Recent findings
Clinical trials and natural history studies are difficult for rare diseases like Duchenne muscular dystrophy. Using an online patient self-report survey model, DuchenneConnect provides relevant data that are difficult to gather in other ways. Validation of the overall dataset is supported by comparable mutational spectrum relative to other cohorts and demonstrated beneficial effect of corticosteroid use in prolonging ambulation. These types of analyses are provocative and allow multivariate analyses across the breadth of patient and physician medication and supplement practices. Because the data is self-reported and online, the barrier to participation is low and great potential exists for novel directions of further research in a highly participatory forum.
Summary
Patient registries for Duchenne and Becker muscular dystrophy are powerful tools for monitoring patient outcomes, comparing treatments options, and relating information between patients, researchers and clinicians. DuchenneConnect is an online patient self-report registry for individuals with DBMD that facilitates aggregation of treatment modalities, outcomes and genotype data and has played a vital role in furthering DBMD research, particularly in the US, in a highly participatory and low cost manner.
doi:10.1097/WCO.0000000000000245
PMCID: PMC4608842  PMID: 26356412
Duchenne muscular dystrophy; online registries; patient reported outcomes; Becker muscular dystrophy
25.  Stroke: a Hidden Danger of Margin Trading in Stock Markets 
Using 10-year population data from 2000 through 2009 in Taiwan, this is the first paper to analyze the relationship between margin trading in stock markets and stroke hospitalizations. The results show that 3 and 6 days after an increase of margin trading in the Taiwan stock markets are associated with greater stoke hospitalizations. In general, a 1 % increase in total margin trading positions is associated with an increment of 2.5 in the total number of stroke hospitalizations, where the mean number of hospital admissions is 233 cases a day. We further examine the effects of margin trading by gender and age groups and find that the effects of margin trading are significant for males and those who are 45–74 years old only. In summary, buying stocks with money you do not have is quite risky, especially if the prices of those stocks fall past a certain level or if there is a sudden and severe drop in the stock market. There is also a hidden danger to one’s health from margin trading. A person should be cautious before conducting margin trading, because while it can be quite profitable, danger always lurks just around the corner.
doi:10.1007/s11524-015-9964-1
PMCID: PMC4608931  PMID: 26014381
Margin trading; Stroke; Stock market; Health; Taiwan

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