Social animals can use both social and private information to guide decision making. While social information can be relatively economical to acquire, it can lead to maladaptive information cascades if attention to environmental cues is supplanted by unconditional copying. Ants frequently employ pheromone trails, a form of social information, to guide collective processes, and this can include consensus decisions made when choosing a place to live. In this study, I examine how house-hunting ants balance social and private information when these information sources conflict to different degrees. Social information, in the form of pre-established pheromone trails, strongly influenced the decision process in choices between equivalent nests, and lead to a reduced relocation time. When trails lead to non-preferred types of nest, however, social information had less influence when this preference was weak and no influence when the preference was strong. These results suggest that social information is vetted against private information during the house-hunting process in this species. Private information is favoured in cases of conflict and this may help insure colonies against costly wrong decisions. Being well informed can mean the difference between a good and bad decision. Animals frequently make fitness-critical decisions based on information acquired through individual experience (private information) and via signals or cues from other animals  Social insects exhibit some of the most sophisticated systems of information exchange, from the complex chemical messages encoded in chemical trails to the dance language of honey bees. These systems perform critical roles in the optimisation of collective processes Temnothorax ants and honey bees Temnothorax) and, once a critical number of individuals (‘quorum’) is in favour of a particular site, the process shifts rapidly to that of relocation. A collective response emerges as a product of numerous individual decisions, each of which is made based on the private and social information available to that individual. In this manner, colonies are able to make accurate choices among sites of varying quality while maintaining colony integrity In addition to holding an important role in foraging, information exchange is critical to the process of finding a new home. Social insects relocate to a new nest when the present site becomes unsuitable or during the process of colony fission Myrmecina nipponica relies on pheromone trails to navigate during house hunting M. nipponica, and assess whether the use of pheromone trails in this species can lead to information cascades during nest site selection.Unlike other social insects so far studied (though see M. nipponica (consisting of 14 to 65 ants) were collected from patches of moss and the bases of ferns in broadleaf forest on public land near Chitose City in Hokkaido, northern Japan  in September 2011 and 2012. No permissions were required and this species is not protected. Colonies were housed in plastic boxes floored with plaster and containing an artificial nest consisting of a 2 mm high ring of foam covered with a microscope slide and red filter, and were kept in standard laboratory conditions . In trial three, the navigation box was again rotated, and A groups were randomly assigned a B group from a different colony to test for colony specificity of pheromone trails.Myrmecina nipponica is characterised by several stages, notably the discovery, assessment and transport phases To investigate how social information can influence the relocation process in more detail, six additional colonies of individually marked ants were forced to relocate using a three-box arrangement  or a treatment nest, with one of the following treatments: i) small nest: nest volume (length) was half of that or normal nests; ii) wide entrance: nest entrances were 10 mm instead of the usual 3 mm; iii) tall nest: nests were double height; iv) dry nest: nest boxes (plaster) were allowed to dry for 2 days prior to trials , v) dark versus light nests: one nest was covered with an opaque cover while the other was left with only a microscope slide (the red filter was removed). A group of 12 colonies was each tested once for each of the nest traits.The three most strongly preferred nest types  were chosen for further trials. In the main experiment, an attempt was made to induce negative information cascades by priming colonies with an established pheromone trail leading to a non-preferred nest, in this way simulating an initial string of ‘bad choices’ by scouts. A paired experimental design was employed, with colonies performing one relocation with a trail and one without for each preference test. A total of 35 colonies were used in all trials and treatments were randomly ordered.lme) procedure implemented in R version 2.15.2 glm) were used for analyses within trial groups as colonies were used only once each (for control and treatment) within trials. Colony size of lead and follower colonies had no influence in any of these tests. Exact binomial tests were used to test for preferences between nests of different traits . Means are given as arithmetic mean ± standard deviation unless otherwise stated.Results were analysed with the mixed-effects modelling , indicating that trails influence nest choice and that this effect is not colony-specific. Furthermore, follower groups relocated faster than lead groups, and this difference was significant when one outlier with a very long lead group time  or transport time , but that discovery time was significantly shorter with social information . These data suggest that the reduction in overall relocation time in trials with trails is largely a result of a reduced time spent searching for a suitable site, though the same trend applied to both assessment and transport phases.Relocations undertaken using a three-box setup to examine phase durations concur with results above in that total relocation time was significantly shorter when colonies were provided with existing pheromone trails . A similar trend was observed for colonies in weak preference trials, which selected a higher proportion of non-preferred nests when provided with trails , it was marginally significant when data from both weak preference trials were pooled . The effect of trails was also significant over all trials , though in contrast to other treatments, colonies in strong preference trials selected the preferred nest regardless of trail presence. Both nests were inspected by ants in all trials and no colony splitting was observed during relocations.Results of choice tests without trails aligned well with initial preference trials, indicating a strong preference for wet over dry nests, and a weaker preference for dark over light nests . As for h trails . While tM. nipponica colonies were strongly influenced by existing pheromone trails in choices between equivalent nests, and able to exploit this social information to reduce relocation time. In contrast, trails had no influence on choice when they lead to strongly non-preferred (dry) nests, while in weak preference trials, a higher proportion of colonies again selected non-preferred nests in the presence of trails. The selection of a new nest site is an emergent consequence of numerous semi-independent individual choices based on social and private information. In the main experiment social information (as represented by a fully established trail) was constant, whereas private information obtained by ants visiting non-preferred nests varied in the degree to which it conflicted with social information, from nil (in controls) to high . House hunting ants and bees visiting a given site assess its quality and either decide to accept it and begin recruiting to the site, or otherwise continue searching House-hunting Myrmecina, the cost of acquiring private information is almost certainly high: scouts move slowly and thus finding a new home takes time, during which scouts risk desiccation, predation, and getting lost, and the colony as a whole is exposed. In addition, at least two other factors suggest social information should be favoured in this context. Firstly, social information in the form of pheromone trails can be considered reliable because it is provided by nest-mates with shared interests and the ephemeral nature of trails means that information is up to date. Secondly, Rendell et al. M. nipponica and, while this supposition is perhaps reflected in the strong influence of trails on choices between equivalent nests, the reduced influence of trails leading to non-preferred nests suggests that social information is not blindly accepted, but vetted against private information before a decision is made. These data support previous studies indicating that in the event of conflict ants defer to private information et al.Temnothorax ants relied on prior experience  when chemical markings in their laboratory arena were experimentally reversed. This suggests a preference for private information over social information, though ants of this genus rely on tandem-running for recruitment during consensus decision making MyrmecinaThe relative cost and reliability of private and social information is thought to regulate the conditional weighting of one over the other Lonchura punctulata) could be induced to make maladaptive decisions when strong social information apparently lead them to disregarded personal information in a manner consistent with information cascades. Maladaptive choices connected with the use of social information have also been implicated in fish Conditional use of information sources appears to be common in animal learning, and present evidence suggests it is probably widespread both taxonomically (reviews for fish


What are the psychological mechanisms that make dieting so challenging in our food-rich living environment? Social psychological research on goal priming provides a useful framework for answering this question, as well as implications for how to enhance dieting success. This review presents and discusses recent research which shows that attractive food cues prime the hedonic eating goal in dieters, and thus facilitate overeating. However, external cues priming the goal of weight control can be used to offset these effects and thus to facilitate dieting success, as is demonstrated in both field and laboratory experiments. In addition, recent strategies to prevent hedonic effects of attractive food, such as mindful attention, can facilitate self-regulation. These recent advances in our understanding of dieting behavior have theoretical and practical implications for how successful dieting can be facilitated, both by means of individual strategies, as well as by environmental changes. Overweight and obesity are an increasingly serious and costly health issue in most Western societies. In 2007 to 2008, more than two thirds of US adults were estimated to be overweight or obese . Based oMany people try to reduce or at least control their weight by dieting . HoweverWhy is it so difficult to pursue and maintain healthy weight-control behaviors? It has been argued that the current, food-rich living environments of Western societies play a crucial role in these difficulties in weight regulation –13. ThesWhich psychological mechanisms underlie these effects of attractive food cues on chronic dieters, and how can they be counteracted? Here, I will present and discuss research suggesting that nonconscious goal priming plays a crucial role in both processes . BaA number of recent studies on dieters’ nonconscious cognitive processes have confirmed that chronic dieters display stronger hedonic reactions to attractive food cues than normal eaters , 26, oftThe exposure to food cues has not only been shown to trigger strong hedonic reactions, but also to guide dieters’ visual attention toward attractive food. More specifically, when chronic dieters were exposed to attractive food words, they later displayed increased attention toward tasty food items as a function of their subjective liking of this food . SimilarOnce chronic dieters are thus focused on the hedonic aspects of the palatable food they perceive, thoughts about dieting and weight control are less likely to come to mind. Most foods that are perceived as highly attractive are also high in calories and their consumption is incompatible with the pursuit of the weight control goal. Chronic dieters are very much aware of this, and are therefore highly ambivalent toward palatable, high-calorie food •, 31, 32To sum up, attractive food primes the hedonic eating goal in chronic dieters, which prepares dieters to pursue this goal and leads to the inhibition of the conflicting goal of weight control, making unhealthy choices and overeating more likely. This may explain why the mere exposure to the smell or sight of attractive food triggers unhealthy choices and overeating in chronic dieters, despite their intentions to control their body weight by dieting –17.Applying this goal conflict perspective to understanding dieting behavior, however, also suggests ways for improving the chances for dieting success. As the activation of the hedonic eating goal by attractive food cues leads to the inhibition of the dieting goal and thus to dieting failures, activating the dieting goal by means of dieting cues should activate the dieting goal and thus re-instate its influence on subsequent cognition and behavior. In other words, priming the weight control goal in tempting situations should help chronic dieters to focus on this goal, and thus to be more successful dieters.In line with this reasoning, research on the cognitive effects of diet goal primes indicates that subtly reminding chronic dieters of their goal of weight control reduces their attention for the hedonic aspects of food in their environments. In a study on visual attention, Papies et al.  first exResearch on goal priming in the domain of social psychology has provided ample evidence that subtle cues activating the mental representation of a certain goal can lead to motivated behavior in pursuit of that goal. In their seminal study on this topic, Bargh et al.  subtly eA recent field study has provided a first test of this hypothesis. In a real-life setting, participants were exposed to food temptations and also primed with the goal of weight control, while their eating behavior was observed •. The stIn line with earlier research on the eating behavior of chronic dieters in tempting situations , 16, resMore recently, this test of goal priming to examine whether goal primes can also lead to healthier behavior was extended to a different real-life situation, namely when eating out in a restaurant. This seems a particularly relevant setting, since the consumption of out-of-home meals has been increasing over the last years , while cPapies and Veling  conducteThese experiments suggest that very subtle goal primes, such as words on posters or menus, magazine covers, or even subliminally presented words, can gear dieters toward pursuing their long-term health goal, even in tempting environments. Thus, due to their unobtrusive and cost-effective nature, such goal primes may constitute a useful and effective addition to the toolkit for theory-based interventions in health behavior .The research reviewed thus far has demonstrated how environmental cues priming the hedonic eating goal can facilitate hedonic eating behavior, and how cues priming the goal of weight control can facilitate the pursuit of the goal of weight control. This provides us with theoretical insight into the mechanisms of dieting failures, and with inspiration about how to modify features of the environment to help dieters be more successful. However, in our “toxic” living environment, which frequently confronts us with attractive food cues as reminders of our hedonic goals, rather than our long-term health goals, these processes are much more likely to instigate failures of self-regulation. Reminders of the dieting goal cannot easily be implemented in every part of one’s living environment. Therefore, to enable chronic dieters to successfully pursue their goal of weight control even in tempting environments without diet reminders, van Koningsbruggen et al. • developThis goal-priming technique relies on recent advances in research on behavior regulation and on the benefits of planning one’s behavior. Specifically, forming if-then plans by means of so-called implementation intentions  has beenThe most common applications of implementation intentions identify a specific behavior to be performed in the anticipated situation. However, adapting this technique to enable goal priming among chronic dieters, van Koningsbruggen et al. • slightlThese studies clearly revealed that goal priming by implementation intentions was beneficial only for otherwise unsuccessful dieters, while it did not influence the eating behavior of those dieters who indicate that they are rather successful in regulating their own weight control behaviors •, 51. WhSeveral studies now suggest that the answer to this question may lie in dieters’ differential associations with attractive food cues. Specifically, an initial study on this issue examined the cognitive effects of attractive food primes  and reveSimilarly, a later study revealed that the pattern of goal activation displayed by successful and unsuccessful dieters parallels the behavior of normal weight and overweight dieters. Here, chronic dieters with different levels of body mass index (BMI) were unobtrusively primed with attractive or neutral food cues, before their motivation to obtain tasty food was examined . ResultsAn important question that still needs to be fully resolved is how these differential associations develop. How do some dieters learn to associate tasty food with watching their weight, while others associate it with indulgence? Based on social psychological research on the cognitive mechanisms underlying nonconscious goal pursuit, it has been suggested that these differential associations may develop by repeatedly pursuing either goal when confronted with tasty food cues , 41, 54.Importantly, research has shown that planning to think of one’s weight control goal helped unsuccessful dieters to activate this goal in response to tempting food cues, and thus to resist food temptations in their daily lives, essentially turning them into successful dieters. Thus, this planning technique can serve to overrule unhealthy associations that may have developed by repeated unhealthy behaviors and that would otherwise lead to maintained failures of self-regulation. However, more research is needed to gain insight into how the psychological mechanism of success spontaneously develops in some dieters, enabling them to remain slim in our current “toxic” living environment.In addition to goal priming strategies, recent attempts to facilitate dieting success have also included strategies to reduce the potential of palatable, high-fat food items to activate the hedonic eating goal in the first place. From the perspective of grounded cognition , 56, hedThe studies reviewed here show that the exposure to attractive food cues can trigger a hedonic eating goal in chronic dieters and lead to the inhibition of the weight control goal, facilitating self-regulatory failures. However, chronic dieters can benefit from mechanisms that activate the weight control goal in critical situations, such as diet goal primes provided by the environment or by individual plans, leading to healthier behavior. Thus, the goal priming perspective on chronic dieting provides a useful framework to understand dieting failures, as well as insights into how to use goal priming methods to facilitate more successful self-regulation with regard to eating behavior, which is highly relevant given our food-rich living environment and the current “obesity epidemic” .These findings can inform the development of strategies to facilitate chronic dieters’ health efforts , or by devising personalized diet reminders for strategic places , to influence one’s behavior when one is about to indulge in high-fat snacks . Keepin


Considering that single locations of structural and functional abnormalities are insufficient to explain the diverse psychopathology of schizophrenia, new models have postulated that the impairments associated with the disease arise from a failure to integrate the activity of local and distributed neural circuits: the “abnormal neural connectivity hypothesis.” In the last years, new evidence coming from neuroimaging have supported and expanded this theory. However, despite the increasing evidence that schizophrenia is a disorder of neural connectivity, so far there are no treatments that have shown to produce a significant change in brain connectivity, or that have been specifically designed to alleviate this problem. Brain-Computer Interfaces based on real-time functional Magnetic Resonance Imaging (fMRI-BCI) are novel techniques that have allowed subjects to achieve self-regulation of circumscribed brain regions. In recent studies, experiments with this technology have resulted in new findings suggesting that this methodology could be used to train subjects to enhance brain connectivity, and therefore could potentially be used as a therapeutic tool in mental disorders including schizophrenia. The present article summarizes the findings coming from hemodynamics-based neuroimaging that support the abnormal connectivity hypothesis in schizophrenia, and discusses a new approach that could address this problem. Schizophrenia is a debilitating and often devastating brain disorder, characterized by a heterogeneous presentation of psychological and behavioral dysfunctions. It is now clear that among the classical description of its symptomatology , schizophrenia is characterized by dysfunctions in multiple cognitive domains, which highly correlate with the general functioning of the patient.In the last decades, and thanks to the development of techniques like neuroimaging, the neural bases of these dysfunctions have started to be elucidated. A number of cognitive impairments in schizophrenia have been specifically linked to disturbances of certain brain areas. For instance, working memory (WM) impairments have been linked to dorsolateral prefrontal cortex (DLPFC) disturbances  could address this problem.Hemodynamic-based brain neuroimaging methods  are non-invasive techniques with a spatial resolution that allows more precise understanding of the localized neural substrates than conventional methods based on electrophysiology. Using these techniques, different statistical methods have been developed for the study of connectivity. A useful distinction can be made between methods that measure “functional connectivity” and methods that measure “effective connectivity.” Functional connectivity refers to methodologies that consider only correlations of brain signals across time Friston, . This apCurrently, a substantial number of PET and fMRI studies have reported a disturbed connectivity in schizophrenia in a wide range of cognitive tasks. In the following lines we will summarize the evidence coming from studies exploring three main cognitive realms altered in schizophrenia: language (semantic processing), WM, and emotional processing.Language (semantic) abnormalities have been noted in schizophrenia since early conceptualizations of the disease. Functional imaging studies and also volumetric analysis of gray matter have reported alterations in several language-related areas such as inferior frontal gyrus (IFG), superior temporal gyrus (STG), and inferior parietal lobule. Even before neuroimaging methodologies were available to explore brain connectivity, it was hypothesized that abnormal language (and thought) could be due to an abnormal connectivity of language-related brain areas.In an early study on brain connectivity with a small sample of schizophrenia patients, Spence et al.  tested tIn a subsequent study, Lawrie et al.  used a hJeong et al.  specificper se or to the chronic use of medication. However, at least two studies have used a different experimental group. Boksman et al.  in a task that involved reappraisal of negative stimuli, subjects prone to psychosis did not show the coupling between amygdala and prefrontal areas that healthy subjects displayed toward negative visual stimuli, a factor that might underlay a reduced cognitive control of emotions and vulnerability to psychosis .Apart from the study of task-related brain regions during task performance, recent studies of brain connectivity have focused on the “resting state” of the brain. This methodology has not only generated much interest in the neurophysiological basis of the resting state brain activity, but also has practical advantages as it does not require an explicit task design , or even the particular efficacy of Clozapine (Barr et al., Despite the progress in understanding the neural substrates of schizophrenia, current treatments mainly based on antipsychotics do not incorporate existing know-how in etiology and pathogenesis of the disease, i.e., the abnormal connectivity phenomenon. In fact, to date there are no treatment methods that can produce a direct and significant change in brain connectivity, or are specifically designed to tackle this problem.We would like to propose a novel technique, namely BCIs based on real-time fMRI, to study and potentially alleviate mental disorders such as schizophrenia, by training patients to self-regulate single brain regions as well as modulate brain network connectivity.Brain-Computer Interfaces are novel techniques that utilize neurophysiological brain signals to activate or deactivate external devices or computers (Birbaumer and Cohen, Studies have shown that brain self-regulation with fMRI-BCI can lead to behavioral modifications. Could this change also produce changes in the connections of the brain networks? In order to develop this idea, and to further illustrate the application of fMRI-BCI, we will describe a few experiments conducted in our laboratory.Exploring the use of this technique on brain areas of emotion, our group investigated whether healthy subjects can voluntarily gain control over anterior insular using fMRI-BCI (Caria et al., But, can learned insula self-regulation produce a measurable behavioral modification? In a subsequent study, we explored the relationship between brain self-regulation and emotional behavior (Caria et al., To confirm that learned self-regulation of insula could only be achieved by feedback of the BOLD signal of the ROI and not due to generalized brain activations, the feedback magnitude was computed by subtracting the BOLD signal of a reference slice (Caria et al., These results demonstrate that fMRI-BCI manipulation of paralimbic regions such as insula is possible, and that self-regulation leads to modulations of the emotional response. Furthermore, these studies show that fMRI-BCI provides a novel approach in neuroscience for studying brain reorganization, in which the manipulation of the brain activity can be used as an independent variable that allows the study of subsequent behavioral modifications.In a subsequent analysis of the previous data, we explored whether learned self-regulated was associated with changes in brain network connectivity (Lee et al., The potential use of fMRI-BCI to modulate brain networks connectivity has also been confirmed in two recent studies in healthy populations. Hamilton et al.  tested wParticularly in schizophrenia, fMRI-BCI could offer a new method to directly correct brain dysfunctions that accounts for the stable and intractable symptoms and cognitive deficits of the disorder.We attempted for the first time to apply fMRI-BCI on schizophrenic patients (Ruiz et al., These results demonstrated that with sufficient training, schizophrenia patients are able to learn volitional regulation of the insula cortex by fMRI-BCI. Particularly for schizophrenia, it has not been previously shown that patients would be able to self-induce neural activation modifications, leading to behavioral effects. Here we could demonstrate for the first time a completely novel approach in psychiatric disorders, involving functional brain changes due to self-regulation of cerebral activation patterns. Learned self-regulation led to changes in the perception of emotional faces, a major dysfunction in schizophrenia, showing that behavioral modulation by this new technique in schizophrenia is possible. Finally, the enhancement of the connections in brain emotional network suggests that fMRI-BCI can be used to “re-connect” the schizophrenic abnormal neural connectivity.So far, the few studies using fMRI-BCI that have analyzed brain connectivity suggest that reorganization or the functional connection in the brain is possible. However, at the neural level, enhancements of brain connections have been achieved as a positive by-product of single ROI self-regulation training, and not by a “direct” training of the brain connectivity. Progress in real-time fMRI methodology now enables the direct feedback of the connections between brain areas, creating exciting possibilities for the direct modulation of brain networks by self-regulation.In a recent study, we attempted to use fMRI-BCI to “directly” enhance neural connectivity in a group of young healthy subjects (Ruiz et al., The equation to compute the magnitude of feedback was:Preliminary results suggested that participants were able to learn self-regulation of the connectivity between IFG and STG Figures  and 8. SGrowing evidence has shown that an abnormal connectivity of different brain areas is central to schizophrenia. Considering that no therapeutic approach has been designed to alleviate this problem, fMRI-BCI offers a novel and promising possibility to enhance brain connectivity, without adverse effects. Schizophrenia patients are able to learn self-regulation of single brain areas using this technology, leading to behavioral modifications and brain network modulation. Furthermore, the possibility to train patients to directly enhance brain connectivity offers new and exciting possibilities for brain network remodeling.As fMRI-BCI is an emerging methodology, there are still unanswered questions regarding technical aspects and clinical applications. As an example, although much is known regarding how BOLD changes are associated with underlying neural activity, the fact that both neural excitatory and inhibitory responses lead to increase in BOLD (Logothetis, automatically” or “unconsciously.” In that sense, future research must improve our understanding regarding the processes by which subjects achieve brain self-regulation with fMRI-BCI, including the degree to which explicit or implicit mechanisms are used.Furthermore, although fMRI-BCI training purportedly implies learning through operant conditioning, little is known of the deeper mechanism of learning using this methodology. As an example, Ruiz et al. , schizopRegarding clinical applications, important questions need to be addressed before the use of this methodology as a therapeutic tool becomes a reality. In fact, very few studies have explored whether brain self-regulation persists if feedback is removed, with dissimilar results (Sitaram et al., Despite these current limitations, we believe that the presented results open the door for future applications of fMRI-BCI as a research tool and therapeutic approach against brain diseases. In addition, it can also serve as a way for stimulating self-efficacy in patients and offers the possibility to remodel once own brain.Recent progress in real-time pattern classification and feedback of fMRI signals (LaConte et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Regulatory agencies have enforced allergen labelling rules for food ingredients on pre-packed food. HACCP procedures driven on by food manufacturers reveals that possible cross-contaminations of their products cannot be absolutely discarded or checked. As a result and because allergen absence cannot be accurately warranted in most food industry, numerous warning mentions on pre-packed foods appeared to inform allergic consumers of potential cross contaminations even if levels are very low. For Allergic consumers, accessibility to food is clearly restricted.In a practical view, the Unit of Allergology in Angers Hospital (France) has developed an oral reintroduction protocol of low doses of allergens to evaluate the sensitivity of allergic patients. It appeared that most of the patients tolerate low amount (few mg) of allergen and would support the consumption of product contaminated by traces of allergen.Based on these facts, the French competitiveness cluster "Pôle Enfant" gathered four food manufacturers , ATLANGENE®-SILLIKER specialized in food analysis, ten university hospitals and hospitals, 3 academic laboratories , and an association of French allergic consumers (AFPRAL) to construct the "MANOE project". This project funded by the regional council of Pays de la Loire aims to develop food products designed for the general population which would be tolerated by children allergic to peanut, egg, milk or wheat. In a large multicentric clinical trial, 400 allergic children will be submitted to the standardized reintroduction protocol. The acceptance and the usefulness of these new products by allergic children and their parents will be evaluated.In the context where thresholds values for allergen labelling rules are in discussion all around the world, this integrated project will provide a practical insight on how food companies will deal with thresholds, if the analytical methods are good enough to guaranty these levels, and how the patient will use this new information.


The dorsal attentional network is known for its role in directing top-down visual attention toward task-relevant stimuli. This goal-directed nature of the dorsal network makes it a suitable candidate for processing and extracting predictive information from the visual environment. In this review we briefly summarize some of the findings that delineate the neural substrates that contribute to predictive learning at both levels within the dorsal attentional system: including the frontal eye field (FEF) and posterior parietal cortex (PPC). We also discuss the similarities and differences between these two regions when it comes to learning predictive information. The current findings from the literature suggest that the FEFs may be more involved in top-down spatial attention, whereas the parietal cortex is involved in processing task-relevant attentional influences driven by stimulus salience, both contribute to the processing of predictive cues at different time points. Regularities in the visual environment are predictive of future events. Learning of such regularities may therefore help the visual system generate anticipatory activities  and reduce computational burden. Take traffic lights, for example; there is a serial order for which signals light up , as well as the color (feature based) and location  of each light, thus reflecting regularities in several domains of one's daily life. This information can be fully predictive of future events if they are always 100% valid, such as the traffic light. But even with partial predictive power , which we refer to as probabilistic, it remains advantageous to pick up such information, as the knowledge of any regularities can help the visual system reduce its computational load because future events can be anticipated and better managed in advance. This learning of predictive information is especially useful given that our ability to represent multiple objects within a scene at any given moment is rather limited  and the posterior parietal cortex (PPC), where PPC includes the superior parietal lobule (SPL) and intraparietal sulcus (IPS). The dorsal network has been shown to be involved in voluntary top-down orienting of visual attention. This network shows strong activity when a spatial cue is presented, explicitly indicating where participants should direct their attention  PPC has been associated with a variety of functions in visual attention (Behrmann et al., Using brain stimulation, another direct test of such idea was carried out by Chao et al. , with thWithout a salient distractor, is PPC still involved in predictive processing? As mentioned, research has shown that as long as predictability is a relevant aspect of the task, PPC should also play an important role in processing targets and predictive information. For example, a TMS study by Ellison et al.  found thHere it is important to emphasize again the goal-directed nature of the dorsal network when interpreting these results regarding PPC. Specifically, PPC does not respond to all perceptually-salient distrators, but only those that are relevant to the current task set. One important fMRI study by Downar et al.  instructOn the other end of the dorsal attentional network is FEF. As its name implies, much of the work on FEF have been devoted to the oculomotor control of eye movements and visual attention, although studies have begun to document FEF involvement in other domains of cognition such as inhibitory control (e.g., Muggleton et al., More recently, Geng and Behrmann  investigThe neural mechanism behind such spatial probability learning in oculomotor behaviors likely involves FEF, as it tends to produce pretarget-related neural activity during saccade selection and saccade preparation, respectively (Schall et al., If FEF and PPC both process predictive and probabilistic cues in the environment, how do they differ from each other in terms of timing and function? Several neuroimaging and stimulation studies that compares FEF and PPC involvement using the same paradigm may provide some clues to this question. First, in a non-predictive visual search array, Kalla et al.  applied In this paper we have briefly reviewed how predictive information in the environment can powerfully modulate human visual attention and oculomotor control. Importantly, neurophysiological studies suggest that such learning requires a dynamic interplay between regions within the dorsal attentional network, which includes PPC and FEF. Specifically, FEF is responsive to predictive information via its top-down early preparatory neural activity buildup that biases the processes of target selection and saccade preparation; whereas PPC responds to salient bottom-up stimuli that carry predictive information, even if they are not targets, if such information matches one's current behavioral goal. Much of the work until now has emphasized the individual contributions of these regions to mediate probability learning. Future studies that disentangle the timing, roles, functional connectivities, and interactions between these regions will provide exciting new insights into how the visual system strategically adapts to the environment.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Axons form many presynaptic terminals, which are dynamic structures sharing presynaptic material along the axonal shaft. We discuss how internal  and external factors  may affect the formation and plasticity of inhibitory synapses.Synaptic connections in our brains change continuously and throughout our lifetime. Despite ongoing synaptic changes, a healthy balance between excitation and inhibition is maintained by various forms of homeostatic and activity-dependent adaptations, ensuring stable functioning of neuronal networks. In this review we summarize experimental evidence for activity-dependent changes occurring in inhibitory axons, in cultures as well as  Our brain is a complex organ with tremendous self-organizing abilities. Its computational power is based in the adjustable synaptic connections between neurons. When new experiences and memories are established, specific synapses in specific brain regions are changed, both in strength and in number. To ensure proper global functioning despite changes in local connectivity, these synaptic changes must be coordinated within neurons, as well as within neuronal circuits. An important aspect is the coordination between changes in excitatory and inhibitory synapses to regulate and maintain an overall balance between excitation and inhibition. When this balance is disturbed, neurological diseases such as autism or schizophrenia can develop .Homeostatic plasticity is a term that is used for plasticity mechanisms which ensure that overall neuronal spiking activity is maintained within neuronal networks. Many forms of homeostatic plasticity have been described in excitatory and inhibitory neurons . In neurin vitro  and in vivo studies.When prolonged changes occur in network activity, homeostatic mechanisms come into play which adjust excitatory and inhibitory synapses to compensate and restore the activity level in the network . GeneralActivity manipulations in cultures of dissociated hippocampal or neocortical neurons generally affect excitatory and inhibitory synapses in opposite directions. After a prolonged period of activity blockade, excitatory synapses get strengthened and inhibitory synapses are weakened, and synaptic changes are in opposite directions when activity is enhanced . Therefoin vitro homeostatic rules for scaling inhibitory synapses get complicated in more complex networks. In addition, other factors such as different cell (glia) types or the extracellular environment in more intact tissue potentially influence homeostatic plasticity compared to dissociated cultured cells.In contrast to dissociated cultures neurons in more intact tissue, such as acute slices or organotypic cultures, make more specific connections and form structured networks. This network configuration makes the interpretation of synaptic changes more complex. In slices that were submitted to activity manipulations, changes in inhibition have been observed opposite to  as well in vivo, sensory deprivation is used as experimental paradigm to lower activity levels in the primary sensory cortex . While in vitro activity manipulations by pharmacological means affect the activity of all neurons in equal amounts, sensory deprivation in vivo will affect different neurons in the circuitry differentially. Therefore, in vivo responses of inhibitory synapses to changes in activity vary widely and strongly depend on the specific cell types, cortical layer, and specific circuitry  along its shaft and contacts many different postsynaptic neurons. Presynaptic boutons along an axon show a large variety in their volumes, in the number of synaptic vesicles and in the presence or absence of mitochondria . It is nThe exchange of presynaptic proteins means that the exact composition of presynaptic terminals is continuously changing. These changes can occur in a correlated fashion with the postsynaptic site in some synapses, but can be uncoordinated in others . ReleaseSynaptic vesicles are kept at the presynaptic terminal by interacting with a scaffolding meshwork of actin, β-catenin, synapsin, and many other proteins . SynaptiLive imaging of axons have shown that transient and mobile release sites exist  and thatSynapse assembly is a complicated process involving interactions of multiple proteins. It does not necessarily need to be a linear process, where one component necessarily recruits the next, but some of the interactions could occur in parallel and the sequence of protein recruitment may vary. Rapid self-assembly of presynaptic components may be an important element during synaptogenesis. This would mean that the formation of a presynaptic terminal merely needs an initial trigger to ascertain a specific axonal location or postsynaptic partner, but then the new presynaptic terminal ``unfolds'' automatically by spontaneous clustering of its components. It is likely that multiple triggers can induce self-assembly. Indeed, it was recently reported that synaptic material is actively prevented from aggregating and assembling new synapses during transport , supportFigure 1). For instance, enhancement of synaptic strength by increasing vesicle capture or anchoring at presynaptic terminals would also result in lower amounts of ``free'' vesicles in the axonal shaft thereby reducing the chance that new synapses are formed at nascent sites . This illustrates that presynaptic plasticity and synapse formation should be considered mutually dependent processes when neighboring presynaptic terminals are sharing synaptic proteins and vesicles.A dynamic control of the strength and number of presynaptic terminals in axons implies that control of transport, capture, and release of synaptic material are essential processes regulating the formation, maintenance, and strength of presynaptic terminals. In a dynamic axon with competing presynaptic terminals, a general change in synaptic strength is expected to also have an effect on ongoing synapse formation within the same axon and vice versa  and we summarize current knowledge of cell adhesion molecules that are specific for inhibitory synapses.Cell adhesion molecules are transmembrane proteins, which play a role in recognition of synaptic partners during the initial contact and provide specificity of synaptic connections . In addiFigure 2A). Indeed, for a number of cell adhesion molecules, activity-dependent changes in expression level have been observed .To have their effect specifically at synapses, cell adhesion molecules should be enriched at synaptic membranes. There is experimental evidence that the distribution of cell adhesion molecules over the cellular surface can be regulated . For instivation . FurtherFigure 2C).Synaptic adhesion molecules execute their function by binding to a trans-synaptic partner at their extracellular domain. In some cases, the extracellular domain can be cleaved, with strong effects on local synaptic adhesion. For instance, activity-dependent cleavage of agrin was shown to mediate the formation of dendritic filopodia  and cleaFigure 2D).For some cell adhesion molecules activity can regulate the binding properties of the proteins. For instance, interactions between cadherins are affected by extracellular calcium concentrations  and inteUpon binding to other cell adhesion molecules, cell adhesion molecules cluster at the cell membrane and signal through interactions with many intracellular proteins, whose levels may be regulated in an activity-dependent manner. Ultimately, signaling through synaptic adhesion molecules in the presynaptic terminal result in direct or indirect alterations of the actin cytoskeleton and vesicle recycling, affecting the number, function, and/or stability of synapses . It willThe list of known synaptic adhesion molecules is rapidly growing, but our knowledge on the precise function of most of these proteins remains incomplete. Interestingly, several synaptic cell-adhesion molecules have been reported to be specifically involved in inhibitory, and not excitatory, synapses. These include sema4D , slitrk3Postsynaptic neuroligins and their presynaptic partners neurexins are transmembrane cell adhesion molecules that have been established as important synaptic regulators . When exLeucine-rich repeat (LRR) proteins have received considerable research attention recently. The members of the subfamily of Slitrk (Slit and Trk-like) proteins are involved in synapse formation and has been linked to several neurological disorders . Slitrk3Members of the closely related subfamily of leucine-rich transmembrane proteins (LRRTMs) have also been implicated in excitatory synapse formation and plasticity , but so in vitro model for epilepsy (Semaphorins are well-known as (repulsive) axon guidance molecules acting through rearrangements of the cytoskeleton in the growth cone. They play an important role in the early development of the brain . Some seepilepsy . The effepilepsy . It was epilepsy , but theepilepsy . It was epilepsy .There are many other cell adhesion molecule proteins and with continued research on inhibitory synapses, it is expected that more of them will be found to play a role at inhibitory synapses. Here we just mention a few that have been reported at inhibitory synapses.ephrin family, ephrinA5 and EphA3, can affect inhibitory synapses and they require NCAM for their action  in an experience-dependent manner and developmental downregulation of NCAM-PSA was shown to coordinate maturation of perisomatic inhibitory synapses in the visual cortex  has been reported to be important for the maturation of perisomatic inhibitory synapses in the cortex . NCAM acr action . In vivol cortex .Several components of the dystrophin-associated glycoprotein complex (DGC), such as dystroglycan, dystrophin, and dystrobrevin, are also specifically located at a subset of inhibitory synapses , but theIntegrins are receptors for extracellular matrix proteins, soluble factors, and counter-receptors on adjacent cells and they have an intracellular link to actin filaments via adaptor proteins . IntegriFinally, the cell adhesion molecule neurofascin has been shown to regulate the formation of a specific subset of inhibitory synapses on the axon initial segment of principal neurons .Above we have described how cell adhesion molecules may provide signals to inhibitory axons from direct cell–cell contacts. However, inhibitory synapses may also be affected by signals from more distal origin. Nearby dendrites or surrounding cells can secrete trophic (or anti-trophic) factors, which may affect inhibitory synapse function and/or formation. Indeed, retrograde signals from the postsynaptic dendrite, such as endocannabinoids, nitric oxide (NO) or brain-derived neurotrophic factor (BDNF), or glutamate spillover from nearby excitatory synapses are known to regulate synaptic release at inhibitory synapses during many forms of short-term and long-term plasticity . Here weBrain-derived neurotrophic factor (BDNF) is a secreted neurotrophin that has been shown in many different preparations to promote the formation and maturation of inhibitory synapses by presynaptic modifications . Only exA receptors  in neuregulin1 have been linked to schizophrenia . The maieceptors . This suFibroblast growth factors (FGFs) are secreted signaling glycoproteins, which exert their effect by binding to FGF receptor tyrosine kinases (FGFR). In the brain, FGF signaling is important for several developmental processes, including patterning of different brain structures and neurogenesis . In addiStudies with neuronal and astrocyte co-cultures and astrocyte-conditioned medium have shown that astrocyte-released factors are crucial for synapse formation and plasticity . For insA and GABAB receptors have been implicated in mediating this regulation . In this review we have painted a picture of the inhibitory axon as a dynamic structure that can quickly adjust to a changing environment, by responding to local signals from postsynaptic cells via adhesion molecules and to global signals from the local neuronal network. A highly dynamic inhibitory system might serve to quickly respond to changes to allow circuit rearrangements by excitatory connections. For a healthy brain changes at inhibitory and excitatory synapses need to be well-coordinated at all times as subtle defects in this coordination can cause defects in circuitry and may underlie psychiatric disorders. This means that the interplay between plasticity of excitatory and inhibitory synapses is an important factor for the stability of neuronal circuits. The precise response of the inhibitory axon will be determined by the combination of internal and external factors, such as the availability of synaptic proteins within the axon, or the combination of the extracellular factors and cell adhesion molecules that are present at the membrane. It will be an important challenge for future research to unravel the precise molecular and cellular mechanisms and to further uncover pathways that affect synapse formation and plasticity of inhibitory synapses.Research on activity-dependent adaptations in inhibitory axons continues to generate novel insight in the cellular processes of synapse formation and plasticity. Many open questions remain to be answered in the future and we listed a few of these in a small scheme (The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Distinct upstream regulators, including growth factors that modulate maturation and integration of newborn neurons have been shown to also recruit the small Rho GTPases. Here we review recent findings and highlight the possibility that small Rho GTPases may act as central assimilators, downstream of critical input onto adult-born hippocampal neurons contributing to their maturation and integration into the existing dentate gyrus (DG) circuitry.Adult neurogenesis, restricted to specific regions in the mammalian brain, represents one of the most interesting forms of plasticity in the mature nervous system. Adult-born hippocampal neurons play important roles in certain forms of learning and memory, and altered hippocampal neurogenesis has been associated with a number of neuropsychiatric diseases such as major depression and epilepsy. Newborn neurons go through distinct developmental steps, from a dividing neurogenic precursor to a synaptically integrated mature neuron. Previous studies have uncovered several molecular signaling pathways involved in distinct steps of this maturational process. In this context, the small Rho GTPases, Cdc42, Rac1, and RhoA have recently been shown to regulate the morphological and synaptic maturation of adult-born dentate granule cells  Throughout lifespan new neurons are continuously born in the mammalian hippocampus. It is now widely accepted that the process of adult neurogenesis is not merely a remnant of embryonic development, but a highly responsive and regulated process that appears to be critically involved in hippocampus-dependent behavior in health and disease  maybe recruiting Rho GTPases for mediating their effects on neuronal maturation in adulthood. We begin by describing the maturation process of adult born hippocampal neurons and give a broad overview of neuronal Rho GTPase signaling, followed by a discussion of evidence showing how important regulators of neuronal maturation may be modulating small Rho GTPases as downstream effectors. We conclude with hypotheses on mechanisms for signal convergence and a brief discussion of how Rho GTPases may act to assimilate multiple upstream signals to decisively influence cell cytoskeleton and neuronal cytoarchitecture. For a more detailed discussion on Rho GTPase signaling in neurons, please refer to other reviews , neurotransmitters such as GABA and glutamate, and signaling molecules like Disrupted-in-Schizophrenia 1 (DISC1) Figure . These rRho GTPases are part of the larger Ras superfamily of monomeric GTPases. These small GTPases are thought to act as binary molecular switches, transducing upstream signals to downstream effectors by alternating between the “active” GTP-bound and the “inactive” GDP-bound state , Rac1 (ras-related C3 botulinum toxin substrate 1) and RhoA (ras homolog family member A) are the best-studied members of the small Rho GTPase family, especially in the neuronal context. Despite early indications of important roles of the Rho GTPases in neuronal maturation in vivo, Keung et al. found an inverse relationship between RhoA activity and the percentage of cells differentiating into neurons  and dominant negative  forms of RhoA in adult hippocampal neurons Taken together, these findings hint at stage-specific roles of the Rho GTPases in adult hippocampal neurogenesis. This may be due to differential recruitment of the Rho GTPases by upstream factors during different stages of neuronal maturation. We next discuss how upstream signaling molecules may recruit Cdc42, Rac1, and RhoA, for mediating their effects on maturation and integration of newborn neurons in the adult hippocampus.BDNF is among the most well studied neurotrophins and has been shown to have a specific role in maturation and integration of newborn neurons in the adult hippocampus , which translocates to the nucleus where it interacts with RBP-J to activate transcription of several genes. Notch signaling has been extensively explored during development and shown to be critical for neuronal cell-fate choice and neurite development during embryonic neurogenesis  and Cyclin-dependent kinase 5 (Cdk5) were found to regulate the maturation of adult born neurons  is Cdk5 dependent. This phosphorylation of TrkB at S478 regulates its interaction with Rac1-GEF TIAM1, and downstream Rac1 activation , we hypothesize that there must be mechanisms that allow for the convergence of multiple pathways leading to a single decision resulting in either neurite extension, stabilization, or collapse at a given time.Research over the last two decades has given us a large amount of information regarding the molecular mediators downstream of diverse cellular inputs. We now understand how an upstream activator may have diverse effects on cellular behavior by recruiting multiple signaling cascades. In the context of maturation and integration of adult-born neurons, cellular behaviors such as neurite and spine growth are readouts, used as indicators of the state in which the cell is, as well as key endpoints with functional relevance. Neurite outgrowth and spine morphogenesis, at their core, are regulated by subcellular events leading to the stabilization, extension, or collapse of local cytoskeletal elements. Therefore, despite simultaneous activation of multiple signaling pathways, decisions of actual neurite growth or retraction are consequences of single subcellular events via modulation of local microtubules or actin filaments. Studies exploring different signaling pathways have revealed how the bifurcation or divergence of signals via diverse signaling cascades enables different cellular responses to the same input, but it remains unclear how convergence of pathways might be taking place. One possible mechanism for signal convergence could be that following the peak of signal divergence some signaling cascades “funnel-in” by having fewer and fewer downstream targets until they directly influence cell neurite growth. For example, pathways such as mitogen-activated protein (MAP) kinase and CREB are common targets of many upstream regulators and have been hypothesized to act as signal integrators for certain cellular processes  threshold for upstream signaling. Further, regulating the concentration and regional availability of Rho GTPases may additionally enable localized assimilation of upstream signal. Sufficient input regulating the Rho GTPases' activity may come from multiple upstream pathways, where the Rho GTPases may be facilitating detection of coincident upstream input. Whether or not this is actually the case in maturation of newborn neurons remains to be resolved.in vitro and in vivo. While these approaches have generated valuable information about the basic roles of the Rho GTPases, their dispensability (knockout or dominant-negative constructs), and/or maximum functional capacity (overexpression or constitutively active constructs), we may have missed the nuanced roles of these signaling pathways of these signaling pathways under physiological conditions in neurons. Understanding whether such convergence indeed plays a role in signal transduction leading to decisive cellular events would minimally require experiments investigating activation of endogenous small GTPases, in real time, in vivo. This would provide us with significant insights into the physiological roles of these molecules and the decisive influence of regulatory pathways in mediating specific cellular behavior in the context of adult hippocampal neurogenesis.Clearly, the small Rho GTPases Cdc42, Rac1, and RhoA have functional ties with intrinsic regulators of neuronal maturation. Given their switch-like nature and a large repertoire of GEFs and GAPs regulating their state, it is likely that they are among the “decision-making” moieties via which diverse upstream regulators maybe decisively influencing neuronal architecture in the adult brain. So far, a majority of studies exploring the role of signaling molecules on neuronal function have utilized knockdown or overexpression models, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Pancreatic cancer is highly chemoresistant. A major contributing factor is the characteristic extensive stromal or fibrotic reaction, which comprises up to 90% of the tumor volume. Over the last decade there has been intensive research into the role of the pro-fibrogenic pancreatic stellate cells (PSCs) and their interaction with pancreatic cancer cells. As a result of the significant alterations in the tumor microenvironment following activation of PSCs, tumor progression, and chemoresistance is enhanced. This review will discuss how PSCs contribute to chemoresistance in pancreatic cancer. Pancreatic cancer is a highly aggressive malignancy with a notoriously dismal prognosis. Contributing to ~227,000 annual deaths worldwide, this insidious disease is the fourth leading cause of cancer-related death in developed countries  deposition, which compresses and distorts intratumoural vasculature, causing hypoxia  and losing the anti-fibrogenic lipid droplets  suppressing HIt is important to note that in addition to the impact which stellate cells have on pancreatic cancer chemoresistance, it is now well established that the immune cells also impact on tumor progression and chemoresistance , a well-established marker for cells under hypoxic stress  in patients with stage IV previously untreated pancreatic cancer was presented by Hingorani et al. . The stuA Phase 3 trial is currently testing gemcitabine in combination with TH-302 in patients with locally advanced unresectable or metastatic pancreatic adenocarcinoma. As outlined above, pancreatic cancer is highly hypoxic and TH-302 is a chemotherapeutic agent which is selectively activated in a hypoxic tumor microenvironment  has generated great interest as a novel therapeutic for pancreatic cancer. A recent phase III MPACT  trial demonstrated that the addition of Nab-paclitaxel with gemcitabine was able to significantly improve the median survival of metastatic pancreatic cancer patients (8.5 months) when compared to gemcitabine treated only arm (6.7 months) and reduce toxicities (neuropathy and neutropenia) commonly associated with the cremaphor formulation used to dissolve paclitaxel thereby, allowing for a higher paclitaxel dose to be delivered to the patient (Von Hoff et al., Finally, Nab-paclitaxel or AbraxaneAs outlined above, a significant body of work corroborates the notion that CA-hPSCs are not relegated to a bystander role in PDAC chemoresistance, but instead, they are critical in driving it via both direct and indirect mechanisms. This occurs by way of PSC generated fibrosis creating a hypoxic microenvironment that directly fuels the chemoresistance of cancer cells. Concurrently, fibrosis impairs effective drug perfusion to cancer cells, which indirectly augments chemoresistance. Furthermore, there is mounting evidence that not only is stromal depletion therapeutically possible in mice with pancreatic tumors, but it also facilitates the delivery of chemotherapeutics to pancreatic tumors. Notably, stromal depletion entails a reversion of fibrosis as well as a decline in the number of cells generating fibrosis because reducing the number of activated PSCs in turn would diminish collagen production. Thus, in light of their major contribution to fibrosis in pancreatic cancer as well as their highly proliferative capacity, cancer-associated PSCs are ideal candidates for the identification of stromal-related therapeutic targets that may act as additional targets for potentiating existing chemotherapeutics Figure .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


PLOS Medicine:This Perspective discusses the following new study published in doi:10.1371/journal.pmed.1001561Grundy Q, Bero L, Malone R (2013) Interactions between non-physician clinicians and industry: A systematic review. PLoS Med (10)11: e1001561. In a systematic review of studies of interactions between non-physician clinicians and industry, Quinn Grundy and colleagues found that many of the issues identified for physicians' industry interactions exist for non-physician clinicians.Promotion of medical products by manufacturers to physicians in the US has been widespread for over a century With greater regulatory attention to traditional promotional practices, “non-traditional” forms of promotion remain an option for pharmaceutical and medical device companies. Non-traditional promotion can include scientific pursuits or other business relationships that might appear to be outside the realm of promotion but that are conducted for a marketing purpose, such as seeding trials or funding of patient advocacy organizations PLOS Medicine, provide a systematic review of literature addressing the nature of non-physician providers' interactions with the medical products industry Grundy and colleagues, in this week's issue of The pervasive contact between non-physician providers and the medical products industry recalls a survey by Campbell and colleagues in 2004 that found 94% of physicians reporting recent interactions with pharmaceutical industry sales representatives Current programs intended to provide some transparency about the prevalence of pharmaceutical industry marketing may not reach the non-physician provider population; most notably, the Open Payments program only gathers data on payments provided to physicians, not nurses, pharmacists, or other non-physician providers. Though this legislation could be revised to cover all providers of health care who are currently omitted from this federal mandate, we believe it is unlikely that Congress would be interested in revisiting the wording of this statute in the near future. Better regulation should be taken up at the local level, where institutional policies should be constructed to apply to all providers of patient care. For example, Partners HealthCare, the enterprise that manages our academic medical center, has implemented an industry interaction policy that applies to all employees In addition to the pervasiveness of industry interactions among non-physician providers, Grundy and colleagues also highlight parallels in how physicians and non-physician providers regard these interactions. For example, the review revealed that non-physician providers were confident that they themselves were immune to marketing influences and that they were able to detect biases while their own colleagues were less able to do so. This cognitive dissonance mirrors similar results found in physicians and physician trainees Substantial progress has been made in recent years in raising awareness among physicians about the conflicts of interest that can arise in health care delivery and the effect of marketing on medical practices. It is time to shine a similar light on non-traditional forms of promotion, including marketing to non-physician providers.


Women are approximately twice as likely as men to develop posttraumatic stress disorder (PTSD) after trauma exposure. Mechanisms underlying this difference are not well understood. Although sleep is recognized to have a critical role in PTSD and physical and psychological health more generally, research into the role of sleep in PTSD sex differences has been only recent. In this article, we review both animal and human studies relevant to sex differences in sleep and PTSD with an emphasis on the roles of sex hormones. Sleep impairment including insomnia, trauma-related nightmares, and rapid-eye-movement (REM) sleep fragmentation has been observed in individuals with chronic and developing PTSD, suggesting that sleep impairment is a characteristic of PTSD and a risk factor for its development. Preliminary findings suggested sex specific patterns of sleep alterations in developing and established PTSD. Sleep maintenance impairment in the aftermath of trauma was observed in women who subsequently developed PTSD, and greater REM sleep fragmentation soon after trauma was associated with developing PTSD in both sexes. In chronic PTSD, reduced deep sleep has been found only in men, and impaired sleep initiation and maintenance with PTSD have been found in both sexes. A limited number of studies with small samples have shown that sex hormones and their fluctuations over the menstrual cycle influenced sleep as well as fear extinction, a process hypothesized to be critical to the pathogenesis of PTSD. To further elucidate the possible relationship between the sex specific patterns of PTSD-related sleep alterations and the sexually dimorphic risk for PTSD, future studies with larger samples should comprehensively examine effects of sex hormones and the menstrual cycle on sleep responses to trauma and the risk/resilience for PTSD utilizing various methodologies including fear conditioning and extinction paradigms and animal models. Posttraumatic stress disorder (PTSD) is a psychiatric condition that develops in some individuals after experiencing events involving threat of injury, physical integrity, or death. ApproxiWomen have a higher lifetime prevalence of PTSD (10% in women vs. 5% in men) as well as a greater risk of developing PTSD following trauma exposure (13-20% vs. 6-8%), even though men have a higher risk for exposure to traumatic events (51% vs. 61%) revealedVarious psychosocial and biological factors have been hypothesized to contribute to the sex differences in the risk for PTSD  are mixed, with some studies not finding differences between individuals with and without PTSD and the other studies documenting PTSD-related sleep impairments. OverestIn the past decade, quantitative electroencephalography analysis (qEEG) has begun to be utilized in the field of sleep research, and a limited number of qEEG studies have been conducted in PTSD. In a lab-based PSG study, Woodward and colleagues found reA role for REM sleep alteration is suggested by animal models of PTSD sleep disturbance that utilize fear conditioning. Male mice and rats exhibited reduced REM sleep and total sleep time (TST) during light phases  immediately following the footshock training-50. In aIn summary, subjective reports of insomnia and trauma-related nightmares are common among people with PTSD. These sleep disturbances were also reported immediately before and after trauma exposure by people who developed PTSD, suggesting sleep disturbances increase the vulnerability for PTSD. However, it is also possible that these associations are a consequence of common risk factors. Although PSG studies inconsistently documented disturbances in sleep initiation and maintenance and sleep depth in PTSD, disrupted REM sleep has more consistently been reported. REM sleep fragmentation was found in individuals with chronic PTSD as well as recently traumatized people who subsequently developed PTSD. Analogous alterations of REM sleep were observed in rats and mice following exposure to footshocks and re-exposure to cues previously paired with footshocks. Strain comparisons revealed genetic influence on susceptibility to REM sleep disturbances following exposure to footshocks and stress cues. These findings of animal and human studies suggest that REM sleep disruption is not only a characteristic of established PTSD, but also a contributor to the development of PTSD.Given the role of sleep in PTSD, it is possible that sex differences in sleep contribute to the increased prevalence in women. In the general population, women across the adult age span are more likely than men to report having sleep initiation and maintenance problems, as well as nightmares-59. HoweSex hormones and their fluctuations throughout the menstrual cycle likely contribute to the paradoxical relationship between sex and subjective/objective sleep. Female sex hormones have sleep-promoting effects when they are exogenously administered. Administration of progesterone to men increased non-REM sleep, and estrogen replacement improved sleep initiation and maintenance in hypogonadal and perimenopausal women. In contNs = 5–18). Preliminary results of those studies include shallower sleep, longer sleep onset latency (SOL), and altered REM sleep mostly during the mid- or late-luteal phase when progesterone is high and estrogen is moderate  or both hormones are decreasing  compared to the mid-follicular phase. The secondary analysis found sex differences in indices of overall sleep maintenance. Women who developed PTSD had longer WASO and less TST compared to men who developed PTSD and women who did not develop PTSD, respectively. Contrary to expectations, better sleep continuity indexed by shorter WASO was found in men who developed PTSD compared to men who did not develop the disorder. As both the PSG studies examining sex differences in established and developing PTSD had a small number of participants, results should be considered preliminary.Only a limited number of studies have directly compared men’s and women’s subjective or objective sleep in PTSD. A study examining subjective sleep in chronic PTSD did not find sex differences (190 women and 177 men) in sleep reported in a sleep questionnaire. As ment(n = 14). This st(n = 14),84. HoweThe aforementioned meta-analysis of PSG studies performed subgroup analyses with studies consisting of only male participants (13 studies). ResultsIn summary, only a few studies with a small number of participants have directly investigated sex differences in PTSD-related sleep alteration. Although fragmented REM sleep in the aftermath of trauma was associated with the development of PTSD in both sexes, the association might be stronger in women. Sleep maintenance impairment soon after trauma might be associated with the development of PTSD in women. Results of studies examining objective sleep of either men or women have revealed differences and similarities in PTSD-related sleep disturbances between sexes. Reduced deep sleep has been found in studies with only men, and impaired sleep initiation and maintenance with PTSD have been found in both studies with only men and only women. The role of sex hormones and the menstrual cycle on the PTSD-related sleep disturbances have not been studied.Research of chronic and developing PTSD has revealed that sleep impairment is a characteristic of PTSD and a risk factor for the development of PTSD, although the associations may also be related to common risk factors. Sex differences in the risk of developing PTSD following trauma exposure have been well documented; however, investigation into roles of sleep in the sex difference has only recently begun. Although recent preliminary evidence points to sex specific patterns of sleep impairment related to chronic and developing PTSD, mechanisms connecting the sex specific patterns and the development and maintenance of PTSD have not been investigated. The effects of sex hormones and the menstrual cycle on sleep and PTSD add complexity to the efforts to elucidate the mechanisms. Investigation of the roles of sex hormones in the development of PTSD and post-trauma sleep in trauma-exposed individuals entails methodological challenges  and has not been conducted. The use of fear-conditioning and extinction paradigms may circumvent some of the methodological challenges and will yield information leading to further understanding of the roles of sex hormones in the development of PTSD. Animal PSG studies showed that exposure to footshock stress reduced REM sleep and the duration of REM segments,51,52. IPTSD: Posttraumatic stress disorder; PSG: Polysomnography; REM: Rapid eye movement; EEG: Electroencephalogram; qEEG: Quantitative electroencephalography analysis; WASO: Wake after sleep onset; SOL: Sleep onset latency; SE: Sleep efficiency; TST: Total sleep time; TIB: Time in bed; SWS: Slow wave sleep; N1: Stage 1 sleep; N2: Stage 2 sleep.The authors declare that they have no competing interests.IK reviewed the literature and drafted the manuscript. NC helped to review the literature and draft the manuscript. TAM helped to conceptualize and draft the manuscript. All authors read and approved the final manuscript.


In contrast to humans and most other animals, rhesus macaques strongly prefer risky rewards to safe ones with similar expected value. Why macaques prefer risk while other animals typically avoid it remains puzzling and challenges the idea that monkeys provide a model for human economic behavior. Here we argue that monkeys’ risk-seeking preferences are neither mysterious nor unique. Risk-seeking in macaques is possibly induced by specific elements of the tasks that have been used to measure their risk preferences. The most important of these elements are (1) very small stakes, (2) serially repeated gambles with short delays between trials, and (3) task parameters that are learned through experience, not described verbally. Together, we hypothesize that these features will readily induce risk-seeking in monkeys, humans, and rats. Thus, elements of task design that are often ignored when comparing studies of risk attitudes can easily overwhelm basal risk preferences. More broadly, these results highlight the fundamental importance of understanding the psychological basis of economic decisions in interpreting preference data and corresponding neural measures. In 1996, Kacelnik and Bateson published a comprehensive review of the literature on animal risk preferences . Given a choice between a medium-sized squirt of cherry juice and a risky option that offered a 50% chance a large amount of juice and a 50% chance of a small amount, the monkeys reliably preferred the risky option, even though the expected values of the two options were matched. As the size of the large and small reward diverged, and risk level of the risky option thus increased, monkeys became even more risk-seeking. These monkeys even continued to prefer the risky option in a control experiment where the probability of winning was only 1/3 and the mathematical expected value of the gamble was lower than that of the safe option  decisions have very small stakes, a squirt or two of juice, (2) decisions are repeated hundreds or thousands of times with short delays (a few seconds) between trials, and (3) the reward structure of the task is learned through experience, rather than explained through language. These elements were preserved across studies in several laboratories in large part because they are optimal for neurophysiological recording, and they show up in rhesus macaque studies because monkeys are generally trained to gamble for the purpose of neuronal recording studies. Although the many studies listed above varied considerably from the original McCoy and Platt experiment, for example, by use of priming stimuli  a standard risky option with a 50/50 chance of a large and small juice reward and 2) an alternating option that provided either the large or small reward; its value alternated between these two reward sizes each time it was chosen , a large number of trials  presented very quickly , and task structures learned through experience (because monkeys have no language). We consider each of these factors here.In humans, risk-aversion is weaker when the reward stakes are small  description rather than through experience. It is assumed that results from these studies have predictive validity to contexts in which gamble parameters are learned through experience. However, studies using repeated gambles in which contingencies must be learned from experience elicit strikingly different preference patterns in humans. Ido Erev and colleagues have shown that when humans rely on feedback instead of descriptions to learn about outcomes, they can become risk-neutral or even risk-seeking in the gains domain  and exploration  decisions. Rhesus macaques are hoped to be a viable model for human economic preferences. Although a cursory examination of human vs. macaque preferences would suggest that they are quite different , here we have argued that similar psychological factors influence both species. Thus, macaque models of decision-making may accurately reflect the many cognitive biases influencing human risk preferences. These results therefore highlight the fundamental importance of identifying and accounting for the psychological processes behind decisions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Ascaphus montanus, and Idaho giant salamanders, Dicamptodon aterrimus). We tested three DNA extraction and five PCR protocols to determine whether we could detect eDNA of these species in filtered water samples from five streams with varying densities of these species in central Idaho, USA. We successfully amplified and sequenced the targeted DNA regions for both species from stream water filter samples. We detected Idaho giant salamanders in all samples and Rocky Mountain tailed frogs in four of five streams and found some indication that these species are more difficult to detect using eDNA in early spring than in early fall. While the sensitivity of this method across taxa remains to be determined, the use of eDNA could revolutionize surveys for rare and invasive stream species. With this study, the utility of eDNA techniques for detecting aquatic vertebrates has been demonstrated across the majority of freshwater systems, setting the stage for an innovative transformation in approaches for aquatic research.Stream ecosystems harbor many secretive and imperiled species, and studies of vertebrates in these systems face the challenges of relatively low detection rates and high costs. Environmental DNA (eDNA) has recently been confirmed as a sensitive and efficient tool for documenting aquatic vertebrates in wetlands and in a large river and canal system. However, it was unclear whether this tool could be used to detect low-density vertebrates in fast-moving streams where shed cells may travel rapidly away from their source. To evaluate the potential utility of eDNA techniques in stream systems, we designed targeted primers to amplify a short, species-specific DNA fragment for two secretive stream amphibian species in the northwestern region of the United States (Rocky Mountain tailed frogs,  Stream species are difficult to inventory due to the complexity of topography and vegetation in streambeds and riparian areas, water turbidity and flow rate, low densities of individuals, cryptic coloration, and the use of microhabitats. Due to these and other factors, surveys for native and exotic species in streams can be expensive and inaccurate Ascaphus montanus, and Idaho giant salamanders, Dicamptodon aterrimus) known to be present at the sites. To achieve this, we designed species-specific primers and tested multiple DNA extraction and PCR protocols designed to amplify low quality DNA templates.Researchers have been using DNA from feces, urine, hair, feathers, shed skin, and eggshells to detect terrestrial vertebrate species for the past decade 3 s−1, in the study stream.In the first phase of the project, we collected one 10-L and two 5-L water samples from a headwater stream  with knob gene (obtained from GenBank) Dicamptodon and 85 base pairs for Ascaphus. This test was designed to amplify previously-published sequences characteristic of these species; no new sequence data was generated that had not already been published. All extractions and PCR set-up were done in a room dedicated to low-quantity DNA sources; no DNA from amphibians had previously been handled in this room.We designed a set of species-specific primers for each species targeting a small region of the mitochondrial DNA (mtDNA) cytochrome In this first phase, we tested two DNA extraction and three PCR protocols for the detection of Rocky Mountain tailed frogs and Idaho giant salamanders using eDNA from these filter samples. First, we removed the filters from the ethanol and air-dried them overnight. We then divided each filter in half and extracted each half with either the DNeasy Tissue and Blood Kit  or the UltraClean® Soil DNA isolation kit . We then attempted to amplify DNA from each sample using a standard PCR protocol  with this multiplex, independently  and together with DNA from the target species, to verify the specificity of our diagnostic test.We sequenced products of the most successful combination of protocols using the BigDye system on a 3130xl capillary sequencer (Applied Biosystems). To streamline the assay for large-scale application, primers were labeled with fluorescent dyes and a PCR multiplex was created using primer sets for both species with PCR Protocol 3. We tested additional negative controls of DNA from sympatric amphibian species  the correct fragment was also detectable at 0.1X DNA concentration for Rocky Mountain tailed frogs and down to 0.001X DNA concentration for Idaho giant salamanders. Tests for inhibition with PCR Protocol 1 showed that samples from the DNeasy extraction method were inhibited (but the extraction negative control was not), while samples from the MoBio extraction were not inhibited, indicating the lack of target species DNA in the results of these extractions. PCR multiplexing with fluorescently-tagged primers provided clear and efficient detection of amplified fragments , with alF1,3 = 0.036, P = 0.86).In the second phase of the project, where samples were collected in the early spring, we detected Idaho giant salamanders in all filter samples using PCR Protocol 3 but did not detect Rocky Mountain tailed frogs. Amplifications for Idaho giant salamanders were weak  make this technique widely applicable to broad-scale inventory and monitoring efforts. The probability of detection of eDNA across densities likely varies with species, stream size, and discharge rate, and by season, as suggested by this study. However, the potential impact of this technique for inventorying species in stream systems is far-reaching, including detection of rare or imperiled vertebrates.We found that only the DNeasy Blood & Tissue kit with the Qiagen Multiplex PCR kit detected eDNA for both species in water filter samples. We did not successfully extract DNA from the filter samples using the UltraClean® Soil DNA isolation kit ; possibly the PowerWater DNA Isolation kit  used to detect eDNA of Asian carp Although we only sampled one stream in the first phase of our project, our results suggest that detection of Rocky Mountain tailed frogs and Idaho giant salamanders using eDNA may be more difficult when samples are taken in early spring rather than early fall. This could be due to decreased metabolism during cold weather or changes in behavior of the target species, such as moving into the hyporheic zone. For Idaho giant salamanders, we were able to compensate for this by modifying protocols, but for Rocky Mountain tailed frogs, detectability was still relatively low in early spring samples. This difference between species may be due to species-specific seasonal changes in density; while streams in the spring are likely to have one fewer Rocky Mountain tailed frog tadpole cohort than in the early fall due to timing of metamorphosis Our approach was to design species-specific primers to detect species of interest; these kinds of targeted primers can be multiplexed to test for many species in a single PCR reaction. However, when the species list is large or inventory for unknown species is the goal of sampling, universal primers and next-generation sequencing techniques could be applied The success of eDNA for detecting vertebrates efficiently across freshwater systems indicates that this new tool has the potential to revolutionize surveys for aquatic species with the techniques currently available. The ability to survey for species across taxa with a single water sample would greatly enhance data availability for aquatic species and benefit resource managers and many fields of research, including community ecology, biogeography, evolutionary biology, conservation biology, and invasion biology. eDNA techniques could be used to form cost-efficient multi-species inventory and monitoring programs for sensitive species, in combination with occupancy models Table S1Ascaphus montanus) and Idaho giant salamanders (Dicamptodon aterrimus) from stream water.PCR protocols and results for amplifying DNA of Rocky Mountain tailed frogs ((DOCX)Click here for additional data file.