A central thesis of mechanisms of action of tryptophan and its metabolites in the intestines, have broadly implicated nuclear receptors and other host enzymes. The notion that all indole metabolites, of necessity, have the same degree and predictable interactions with nuclear receptors has clearly been challenged. The existence of receptors that complement actions of other well-known receptors has now taken center-stage in elucidating the roles of tryptophan metabolites in the host. Our laboratory, along with other laboratories working in this space, has sought to explore these interactions in depth. This commentary serves as a summary of ongoing work on the interactions of indole metabolites, specifically those produced by microbiota and nuclear receptors in eukaryotes.+ channel blockade and an inhibitory effect caused by suppression of mitochondrial metabolism [in vivo [Recent work on indoles, specifically those generated via microbial metabolism, show that several host receptors might be salient targets regulating host-microbe homeostasis. Some include the aryl hydrocarbon receptor (AhR) , the pretabolism , and fre[in vivo –5. Howev−/− mice. Indeed, our group has generated floxed mice ), which will then allow us to generate tissue-specific PXR knockout mice. We have extensive experience with use of these models in further developing chemical and genetic models of colitis.In keeping with this idea, our laboratory has embarked on using the Pregnane X Receptor (PXR) as a prime target for indole propionates and like analogs. The importance of PXR (and AhR) in regulating intestinal innate immunity, inflammation and perhaps even colitis-induced colon cancer has now been well demonstrated in the literature. Based on our studies, we hypothesize that the synergistic binding of indole(s) to the human PXR ligand binding domain (LBD) can be chemically mimicked  leading to the discovery of novel, more potent chemical entities and drugs that activate PXR and repress inflammation . Thus, iAn important aspect of developing small molecules is to define the biochemistry of indole interactions with PXR. In collaboration with The Freire Laboratory at Johns Hopkins, we have used isothermal titration calorimetry and isothermal chemical denaturation to investigate indole interactions with PXR protein in solution. These studies will provide us with critical binding affinity estimates to pure protein in solution and help guide compound selection. A full complement of chemical analogs have been developed that mimic the indole propionate pharmacophore and these studies are ongoing.Overall, our commentary provides a synopsis of the work underway that will eventually define potent and hopefully non-toxic modulators of PXR (as well as PXR/AhR) in the intestines. There are several hurdles that need to be addressed; however, with the expertise available we hope to position this aspect of drug mining as a feasible means towards finding clinically applicable drugs for human inflammatory and other barrier disrupting diseases.


The finding that human infants and many other animal species are sensitive to numerical quantity has been widely interpreted as evidence for evolved, biologically determined numerical capacities across unrelated species, thereby supporting a ‘nativist’ stance on the origin of number sense. Here, we tackle this issue within the ‘emergentist’ perspective provided by artificial neural network models, and we build on computer simulations to discuss two different approaches to think about the innateness of number sense. The first, illustrated by artificial life simulations, shows that numerical abilities can be supported by domain-specific representations emerging from evolutionary pressure. The second assumes that numerical representations need not be genetically pre-determined but can emerge from the interplay between innate architectural constraints and domain-general learning mechanisms, instantiated in deep learning simulations. We show that deep neural networks endowed with basic visuospatial processing exhibit a remarkable performance in numerosity discrimination before any experience-dependent learning, whereas unsupervised sensory experience with visual sets leads to subsequent improvement of number acuity and reduces the influence of continuous visual cues. The emergent neuronal code for numbers in the model includes both numerosity-sensitive (summation coding) and numerosity-selective response profiles, closely mirroring those found in monkey intraparietal neurons. We conclude that a form of innatism based on architectural and learning biases is a fruitful approach to understanding the origin and development of number sense.This article is part of a discussion meeting issue ‘The origins of numerical abilities'. PerceThe ability to discriminate between numerosities, known as number acuity, improves throughout childhood ,14. Humaet al. )4.During the last decades, an impressive amount of empirical research has shown that non-verbal numerical abilities are widespread within the animal kingdom. These findings have been usually interpreted as evidence for evolved, biologically determined numerical capacities across unrelated species, thereby supporting a ‘nativist’ stance on the origin of number sense. In this article, we have framed the problem of the origin of number sense within an ‘emergentist’ perspective , wherebyWe have shown that, although numerical abilities can be supported by domain-specific representations emerging from evolutionary pressure , numerical representations need not be genetically pre-determined as such. Indeed, they can also emerge from the interplay between innate constraints  and domain-general learning mechanisms . Our computer simulations demonstrated that multi-layer (deep) neural networks endowed with only basic high-frequency spatial filters exhibit a remarkable performance in numerosity discrimination. Moreover, following exposure to sets of visual objects, the network gradually refined its internal representation of numerosity, thereby improving discrimination performance up to the level of adult human observers. Thus, our simulations are the proof-of-concept that a form of innatism based on architectural and learning biases is a viable approach to understanding the origin and development of number sense across species.It should be noted that one possible issue with connectionist models is that several modelling choices, such as the format of the input and output representations  or the pKey issues remain to be addressed in future research. For example, it should be stressed that our behavioural task was implemented by training a supervised read-out layer on the internal representations developed by the deep network. Though this is compatible with common experimental procedures, where explicit feedback is provided to the subjects –70,72, mA promising research direction would also be to more carefully investigate how the basic visuospatial filtering implemented in the first hidden layer of our model relates to spatial acuity in newborns. In our simulations, this early processing stage was fixed for simplicity, but it would be more realistic if spatial acuity also could change during development . AlthougAnother interesting question relates to the computational properties of random matrices. How is it possible that random projections, such as those implemented at the deepest layer of our ‘initial’ network, create internal states that can be meaningfully read out by a supervised classifier? Although the advantages of transforming input data using random mappings have been explored in several machine learning algorithms ,95, a paFinally, one of the most pressing questions to be addressed in future research is whether the generic processing and learning constraints incorporated in our model would suffice even for developing more sophisticated types of numerical abilities, such as those underlying symbolic quantification and arithmetic, which likely require cultural mediation  and whos


Recently, there has been increased interest in investigating neurophysiological mechanisms underlying social interactions using a nonhuman primate model system. Several studies in this subfield, known as primate social neurophysiology, have begun to provide novel insights into how single neurons encode socially-relevant variables. This opinion piece intends to provide insight into the state of this field. In doing so, it discusses some common principles learned from primate social neurophysiology experiments. Recently, there has been increased interest in investigating neurophysiological mechanisms underlying social interactions using a nonhuman primate model system. Several studies in this subfield, known as primate social neurophysiology, have begun to provide novel insights into how single neurons encode socially-relevant variables. This opinion piece intends to provide insight into the state of this field. In doing so, it discusses some common principles learned from primate social neurophysiology experiments.Neurophysiologists are interested in discovering the neural codes that are used by the brain to represent variables from the sensory environments, and to plan and execute motor actions following wide-ranging cognitive operations. In the past decade or so, there has been an increasing trend in neurophysiological research to investigate the neurobiological mechanisms of social interaction. This is particularly true of nonhuman primate research, where exploiting the rich social behavioral repertoires of nonhuman primates has allowed researchers to focus on assessing how neurons from various brain regions signal information used for or as a consequence of social behavior. This research endeavor is often referred to as social neurophysiology. This opinion, by way of examining selected empirical results in rhesus macaques, discusses some common principles in social neurophysiology gained by neuronal recording experiments involving nonhuman primate social interactions. Specifically, this opinion narrates the knowledge gained so far indicating that social variables are represented in several parts of the brain involved in motivation and affective processing by way of agent-specific reference frames, contextual gain modulations, and, in some cases, privileged information processing, and mirroring.Nonhuman and human primates share a vast array of social characteristics that are not found in other species. Macaques live in large, hierarchical groups, displaying extensive cohabitation and reciprocity , and strAn increasingly acceptable view is that social processes in the brain are enabled by a variety of repurposed mechanisms that initially evolved to solve basic survival and reproductive needs . Social Compared to more traditional neurophysiological research, social neurophysiology experiments frequently present novel problems in understanding neuronal encoding schemes across self and others. Debatably, the most interesting aspect of social neurophysiology research is in discovering how neurons involved in affective, motivational, sensory and motor processes encode information with respect to oneself and/or a conspecific. There is a parallel to this endeavor in the history of systems neuroscience research. Egocentric and allocentric representations in the brain have been recognized and studied in depth in the visuomotor and the spatial memory systems . EncodinA pioneering effort to understand how neurons represent self and other began when primate neurophysiologists examined how parietal neurons signal the location of food items differentially as a function of whether the location is shared by a conspecific . SpecifiIn addition to the concept of agent-referenced signals, social information could be added to existing encoding schemes by way of gain changes in the signals, independent of reference frames used. In visuomotor processing, when the information about current eye positions  are added by way of multiplicative gain to a target position signal encoded in an eye-centered frame of reference, the signal now embodies new information about the target location with respect to the head, effectively creating a new representation . SeveralAs alluded to by some examples above, motivational factors can exert a rather dramatic influence on firing characteristics of neurons recruited during social interaction. Motivational factors in social settings may differ as a function of impacting individuals with high versus low social status as well as making a self-generated versus observed outcome influencing other individuals. In the aforementioned experiment where a subject monkey is required to lift a lever to deliver a reward to itself and to one of two conspecifics, the reward value-dependent modulations in OFC neurons positively co-scaled with social context, defined by whether the reward was shared with a specific partner over another . MoreoveFinally, some social variables are highly salient over others to the primate brain, possibly having privileged access to the brain. As expected from the ecology of primate social behavior, the neural underpinnings of primate social behavior are tightly linked to facial expressions and social gaze interactions. Like in humans, faces convey special social information to monkeys. Recently, there has been a great amount of progress in how the primate brain computes facial information from both neurophysiological and neuroimaging studies in macaques. Face patches, first discovered in the temporal cortex, consist almost entirely of face-selective neurons . A groupFirst discovered in the ventral premotor cortex (PMv or F5) of monkeys , “mirrorIn summary, recent experiments in primate social neurophysiology suggest that social computations are conducted in the primate brain using agent-dependent reference frames, gain-modulated encoding of social and nonsocial variables, as well as the brain regions involved in motivation and affective processing and, in some cases, a specialized group of neurons tuned to highly salient social information. At this time, the field of primate social neurophysiology is quite young and often exploratory in nature given the lack of rich literature to guide testable hypotheses. There remain several core empirical questions for the field to answer within the next decade. For instance, it still remains unclear whether neurons distinguish between social variables and nonsocial variables sharing similar complexity. This is a particularly challenging question to satisfactorily address since the boundary between what we might call “social” and “nonsocial” processes, or “agency,” may not be categorically configured in the neural circuits, but rather lie on a continuum as a function of, for example, processing complexity and predictability. Furthermore, it would be particularly informative to know how and where in the brain distinct representations relating to self and other originate, merge or diverge during the social cognitive processing. The field of primate social neurophysiology may be able to provide new knowledge into how the human brain computes information about self and other, and makes decisions impacting fellow human beings. Advances in this endeavor may one day provide insight on how to improve the lives of individuals suffering from social dysfunction.


Glaucoma is a multifactorial neurodegenerative disease affecting 64.3 million people worldwide  pathway, and nicotinamide treatment are three recently investigated clinical therapies for glaucoma-related mitochondrial dysfunction    and/or electroneutral Ca2+/2H+ exchangers (mHCXs) located on the inner mitochondrial membrane. mNCXs are the main efflux channels in excitable tissues, including RGCs, while mHCXs are found mainly in non-excitable tissues  in concentrated amounts directly to the mitochondria during glaucoma using these systems would allow some of the downstream detrimental changes to be managed before vision loss. While some current  and future drugs targeting mitochondrial calcium channels already innately target the mitochondria, the use of MITO-porters and similar delivery systems would not only allow higher concentrations to be delivered, but would also avoid any unknown effects on other organelles. Furthermore, delivery systems could also be used to package multiple drugs/compounds together in order to have the greatest therapeutic effect. Ultimately, these drugs would collectively reduce calcium efflux and restore calcium homeostasis as well as prevent mPTP formation, ATP depletion, ROS production, and cytochrome C dissipation. Doing so would prevent the second wave of apoptosis, allowing the cells to function normally even after the initial insult. While these drug delivery systems are not currently used as an ocular disease treatment, their potential to transport drugs to the retina and/or optic nerve/visual cortex that will subsequently manipulate mitochondrial function is a promising research avenue for novel treatment development for glaucoma as well as other retinal pathologies.Mitochondrial dysfunction and the associated changes in calcium homeostasis, ROS production, and energy supply are intimately related to RGC death/dysfunction during glaucoma, making it an attractive treatment target. Mitochondrial-targeting drug delivery systems, which have been developed and validated in other cellular environments, could potentially avoid these issues by packaging multiple drugs and delivering them at high concentrations directly to the mitochondria. In discussing the recent advances in these techniques within the context of mitochondrial calcium regulation during glaucoma for the first time, we pose the question: Is this the future of glaucoma treatment? The relationships highlighted in multiple keystone studies investigating glaucoma and mitochondrial disease/aging in addition to the essential role of calcium signaling in these processes indicate an affirmative answer. Thus, while the full potential of these systems has yet to be fully established, we believe that mitochondrial-specific delivery of calcium channel regulators could effectively change how glaucoma and other neurodegenerative diseases affecting the retina are treated.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


The growing complexity and global nature of wildlife poaching threaten the survival of many species worldwide and are outpacing conservation efforts. Here, we reviewed proximal and distal factors, both social and ecological, driving illegal killing or poaching of large carnivores at sites where it can potentially occur. Through this review, we developed a conceptual social–ecological system framework that ties together many of the factors influencing large carnivore poaching. Unlike most conservation action models, an important attribute of our framework is the integration of multiple factors related to both human motivations and animal vulnerability into feedbacks. We apply our framework to two case studies, tigers in Laos and wolverines in northern Sweden, to demonstrate its utility in disentangling some of the complex features of carnivore poaching that may have hindered effective responses to the current poaching crisis. Our framework offers a common platform to help guide future research on wildlife poaching feedbacks, which has hitherto been lacking, in order to effectively inform policy making and enforcement. People and large carnivores are parts of social–ecological systems (SESs), in which human and biophysical subsystems mutually influence one another  of carnivores is an especially challenging conservation issue in SESs  in northern Sweden and (2) tigers (Panthera tigris) in Laos. The application of our SES framework to the two cases underscores how conservation interventions are more likely to be effective when both proximal and distal social–ecological causes and consequences of human–wildlife interactions are accounted for—a process that takes time and meaningful engagement with various stakeholders.We have two objectives in this paper. First, we review the literature to develop a conceptual SES framework for understanding the multiple factors and feedbacks influencing carnivore poaching. Second, we apply the conceptual SES framework to two case studies: (1) wolverines  inadvertently increased the demand for and trade of this bird of prey  by simulating the dynamic interactions and adaptations between patrols and poachers while considering the movement patterns of the wildlife species of interest  repeatedly using den and rendezvous sites and vocalizing in the vicinity are more vulnerable to potential poachers, especially those actively searching for litters or aiming to eradicate entire wolf packs  is a common response to livestock predation. However, a previous study suggests that livestock losses can increase following lethal harvests, as the cougar’ social organizations are disrupted  and leopards (Panthera pardus) kill livestock belonging to Maasai people in Kenya in high numbers, lions (Panthera leo) appear to be much more vulnerable to illegal killing  norms about poaching, cultural uses of wildlife, and natural resource-protective policies, shape individual motivations to poach Fig. . A normaUrsus arctos) used remote areas, whereas adult females and some sub-adults used areas closer to roads or human-dominated areas (Steyaert and Kindberg Lycaon pictus)  is used to kill carnivores depends not only on policies controlling the availability of each method to would-be poachers but also on carnivore behavior, abundance, and habitat preferences. Although firearms are a powerful weapon, it is very difficult to track and shoot an elusive tiger in dense tropical forest habitat versus setting and baiting snares, which are effective and difficult to detect by anti-poaching units. Poaching interventions that account for factors at multiple levels are therefore needed. For example, although poaching of tigers for the global market is a persistent challenge to conservation, multiple factors operating at different levels  have significantly enhanced poaching interdiction and deterrence in Nepal Nowell . Below wA better understanding of the feedbacks within and across levels can improve the effectiveness of policy interventions aimed to reduce poaching. The information used to construct each SES diagram Figs. , 3 for t2 with significantly lower abundance where human population and disturbance were greater  is an IUCN Category VI protected area where a proportion of the area is open to sustainable use of natural resources  to over a fourfold increase (0.25–1.2) for Sambar deer (Cervus unicolor). Yet, despite greater prey abundance, there was a sevenfold decline (0.24–0.03) in mean relative abundance index for tigers over the same period  in NEPL NPA  underscore how cross-scale linkages  in the SES likely led to different underlying human motivations to poach ungulates versus tigers, which in turn led to divergent trends in their populations. Locals targeted ungulates mainly for subsistence and local trade. Engaging local communities and clarifying regulations on when and where people could legally hunt less-threatened ungulates for subsistence  likely bolstered public support for the protection of ungulate source populations within NEPL NPA, while the increased enforcement was sufficient to reduce pressure on ungulates within the core zones for the less lucrative local trade. In contrast, global demand for tiger products  created strong economic incentive for locals to poach tigers and sell their parts to traders. This was facilitated by traders from Vietnam and China altering the control beliefs of a subset of local hunters by providing them with snares for tigers Fig. , which wReindeer herding is central to the livelihoods of the Sami people in Sweden (Zabel and Holm-Müller In the past, reindeer herders killed large carnivores, including wolverines, in response to real or perceived reindeer losses from depredation (Persson et al. Instead of a traditional ex post compensation scheme, the Swedish government intervened in 1996 in a way that reduced female wolverine poaching, which has probably contributed to the wolverine population recovery (Persson et al. The performance payment changes human behaviors by removing the moral hazard and reducing the motivation to poach by altering both behavioral and normative beliefs regarding wolverine conservation. The performance payment also feeds back into the ecological system by reducing poaching of females Fig.  while poIdentifying and quantifying the strength of feedbacks related to carnivore poaching is challenging. Furthermore, multi-scale and multi-disciplinary data needed to elucidate social–ecological interactions and feedbacks are difficult to come by and to integrate. A range of techniques exists to collect data on various factors and processes affecting poaching opportunity (Gavin et al. Co-development of a site-specific poaching SES framework between researchers and local organizations can help identify and test key linkages in the SES that influence poaching (Steinmetz et al. Computer modeling and scenario testing can be effective tools for designing, monitoring, and evaluating conservation interventions (Pressey et al. The growing complexity and global nature of poaching for the global commercial market threaten recovery efforts worldwide and are outpacing efforts to understand and address its effects. Understanding and addressing large carnivore poaching are especially challenging, because carnivore poaching is driven by a range of motivations influenced by various social–ecological dimensions spanning from individual to broader social and landscape levels. Emotions, cognitions, and livelihoods, among other attributes, interact to influence individual motivations to poach. Likewise, the behaviors, space use, and life-history traits, among other attributes, of individual animals interact to influence their vulnerability to poaching. Furthermore, the social, economic, and ecological conditions affect the behavior of individual actors—human and wildlife. These environmental conditions define the context in which behavior occurs, and shape it in ways that can be counterintuitive.Based on this review, we developed a SES framework for carnivore poaching that ties together many of the factors across levels that influence poaching. The framework is useful in several ways. As with most major problems that lie at the intersection of social and environmental contexts, the framework suggests the high likelihood of feedbacks among systems of interactions between people and wildlife. The framework offers a common platform to help guide future research on poaching feedbacks, which has hitherto been lacking. Explicating these social–ecological interactions and feedbacks will likely help disentangle some of the complex features of carnivore poaching that has hindered effective global responses to the problem. The framework also provides entry points for site-specific studies through which more detailed measures and variables can be derived and analyzed. With continuing efforts to connect insights about poaching from disparate fields, we anticipate that the framework can be applied to other large mammal species, such as rhinoceros and elephant species, and can be the conceptual bases upon which a course for more effective and comprehensive poaching policy interventions is laid out.


Introduction: With increasing life expectancy, couples with at least one partner afflicted with HIV are more commonly pursuing the opportunity to have biologic offspring. Currently, there are no universally accepted recommendations regarding first line reproductive treatments for HIV serodiscordant couples lacking a history of infertility. We strongly believe that fertility care intervention should be the first line treatment, when affordably accessible, over natural conception for HIV serodiscordant couples to achieve pregnancy in a safe and efficacious manner.Discussion: In the era of highly active anti-retroviral therapy, in combination with timed intercourse and pre-exposure prophylaxis for the HIV negative partner, some members of the medical community are arguing in favour of natural conception as a means of achieving pregnancy in this patient population. In our opinion, laboratory assisted fertility methods, including intrauterine insemination, in vitro fertilization, and intracytoplasmic sperm injection with semen washing should be the first line treatment recommendation for HIV serodiscordant couples desiring pregnancy for the following reasons: (1) abundance of evidence in the medical literature supporting the safety profile and efficacy of fertility care intervention in couples with HIV; paucity of data addressing safety of natural conception in comparison to fertility intervention techniques (2) unknown public health impact of promoting natural conception as a safe means of achieving pregnancy (3) ethical implications: patients should be offered the available and accessible treatment option posing the lowest possible known risk to the uninfected partner.Conclusions: We believe that physician assisted fertility care, when affordably accessible, should be the treatment of choice over natural conception. While the preliminary data on natural conception in couples using highly active anti-retroviral therapy/pre-exposure prophylaxis/timed intercourse appears promising, we believe that this approach should be limited to patients in resource poor settings where more sophisticated measures do not exist or for patients that simply cannot afford subspecialty care. There are likely to be unknown psychological and behavioural factors impacted by promoting natural conception and diminishing the importance of safe sex practices. Additionally, it is our moral obligation to patients to offer the affordably accessible treatment interventions that pose the least known risk when considering reproductive options. In the past, a diagnosis of HIV was associated with debilitating illness, a shortened life expectancy and untimely death. The advent of anti-retroviral therapy (ART) led to vast improvements in both quality of life and life expectancy of children and adults infected with the virus ,2. CurreIn 2012, the United States Food and Drug Administration (FDA) approved emptricitabine/tenofovir disoproxil fumarate as a pre-exposure prophylaxis (PrEP) measure to lessen HIV acquisition in sexually active adult men and women . Publishinvitro fertilization (IVF), and/or intracytoplasmic sperm injection (ICSI) appear to be effective.Physician assisted reproductive interventions intended to aid individuals with HIV were met with resistance from the medical community, perhaps because of the presumed shortened lifespan of the HIV infected parent, or over concerns for the risk of horizontal and vertical transmission to the uninfected partner and child. Additionally, there were theoretical worries related to HIV infecting laboratory personnel who process gametes/embryos, as well as the potential for cross contamination of other patients’ embryos/gametes. Since 2001, the Centers for Disease Control and Prevention (CDC) in the United States encouraged health care professionals to provide information and support for HIV-infected couples who wish to explore their reproductive options, but without a treatment recommendation . In 2015developed countries [Currently, there are no universally accepted recommendations regarding first line reproductive treatments for HIV serodiscordant couples lacking a history of infertility. In developing countries, assisted reproductive technologies are not available, and therefore other methods of minimizing risk through natural conception are recommended. Strategies include delaying conception attempts until the partner living with HIV is on ART with suppressed viral loads, receiving treatment for other sexually transmitted infections (STIs), and limiting unprotected sex to times known to be associated with peak fertility potential. A strategy of managed conception in the setting of full viral suppression can minimize, yet likely does not fully eliminate, HIV transmission risk . Howeverountries . Yet, thin vitro fertilization and intracytoplasmic sperm injection in combination with semen washing have been advocated for over 25 years to decrease the risk of transmission. Regardless of the method chosen, controlling the disease of the partner living with HIV with ART is important to success. Appropriate ART to suppress viral replication and prevent progression to AIDS, is of vital importance in minimizing risk regardless of how conception is achieved.Laboratory assisted fertility methods, including intrauterine insemination, in vitro fertilization (IVF), and ICSI, although these procedures represent high cost interventions and access to care may be limited [For female HIV-seropositive individuals, non-coital ovulatory vaginal or intrauterine insemination is a low technology method offering a safer option to achieve pregnancy than sexual intercourse. There are limited data on the use of high-technology assisted reproductive methods for HIV-seropositive women, which include IUI,  limited . Additio limited ,14,15.For HIV-seropositive males, risk reduction requires prolonged intervention given the possibility of passing virus through seminal fluid. The basic principle underlying assisted fertility methods for males living with HIV involves separating motile spermatozoa from seminal plasma and non-seminal cells that may harbour virus. The process of “sperm washing” in order to reduce transmission risk was introduced in 1989 by Semprini . Sperm wThere have been numerous studies reporting the efficacy of sperm washing (SW) in combination with IUI in terms of pregnancy rates, live birth rates, and HIV transmission incidence –21. One IVF with ICSI was offered to HIV serodiscordant couples to circumvent concerns related to “insemination” techniques. Using ICSI, a single spermatozoon is injected directly into the oocyte, minimizing transmission risk to a cellular level . Also, HDespite the safety and efficacy of fertility care interventions, including semen washing with IVF/ICSI or IUI, there remains an issue of access, even for clients for whom these interventions are affordable. In one study that sought to investigate policy on patient access to services at assisted reproductive technology centres in the United States, only 7.1% of centres reported that they offer care to HIV+ women and 18.1% reported that they offer ART or IUI when the male was HIV seropositive .For couples in resource limited areas without access to assisted reproductive technology, achieving pregnancy is limited to natural conception. Given the prevalence of HIV infection in resource poor settings, it is critical that sexually active couples be provided appropriate counselling and guidance in terms of the safest manner in which to achieve pregnancy. If available, ART is recommended for the HIV positive partner, and unprotected intercourse, or self-insemination, is timed to ovulation to minimize exposure of the unaffected partner. Additionally, if available, PrEP should be provided for the HIV-seronegative partner around the time of unprotected intercourse. With these non-invasive interventions requiring no advanced reproductive technology, transmission risk appears to be decreased.Abundance of evidence in the medical literature supporting the safety profile and efficacy of fertility care intervention in couples with HIV; paucity of data addressing safety of natural conception in comparison to fertility intervention techniquesDespite reduced HIV transmission rates for couples utilizing ART with PrEP, it is our belief that laboratory based interventions should remain the preferred option for those that have access for the following reasons:To date, most research has looked at the efficacy and safety of SW- IUI and IVF-ICSI as fertility treatments among HIV serodiscordant couples in which the male partner is HIV-infected. Substantial evidence points to the relative safety of these procedures, although some methodological limitations impede the evaluation and comparison of these studies , 26. TheFor natural conception, data on safety profile is limited. This risk of infection from attempts at conception via unprotected intercourse depends on viral load, the presence of sexually transmitted infections, and the length and frequency of exposure . The safIn one recent analysis of 91 HIV-serodiscordant couples, , there were 196 unprotected sexual exposures, resulting in 100 conceptions and 97 newborns. There were no cases of HIV seroconversion in uninfected sexual partners . There aUnknown public health impact of promoting natural conception as a safe means of achieving pregnancyTo date, there are no randomized controlled trials comparing natural conception with PrEP to IUI with semen washing or IVF/ICSI to demonstrate feasibility, safety and effectiveness. Until there is more evidence, fertility care interventions by reproductive specialists in collaboration with infectious disease physicians overseeing patient health and well-being should remain the standard approach for couples seeking pregnancy in couples who have affordable access to these services.Unprotected sex has not been the standard of practice recommended by most practitioners and researchers caring for HIV serodiscordant couples. A central concern is that compromising the “safe sex” message for the purpose of conception, even if only during a woman’s fertile window, might have deleterious effects on condom use and public health more broadly . Risk coIn one study examining fear and anxiety in HIV-serodiscordant couples interested in assisted reproductive technologies, at baseline both men and women displayed high state anxiety levels, but despite their anxiety, women were prepared to take risks to fulfil their desire for a child . To our Ethical implications: patients should be offered available and accessible treatments that pose the lowest possible known risk to the uninfected partnerThe impact on promoting natural conception as the first line treatment in terms of consequences on risk taking behaviour and the effect on anxiety levels have yet to be determined.Many ethical issues are brought to bear in caring for seropositive couples desiring conception. Central issues include: the welfare of the child, prevention of harm, access to care and discrimination, acceptable levels of risk, and professional obligations of health care workers. Today, with the addition of ART and subsequent prolonged lifespans, HIV infection is now regarded as a chronic illness, and as such, medical interventions should not be categorically withheld when treating HIV-seropositive patients. The risk of infection needs to be evaluated against the benefits of parenthood, and given the progress of medical care, we believe it is ethically acceptable to attempt pregnancy so long as couples and doctors take all reasonable precautions to prevent transmission, and understanding that parents are prepared to take care of children regardless of resulting medical conditions .Health care providers take a Hippocratic Oath at the beginning of their medical careers, and pledge to first “do no harm.” It is our moral obligation to provide our HIV-seropositive patients with the safest, evidence based treatment options. To date, fertility care interventions utilizing sperm washing techniques have been the most extensively studied treatment alternatives and appear both safe and efficacious. We are obliged to present the current options and recommendations, and counsel patients accordingly. In cases where fertility care interventions are accessible and affordable to the patient, this should be first line recommendation. Natural conception utilizing timed intercourse with PrEP should also be discussed as a risk reducing method of achieving pregnancy. Acknowledging that cost and accessibility of fertility care is an issue for many patients, natural conception may be the only pragmatic recommendation for indigent patients, especially in the developing world, and in carefully selected populations this may be the most appropriate option to protect the public health.In resource poor settings, where inarguably the burden of HIV exists and there is limited access to fertility care inventions, any and all risk reducing strategies should be discussed and employed in this patient population. Even with PrEP alone, there is a 90% decrease in the rate of transmission amongst HIV-serodiscordant couples (CDC HIV Fact Sheet). Utilizing natural conception strategies with PrEP in an indigent population will likely decrease the risk of transmission currently and provide important information in terms of whether or not this option, in couples who are actively attempting pregnancy over a six months or extended time frame, is as safe as the presently recommended fertility care inventions.As health care providers, it is our responsibility to introduce harm-reduction methods and safer conception alternatives for patients with HIV. Given the current knowledge, we believe that physician assisted fertility care should be offered as treatment of choice over natural conception. While the preliminary data on natural conception in couples using ART/PrEP/timed intercourse appears promising, offering a relatively simple, safe and less expensive option, we believe that this approach should be limited to patients in resource poor settings where more sophisticated measures do not exist or for patients that simply cannot afford subspecialty care. Natural conception can and should be discussed with patients as a matter of true informed consent. However, it should not be recommended as the first line approach due to the paucity of data on safety in comparison to better studied and long employed fertility care interventions. Future studies need to be performed to better demonstrate the safety of natural conception. There are likely to be unknown psychological and behavioural factors impacted by promoting natural conception and diminishing the importance of safe sex practices. Finally, it is our moral obligation to patients to offer treatment interventions that pose the least known risk as the primary reproductive option.


Adults demonstrate an upregulation of their pro- and anti-oxidant mechanisms in response to acute exercise while systematic exercise training enhances their antioxidant capacity, thereby leading to a reduced generation of free radicals both at rest and in response to exercise stress. However, less information exists regarding oxidative stress responses and the underlying mechanisms in the pediatric population. Evidence suggests that exercise-induced redox perturbations may be valuable in order to monitor exercise-induced inflammatory responses and as such training overload in children and adolescents as well as monitor optimal growth and development. The purpose of this review was to provide an update on oxidative stress responses to acute and chronic exercise in youth. It has been documented that acute exercise induces age-specific transient alterations in both oxidant and antioxidant markers in children and adolescents. However, these responses seem to be affected by factors such as training phase, training load, fitness level, mode of exercise etc. In relation to chronic adaptation, the role of training on oxidative stress adaptation has not been adequately investigated. The two studies performed so far indicate that children and adolescents exhibit positive adaptations of their antioxidant system, as adults do. More studies are needed in order to shed light on oxidative stress and antioxidant responses, following acute exercise and training adaptations in youth. Available evidence suggests that small amounts of oxidative stress may be necessary for growth whereas the transition to adolescence from childhood may promote maturation of pro- and anti-oxidant mechanisms. Available evidence also suggests that obesity may negatively affect basal and exercise-related antioxidant responses in the peripubertal period during pre- and early-puberty. Aging, exercise, diseases and other clinical conditions are characterized by a pronounced generation of reactive oxygen and nitrogen species (RONS) which readily oxidize various macromolecules such as lipids, proteins, carbohydrates and nucleic acids . In humaChronic exposure to repetitive generation of RONS in response to systematic exercise  may upregulate antioxidant reserves and reduce acute manifestations of exercise-induced oxidative stress ,23,24,25Therefore, the objective of the present review was to present the available data on the unique profile of oxidative stress and antioxidant status responses of children and adolescents. For this review, children are defined as those aged <12 years for studies not reporting stages of sexual maturation or those at stage 1 of the Tanner scale of sexual maturation whereas adolescents are defined as those aged >12 years for studies not reporting stages of sexual maturation or those at stages ≥2 of the Tanner scale of sexual maturation . AccordiAlthough, millions of children and adolescents participate in systematic intense exercise training and/or mild physical activities little is known about the acute and chronic effect of different modes of exercise on oxidative and antioxidant responses of this population. Furthermore, it is not correct to use knowledge derived from adult studies in sport applications for children and adolescents.During developmental stages, children demonstrate changes of smaller magnitude in both intramuscular pH and the ratio of inorganic phosphate to phosphocreatine during exercise, suggesting that they are more dependent on mitochondrial metabolism than adults ,37. ThisAlthough acute exercise effects have been well studied in adults’ population, similar information for the young population is limited. In the field of oxidative stress responses in developmental stages, studies have used various exercise modes, i.e., swimming, cycling, running , soccer and basketball.The Tanner scale  is a scale of physical development in children, adolescents and adults. When 70 healthy untrained pre-adolescent  and adolescent  boys volunteered to participate in an incremental exercise test of 20-m shuttle run (started at 8 km/h with an increase of 0.5 km/h in every subsequent minute), GSH in saliva demonstrated a marked decline post-exercise compared to its baseline values suggesting that acute exercise in children consumes GSH similar to adults . A more Kabasakalis et al.  utilized2max and at 90% thereafter until volitional exhaustion). If we consider that exercise-induced oxidative stress responses are a part of a physiological mechanism aiming to clear cellular debris in skeletal muscle after an intense exercise insult [It is uncertain if training status affects acute oxidative stress responses of children and adolescents. Tong et al.  showed te insult , trainine insult . This ise insult .Team sports such as football, basketball, team handball, volleyball etc., represent a sport category with unique kinesiological characteristics. Movement patterns such as acceleration, deceleration, changes of direction, jumping etc., belong to muscle explosive actions that are inherent in this type of sports. It is well documented that participation in team sports training and/or match activity induced an inflammatory response associated with muscle damage induced by the strong eccentric component of actions used in these sports ,21,49,50It appears that exercise provides a powerful stimulus for the elevation of TAC (represents serum antioxidant reserves) in most studies in both trained and untrained adolescents. However, there is evidence that this response is more pronounced in the more trained individuals probably because they reach higher levels of absolute intensity . HoweverA confounding factor that should be taken into account by future investigations is the body weight status of children and adolescents. Obesity has been shown to cause a reduced antioxidant ability in the adult population ,53,54, t2) as well as the greater elevation of neutrophils in the circulation post-exercise [In conclusion, it appears that children and adolescents, similarly to adults, demonstrate an elevation of pro-oxidant markers which is associated with a parallel upregulation of their antioxidant activity. These responses seem to be of a lower magnitude in youth compared to adults. Pre-pubertal children may also have lower antioxidant reserves than adults. When children are contrasted to adults, it appears that children may be more susceptible to a rise in RONS in response to exercise than adults due to their faster kinetics of oxygen consumption  was made by another cross-sectional study . A totalWhen an attempt was made to examine the effects of total training load, results were highly inconclusive. The main objective of a cross-sectional study performed by Santos-Silva et al.  was to iThere is very limited information on the effects of team sports on oxidative stress response in the pediatric population. Team handball training has been shown to enhance SOD activity and cause a positive correlation between aerobic capacity and catalase activity as well as a negative one between aerobic capacity and hydrogen hyperoxide in ~17-year-old subjects . SimilarCollectively, these results suggest that there is evidence that exercise training induces a positive adaptation in oxidative stress responses in the pediatric population by elevating antioxidant capacity and as such reducing systemic levels of oxidative stress. However, more studies using training interventions are needed. Future research should explore the optimal training characteristics  for such positive responses for various exercise modalities. Adolescence is a crucial period during maturation in humans because it is associated with significant hormonal perturbations that affect not only the individual’s sexual and reproductive characteristics but also affect musculoskeletal characteristics . This peIt is characteristic that a 3-fold increase in RONS has been seen in STAT5A knock-out cells . MoreoveThese findings suggest that exercise is capable of stimulating pro- and anti-oxidant responses during pre- and post-puberty independent of body weight status. However, it appears that entry into puberty coincides with an improvement of antioxidant activity probably due to the augmented production and release of GH and androgens. Obesity appears to decrease antioxidant capacity and thus increase exercise-induced oxidative stress in children and adolescents probably due to a GH-dependent mechanism, further highlighting the negative implications of obesity. Whether the transition from pre-adolescence to early adolescence contributes to the maturation of antioxidant mechanisms warrants further investigation by future studies. This possibility should be explored in relation to fatness level.The present review attempted to present all available scientific evidence regarding the acute and chronic effects of exercise on oxidative stress responses in the pediatric population. Most studies support the idea that acute exercise may induce a relevant, but transient increase in oxidative markers. It appears that these exercise-induced responses may be dependent on children’s maturity stage and body weight status. Other factors that may affect the magnitude of these responses are fitness status, the total training load and the type of activity. Duration, intensity and frequency of exercise may also play a significant role.


First, we summarize and recontextualize Lang’s bio-informational theory of emotional mental imagery  within contemporary theoretical developments on the function of mental imagery. Second, Lang’s proposal that mental imagery can evoke emotional responses is evaluated by reviewing empirical evidence that mental imagery has a powerful impact on negative as well as positive emotions at neurophysiological and subjective levels. Third, we review contemporary cognitive and behavioral therapeutic practices that use mental imagery, and consider points of extension and departure from Lang’s original investigation of mental imagery in fear-extinction behavior change. Fourth, Lang’s experimental work on emotional imagery is revisited in light of contemporary research on emotional psychopathology-linked individual differences in mental imagery. Finally, key insights from Lang’s experiments on training emotional response during imagery are discussed in relation to how specific techniques may be harnessed to enhance adaptive emotional mental imagery training in future research.This article pays tribute to the seminal paper by Peter J. Lang (1977;  Scientific interest in mental imagery dates back to the 19th century , making Mental imagery refers to perceptual experience in the absence of sensory input, commonly described as seeing with the “mind’s eye,” hearing with the “mind’s ear,” and so on . In thisIn his bio-informational theory of emotional imagery, This associative network of information is said to consist of perceptual information about the stimulus , semantic information about what it means , somatovisceral response information about what it feels like to encounter the stimulus , and preparatory motor responses evoked by the encounter . According to this theory, mental imagery differs from verbal thought in that only mental imagery has the capacity to activate physiological and behavioral response systems . ResearcAs Indeed, numerous studies using a range of associative learning paradigms have shown that mental imagery can produce conditioned responses in the same way as real stimuli cf. . CrucialOf particular relevance to By providing a pivotal testable framework linking mental imagery to emotion, The first half of this review will evaluate evidence pertaining to Lang’s key proposal, that mental imagery has the capacity to evoke emotional responses, and explore how this capacity has been exploited therapeutically in clinical treatment. The second half of the review will consider how subsequent research has built on Lang’s initial work concerning individual differences to illuminate how variability in imagery may relate to emotional dysfunction, and highlight neglected insights from Lang’s research on emotional imagery training that could potentially contribute to future treatment innovation.Developments in clinical psychology over the past 50 years have shown that unwanted and distressing mental imagery is a symptom present in a wide range of anxiety and mood disorders . In anxiWhile clinical presentation suggests that negative mental imagery symptomology can have emotionally distressing consequences for patients, researchers have noted a relative paucity of studies designed to directly evaluate this assumption . Lang, 1It is widely accepted that emotional experience involves activation of the central and peripheral nervous systems . Thus, iUsing verbal scripts depicting emotionally negative or neutral information, In terms of autonomic arousal, Lang and colleagues observed greater heart rate acceleration during mental imagery of high versus low arousal scenarios. In healthy participants, imagery of fear and anger-related scenarios led to greater heart rate acceleration than did imagery of neutral scenarios . SimilarResearch has shown that respiratory responses are also influenced by mental imagery in healthy populations. Specifically, imagery evoked by scripts depicting high arousal scenes (fear and action-related) compared to low arousal scenes (relaxation and depression-related) produced greater drops in end-tidal fractional carbon dioxide concentration, likely reflecting hyperventilation . ImportaIn addition to autonomic indices, mental imagery has been shown to modulate other indices of physiological arousal, such as the startle blink reflex. Finally, mental imagery of food stimuli has been shown to modulate the gustatory salivary reflex. Research in the field of brain computer interfaces (BCI) has found increases and decreases in salivary pH levels compared to baseline as a result of a healthy participant imagining consuming a lemon versus drinking milk, respectively . This fiTogether, the above evidence provides support for per se, rather than the impact of emotional information processing in general. Research addressing this limitation will be discussed in Section III.Furthermore, the studies reviewed in this section have not explicitly contrasted mental imagery representations of emotional stimuli to an alternative mode of representation of the same information, and therefore one cannot conclude based on the evidence that the physiological effects observed reflect the impact of mental imagery According to Neural indices of emotion processing during emotional mental imagery can be evaluated in comparison to activity observed during veridical perception of emotional stimuli, or to emotionally neutral mental imagery. Meta-analytic reviews of neuroimaging studies on healthy participants show that the brain regions most consistently associated with emotional processing are the dorsomedial prefrontal cortex (mPFC), anterior cingulate cortex (ACC) and amygdala , and theMore recent studies have used script-driven emotional imagery to examine the specificity of neural circuits for the processing of emotional valence versus arousal. Studies using fMRI have also compared neural responses to real versus imagined emotional stimuli in the same participants. Finally, direct evidence that visual imagery and visual perception share common neural systems implicated in emotional response comes from a single-cell recording study on human epileptic patients. per se, rather than the impact of emotional information processing in general.As such, results from neuroimaging and single cell recording studies provide converging evidence that mental imagery has the capacity to evoke an emotional response by activating neural networks involved in emotional processing and response coordination with the autonomic nervous system. However, as with the physiology studies reviewed earlier, the neuroimaging studies reviewed here have not explicitly contrasted mental imagery representations of emotional stimuli to an alternative mode of representation of the same information, and therefore one cannot conclude based on the evidence that the physiological effects observed reflect the impact of mental imagery disruption of such imagery should reduce the intensity of such emotional responding. This hypothesis has been investigated using dual task paradigms that reduce the availability of cognitive resources required for mental imagery generation. Typically, in such studies, participants attempt to generate mental imagery while undertaking a concurrent task that consumes working memory resources, such as sequenced finger tapping on a number pad, or mental arithmetic.If mental imagery-based representation of emotional information serves to elicit emotional responses to this information, then it follows that Across several experiments, Clinical researchers have also begun to harness the potential for concurrent tasks to reduce the emotional impact of processing affectively toned mental imagery. The use of a concurrent mathematics task during recall of real-life collective trauma has been shown to reduce the emotional impact of recalling the traumatic event in the general population . LikewisIn addition to voluntarily generated imagery, researchers investigating intrusive flashbacks in PTSD have also begun to evaluate the possibility that capacity-consuming concurrent tasks may also be capable of reducing the frequency and emotional impact of involuntary mental imagery. There is growing evidence that playing the visuospatial computer game “Tetris” following exposure to analogue trauma reduces the frequency of subsequent involuntary memory imagery. Mental imagery-evoked emotional responses have been used to study emotional psychopathology, primarily in anxiety research. Evidence has revealed variations in neural and physiological responses across anxiety disorder subtypes. For example, while there is evidence that, overall, anxiety patients exhibit greater amygdala and insula activity during aversive imagery and picture viewing relative to healthy controls, this hyperactivation is more evident in social anxiety disorder and specific phobias compared to PTSD cf. .Similarly, during fear relative to neutral memory imagery, specific and social phobics showed greater increases in heart rate and startle reflex response (but not skin conductance) compared to healthy participants . HoweverBlunted neurophysiological reactivity to aversive imagery is hypothesized to be attributable to the effects of chronic stress and depression comorbidity, which appears to be more evident in individuals with pervasive anxiety-based disorders rather than focal fear-based phobias . M = 7.3; Experiment 2: M = 5.67), relative to the verbal condition .Following positively, M = + 7.15, SD = 10.30) than those in the verbal condition , as measured using the Positive and Negative Affect Schedule  than did those in the verbal condition . Consistent with research on the buffering effects of positive mood on negative mood . Participants are asked to combine the picture and the word using either imagery  or verbal statement (“form a sentence that combines the next picture and the word”). Thus, in this design, the stimulus materials are comprised of image-based and verbal information. Results from the PWT were consistent with the previous finding that imagery-based representation evoked a stronger impact on subjective emotional experience than verbal representation of the same information. Specifically, M = + 7.06, SD = 5.84) than did the use of verbal processing to combine these cues ; and using mental imagery to combine benign picture-word cues resulted in a greater reduction in anxiety  than did the use of verbal processing to combine these cues .In the studies described above, the information that participants were required to represent was always presented in a verbal format. Thus, it could be the case that the greater emotional impact of the imagery condition reflects the fact that the information is represented in two modalities, both verbal and imagery, while in the verbal condition the information is represented in only a single modality . To addrTherefore, on the basis of the reviewed evidence, it is appropriate to conclude that imagery-based processing of emotional information has a greater impact on subjective emotional experience than does verbal processing of the same information. In relation to Lang’s original postulation that only mental imagery has the capacity to activate physiological and behavioral response systems, evidence from studies on anxiety suggests that more verbal forms of thinking, such as worry, can also impact cardiovascular  and neurWhen Developments in cognitive and social psychology in subsequent decades has shown that an individual’s thoughts can exert a strong influence on his/her behavior and wellbeing. As a result, the content and phenomenology of an individual’s mental imagery-based thoughts have themselves become the subject of analysis and modification A. T. . BuildinImaginal exposure (IE) treatments are still widely used in contemporary clinical practice, with a strong evidence base for treating anxiety disorders ranging from specific phobias , obsessiThere is increasing evidence that the efficacy of IE, at times combined with other behavioral or cognitive treatments, is superior to psychopharmacology for OCD  and PTSDImagery rescripting techniques designed to directly modify the content of emotion-inducing mental imagery have been developed, helping clients transform their unwanted distressing imagery into more benign forms . Such teIn addition to the development of clinical techniques intended to attenuate negative imagery, clinical investigators have also sought to develop methods of fostering the generation of positive imagery, to help clients build more adaptive relationships between self, others, and the world . SymboliA third category of imagery-focused interventions aims not to directly alter potentially distressing negative mental imagery but rather to change how the patient thinks about these images, in ways that reduce their emotional impact. Metacognitive strategies aim to down regulate the impact of distressing mental imagery via reappraisal . TechniqMore recent developments in experimental clinical research have begun to develop mental imagery-focused cognitive training informed by cognitive bias modification (CBM) paradigms. CBM aims to reduce maladaptive imagery styles and boost adaptive imagery via computer-based training . Such meHence, clinical practice is increasingly harnessing the power of mental imagery to facilitate adaptive emotional functioning. The efficacy of such approaches may be further enhanced by future research designed to illuminate the potentially critical role of variability in the strength of the emotional response, observed during imagery in the clinic, in determining treatment outcomes. Given that the elicitation of both subjective and physiological emotional responses during imaginal exposure is a central mechanism of change in the successful treatment of fear, the effectiveness of other treatments that use mental imagery to optimize emotional functioning may also depend on the client’s emotional response during imagery. In our view, research investigating differences between treatment responders compared to nonresponders in the emotional impact of mental imagery may prove fruitful in informing future translational research in this field.So far, this review has discussed mental imagery in terms of its capacity to evoke emotional responses, the presence of disorder-linked variations in this emotional response, and the ways that clinical practice has harnessed mental imagery to facilitate emotional processing. However, one relatively neglected aspect of mental imagery that is of potential clinical significance is differences across individuals in the ability and tendency to experience emotional imagery. Here, “ability” is simply defined as the deliberate generation of imagery, and “tendency” as the nondeliberate  generation of imagery. This section will review research on individual differences in emotional mental imagery tendency and ability in both healthy and clinical populations.An interesting finding from Lang’s experimental work on the emotional impact of mental imagery is the observation that the level of emotional response experienced during imagery is related to how vividly an individual can generate mental imagery in general (imagery generation ability). Lang and colleagues found that, in healthy participants, heart rate acceleration during fearful imagery was more pronounced in individuals with high imagery ability, relative to those with low imagery ability, as assessed by a self-report questionnaire . HoweverRelatively few studies have examined individual differences in mental imagery and its relationship to imagery-based treatment outcomes in clinical populations. In recent years, researchers have begun to investigate whether bias in the relative ability to generate mental imagery of emotionally negative compared to emotionally positive scenarios may be associated with emotional psychopathology. Several studies have used the Prospective Imagery Task PIT;  to assesIn addition, researchers have begun to move beyond cross-sectional data and to examine temporal relationships between imagery vividness and emotional psychopathology. Researchers have also started to explore disorder-linked individual differences in the tendency to spontaneously experience emotional mental imagery in daily life. Negative self-concept in unselected undergraduate students has been found to be positively associated with the frequency of retrospectively reported negative spontaneous cognitions, consisting predominantly of imagery-based memories of past negative experiences . It has Future emotional psychopathology-linked individual differences research may benefit from obtaining convergent measures of emotional response during mental imagery, such as measures of physiology and hemodynamic neural activity. In addition to indices of emotional response during imagery, electroencephalography (EEG) measures of cortical brain electrical activity may provide indices of the level of cognitive resources expended during imagery as an additional measure of the impact of emotional imagery. One recent study from Lang and colleagues examining alpha-band activity during emotional mental imagery suggests EEG may provide an objective measure of neural activity involved in semantic, motor, and perceptual representations of emotional stimuli. . More experimental research is required to investigate if and how the ability and tendency to experience emotional mental imagery is causally related to emotional wellbeing and dysfunction. Several mechanisms have been proposed and require further investigation. One hypothesis is that mental imagery acts as an emotional amplifier and exacerbates states of mood instability, such as in bipolar disorder  training involves repeatedly generating imagery in response to verbal sentences and picture-word pairs depicting hypothetical everyday scenarios that resolve positively. Experimental studies have shown that imagery-based IBM training of this nature improves mood to a greater degree than does verbal-based IBM training . To dateCharting the progress of emotional mental imagery research across the past five decades since In emphasizing mental imagery’s capacity to activate perceptual stimulus representations as well as physiological and behavioral responses, Lang’s theory and experimental work provided crucial insights into the field of behavior therapy. Specifically, physiological fear response during imagery of feared stimuli has been identified as the marker of successful learning during imaginal exposure and habituation. In light of this finding, evidence reviewed in Section I showing blunted physiological fear response in patients suffering more chronic anxiety and mood dysfunction represents a serious concern in the clinical field. Specifically, it suggests that such individuals may require additional support to enhance physiological responding in order to maximally benefit from the corrective effects of imaginal (or in vivo) exposure therapy. Given that the success of imaginal exposure therapy in facilitating fear-extinction hinges upon the patient exhibiting initial physiological arousal to the imagined fear stimuli, the efficacy of other CBT treatments using mental imagery to facilitate emotional processing may also be enhanced by taking steps to ensure that emotional responses to mental imagery are maximized. Future clinical translational and treatment efficacy research may well benefit from using training techniques pioneered by Lang to keep affect “hot” during critical moments in therapy.Recent individual differences research has begun to illuminate how bias in the relative ability to voluntarily generate emotional imagery, and bias in the tendency to spontaneously experience emotional imagery, differentiates those experiencing emotional disturbance from healthy individuals. This line of experimental research has important clinical implications, as an excess of unwanted emotional mental imagery requires therapeutic alteration. Further, the inability to generate positive imagery, or inability to respond to negative imagery, has treatment implications for depression and exposure therapy. Particularly promising is experimental research that investigates how the relationship between mental imagery and emotion can be exploited for clinical benefit via cognitive bias modification training. Future research on positive mental imagery training could be enhanced by incorporating Lang’s method of emotional imagery response training, using imagery-eliciting scripts that contain both stimulus and response information, combined with training procedures that positively reinforce emotional responding during mental imagery. Furthermore, measuring both subjective and neurophysiological indices of emotional response during positive mental imagery training may provide additional information in identifying treatment responders in future research.Nearly 40 years ago, Lang’s seminal work on emotional imagery laid the foundation for a new era of experimental and clinical research on this fascinating topic. While subsequent researchers have been able to build upon this firm foundation in ways that have greatly expanded knowledge and understanding, it is remarkable that Lang’s original questions, and the findings produced by Lang and his collaborators, have remained of such central importance within the burgeoning contemporary literature. We are confident that this will continue to be the case across the years that lie ahead, and we are honored to have been given this opportunity to celebrate, and pay tribute to, Lang’s extraordinary scientific and clinical legacy.The authors declare that there are no conflicts of interest.