The metabolism of immune cells is a rapidly developing field with therapeutic implications. In recognition of this exciting area, our journal is welcoming submissions of primary research articles, perspectives, comments, and review articles in immunometabolism with the aim to highlight these articles in a special collection. Indeed, there is currently a keen interest in cellular reprogramming of different immune cell subpopulations and in understanding the functional role of metabolic factors—key enzymes, metabolites and nutrient transporters—in various immune cell subsets in our biology community. These exciting topics are commonly described under the term immunometabolism.Metabolism has recently become the hub connecting several rapidly growing research areas, including cancer, hematopoietic stem cell biology, and cellular developmentCommunications Biology are welcoming submissions on immunometabolism as part of a special collection to be published in 2021.We at One of the most exciting areas in immunometabolism is regarding memory immune cell subpopulations , which are thought to exert their functional roles by adjusting diverse metabolic programs. Further studies are warranted to dissect the functional roles and molecular mechanisms of metabolites and enzymes of the TCA cycle and glycolysis within each memory immune cell subset. In addition, new insights into metabolism in immune-mediated pathological diseases, such as atherosclerosis, would advance the development of the immune metabolic biomarkers and potential clinical applications in cardiovascular medicine.4. What are the molecular mechanisms underpinning immune-mediated pathologies? Can we target specific metabolic pathways in various immune cell subsets to clinically halt disease? These issues are worthy aims for future research. Uncovering the answers to all these questions might guide the development of immunometabolism-based therapies in future. As I know from my laboratory research activities on microRNAs in immunometabolism, further studies of metabolic alterations by microRNAs in the context of different immune cell subsets are a potential hot topic in this exciting area.Recent evidence indicates that specifically targeting host metabolic reprogramming might provide the host with defenses to fight environmental challenges such as pathogen infections. For instance, targeting glutaminolysis has been suggested to regulate proinflammatory cytokine production and immune cell infiltration upon infectionCommunications Biology since it was launched in early 2018. We have been serving as a harbor for immunologists, endocrinologists and scientists who study metabolism. As illustrated by our journal’s name, communication between biologists is what we envisioned to accomplish when we launched our journal. Following this in our heart, our in-house editors and external editorial board members will keep working hard to provide a home for scientists who advance this exciting area by publishing new findings that are relevant to the field.High-quality articles in the areas immunology and metabolism have already found their home in Communications Biology5 are welcoming submissions on immunometabolism as part of a special collection to be published in 2021. We especially encourage submissions related to metabolic enzymes in innate/adaptive immune responses, nutrient transporters in immune cell activation, metabolites as immunological regulators, strategies targeting metabolism to modulate immune responses, and non-coding RNAs in regulation of immunometabolism; however, we will also consider other areas of immunometabolism. Papers will be published as they are ready and combined into a special collection once a majority have been published. We will consider all submissions related to immunometabolism submitted by March 15, 2021 for the collection. We hope this special collection will benefit scientists who are interested in the state-of-the-art research on immune responses and cellular metabolic reprogramming.We at


Study results indicate that moments of unoccupied rest immediately after learning serve an essential cognitive function: memory consolidation. However, there also are findings suggesting that waking rest after learning has similar effects on delayed memory performance as an active wake condition, where participants work on a cognitive distractor task. Based on these studies, we highlight several potentially modulating factors of the so-called resting effect. Forum article on the impact of a brief period of rest after learning on memory consolidation, Wamsley .Age. Fatania and Mercer (Order of the waking rest condition). These results indicate that, under certain conditions, waking rest has a higher impact on memory consolidation in children and older adults compared to younger adults  found similar effects of waking rest and verbal and visual 2-/3-back tasks on the retention of verbal and visual information. They argue that post-encoding cognitive engagement does not interfere with memory consolidation when task performance has minimal semantic and hippocampal-based episodic memory processing demands   resting exactly means. Can we speak of waking rest when participants talk to the experimenter, read a newspaper article, hear music or lie in a noisy magnetic resonance scanner (for a review, see e.g. Dewar et al. For instance, study results indicate that the time course of memory consolidation is accelerated by prior knowledge relevant to the newly learned information (Dudai et al. To conclude, we presented a list of factors potentially modulating the impact of waking rest on memory, which have to be verified in further studies and additional factors have to be tested. In our view, it is vital to specify under which circumstances the resting effect occurs. Identification of such modulating factors can help in the design of future waking rest studies and interpretation of inconsistent findings; it also may serve as a basis for delineating practical implications on how to incorporate waking rest as a supporting memory retention strategy in everyday life.


Neophron percnopterus) from Spain and France to study how the rearing environment determines dispersal. For 124 vultures, we recorded a median dispersal distance of 48 km (range 0–656 km). Linear models were used to assess the effect of population and individual traits on dispersal distance at two spatial scales. Dispersal distances were inversely related to vulture density in the natal population, suggesting that birds perceive the abundance of conspecifics as a signal of habitat quality. This was particularly true for declining populations, so increasing levels of opportunistic philopatry seemed to arise in high density contexts as a consequence of vacancies created by human-induced adult mortality. Females dispersed further than males, but males were more sensitive to the social environment, indicating different dispersal tactics. Both sexes were affected by different individual attributes simultaneously and interactively with this social context. These results highlight that complex phenotype-by-environment interactions should be considered for advancing our understanding of dispersal dynamics in long-lived organisms.Natal dispersal, the movement between the birth and the first breeding site, has been rarely studied in long-lived territorial birds with a long-lasting pre-breeding stage. Here we benefited from the long-term monitoring programs of six populations of Egyptian vultures ( By relocating genes and individuals across the landscape, natal dispersal affects individual fitness and population dynamics, so it has multiple evolutionary and ecological consequences6. As a key ecological process, it affects the genetic structure, geographical expansion, and the dynamics and stability of (meta)populations4, with profound implications for conservation and management. Despite this, our knowledge of this phenomenon is still inadequate and mostly based on indirect methods5, to the extent that many key unknowns in basic and applied ecology are directly related to a poor understanding of dispersal processes and patterns10.Natal dispersal, the movement between the birth and the first breeding location, usually constitutes the longest effective dispersal displacement that animals make throughout their lives11. This precludes detecting long-distance dispersers, a relevant issue because they can contribute disproportionally to range shifts and population dynamics13. Despite these methodological difficulties, a pervasive pattern even among actively dispersing animals is that the frequency of dispersers decreases with the distance from the source location, with most individuals displacing short or medium distances and a minority moving long distances14.Studying dispersal is complicated, so even descriptive approaches are subject to serious methodological biases. For example, dispersal patterns derived from capture-recapture data are often biased by the limited spatial scale over which movements were studied15. Fixed dispersal strategies are rarely expected16, and it is currently accepted that animals may respond plastically to variations in the costs and benefits of dispersal over the short-term. At this proximate level, dispersal is influenced by the environmental context and by internal state variables of the individual organism . Biotic and abiotic factors comprise the condition-dependent, environmentally induced causes of dispersal. For example, dispersal is a common response of organisms to population saturation or deteriorating habitat quality19. On the other hand, individual traits such as age, sex, body condition, development effects, and the behavioural type may modulate phenotype-dependent dispersal17. A widespread pattern is that dispersal is sex-biased, but there are few data or contradictory results regarding the effect of many other internal traits. This may be explained because the above-mentioned factors can be expected to interact with each other. Understanding these interactions, and in particular how the internal state of individuals interacts with the environmental context to produce different dispersal phenotypes, is of crucial interest for generating landscape-specific predictions about dispersal of individuals or whole populations. This aspect, however, has received little attention22.To the difficulties of obtaining unbiased estimates must be added the fact that dispersal is a complex phenomenon that depends on multiple causes acting at different levels and scales23) or restricted to particular stages of the dispersal process (e.g.24). Here we benefited from several long-term marking and monitoring programs of a territorial bird with a long-delayed onset of reproduction, the Egyptian vulture Neophron percnopterus, to describe large-scale natal dispersal patterns and examine the potential determinants of dispersal distances. Particularly, we investigated the influence of internal and external factors on individual variation in natal dispersal, and how these different forces combine and interact to explain dispersal patterns.Birds are prime models in the study of dispersal in animals. However, most knowledge from long-lived species with a long pre-adult period has a major bias towards colonial species. Studies on dispersal of long-lived territorial species are very scarce and mostly descriptive , but it may be practical to review some general predictions to help understand how these interactions may change the strength and direction of single effects.Our research framework is based on the idea that the dispersal phenotypes are the result of the different sensitivity of individuals to environmental cues and constraints experienced in the natal patch26, with individuals being more prone to disperse and/or moving further the higher the density of conspecifics, due to resource depletion (exploitative competition) and/or direct competitive interactions (interference competition). Conversely, the opposite view of individuals dispersing less from high-density areas has also found some support, arguably because conspecifics may be used as cues of environmental quality27. Density-dependent approaches are, however, often founded on the assumption that density informs on habitat quality and saturation, but this does not necessarily have to be the case28. Density values can have different meanings, so complementary data on individual behaviour and habitat quality may be key to separate social effects from other confounding factors when experimental approaches are unfeasible29. For example, if individuals are able to perceive deteriorating habitat conditions, they may tend to escape from declining populations by moving further30, irrespective of population density. Alternatively, it could be hypothesized that average dispersal distances would be longer from stable populations because of the fewer unoccupied sites to settle and the higher competitive context for these locations in the natal area.Most empirical studies report positive density-dependent dispersal32, so we predicted that this should hold true for Egyptian vultures. As both sexes seem to have different functions in territory acquisition and defence, and because female-biased adult mortality has been reported in Spain33, we predict that the effect of density and competition on dispersal should be higher in males. In such a long-delayed breeder with a large variance in age of first reproduction33, dispersal distance could also be expected to vary with recruitment age. In species with delayed breeding, several non-exclusive hypotheses have been proposed to explain why some individuals hold a territory as soon as they reach sexual maturity while others remain as floaters well beyond this age34. They can be summarized in (1) constrain hypotheses, which postulate that some individuals are inferior and cannot hold a territory until they acquire the necessary age, experience, and skills35. If individuals are constrained in such a way, we would expect young recruits to be of higher quality, thus dispersing shorter distances from high-quality natal areas; (2) restraint hypotheses, which postulate that early reproduction implies future fitness costs in terms of survival and/or breeding prospects36. In this way, some individuals would recruit as soon as they can obtain a breeding vacancy whatever its quality, while others would voluntarily delay breeding to acquire dominance status while queueing for a high-quality territory. Under this hypothesis, birds with a delayed breeding strategy would recruit at shorter distances than early recruits whenever the natal area is perceived as high quality. Other phenotypic traits, mediated by, and interacting with environmental and/or parental effects may determine natal dispersal distances. Dispersal is known to entail costs during transience and settlement stages because individuals have to cope with unfamiliar environments in which they must find food, avoid various sources of mortality, and secure a territory and a mate37. Philopatry to the natal area may be the most advantageous strategy in these circumstances, so we predicted a negative relationship between natal phenotypic traits presumably conferring competitive advantages and dispersal distance. Factors such as date of birth, the hierarchy within the natal brood, or body condition may reflect these natal conditions and may determine dispersal patterns40. However, the benefits of emigrating from poor or deteriorating patches may overcome the fitness costs of dispersal, particularly in bearers of phenotypic traits that reduce dispersal costs17, so in this situation superior individuals are likely to disperse further20. Dispersal can also be an efficient way to avoid competition with kin (reviewed in5). Brood size could be a proximate cue informing on sib-competition, so longer dispersal distances could be expected in vultures from double-chick broods.Among internal state variables, sex-biased dispersal is pervasive in socially monogamous birdsAt the regional scale, we had data on natal dispersal of 124 vultures . The vast majority of birds dispersed to a greater or lesser extent from the natal territory to establish their own breeding territories, but three males recruited in their natal nest  with a median distance of 17.1 km, . Again, females tripled the distances covered by males .Linear models for the whole dataset revealed clear support for the effect of sex, breeding population density, and population trends at the population of origin on natal dispersal distances, as these variables were always included as main effects in the 95% confidence set of models Table . In geneResults at the Ebro valley local scale were congruent with those found at the regional scale Table , but effModel diagnostic checking indicated reasonable agreement with the observed data Figs.  and S2. 25.We investigated natal dispersal patterns and their potential determinants in a long-lived vulture with a prolonged pre-breeding stage. Our large scale analyses involving populations with contrasting densities and trends allowed us to capture wide spatial variation in dispersal distances and environmental conditions. We found that dispersal distance was inversely density-dependent, particularly in declining populations. We also found that some internal state variables influenced dispersal distances, but often interacting with the social environment and differently in each sex. These results show that a complex interplay between phenotypic traits and the natal environmental context determine what types of individuals disperse and how far they move41. Other selective advantages of philopatry are the preservation of co-adapted genomes42, and the familiarity with the natal environment3. Whatever the ultimate mechanism, this result agrees with the prevailing view of distance-decaying kernels in virtually all organisms13, and in birds in particular2. At the same time, there was substantial individual variation. Previous information on long-distance dispersal in Egyptian vultures was anecdotic43, so dispersal has been assumed to be of much lower magnitude in studies of population dynamics47. Our estimates of dispersal at the regional scale were much larger than those derived from the movement of birds at the local scale, remarking the importance of considering appropriate spatial scales in dispersal studies11. Although we did not monitor the whole breeding population of Spanish and French Egyptian vultures, and certainly some individuals were lost from observation, our large-scale approach at the regional scale minimizes this kind of sampling bias distortion. Indeed, natal dispersal patterns found at this scale seem more realistic at explaining two features of the spatial structure and dynamics of Egyptian vultures in southern Europe. First, the dynamics of semi-isolated populations have been shown to be strongly affected by immigration48, which necessitates some level of medium to long-distance dispersal. Second, our findings concur with the genetic panmixia described for the Spanish mainland population, but with a certain signature of isolation in the very peripheral population of Southern Spain49.The general tendency of Egyptian vultures for being philopatric at the landscape scale occurred in spite of their long-distance migratory movements and long and wide-ranging nomadic pre-breeding lifestyle. This can be explained in evolutionary terms by the simple fact that being born in a particular place informs that this place is of sufficient quality for the species to breed26, we found that birds moved shorter distances the highest the density of breeding conspecifics in the surroundings of the natal site. This also contrasts with most theoretical models of dispersal evolution, which predict positive density-dependent dispersal in competitive scenarios53. However, negative density-dependency in natal dispersal has been found in some species of territorial birds56 and other vertebrates26, and could be explained because birds born in dense environments could perceive a higher chance of finding a vacancy and/or a mate in the surroundings of the natal location57. Moreover, the abundance of conspecifics could be used as a reliable indicator of habitat quality27, modulating the propensity of individuals to abandon the natal area58. Consistent with these views, we detected a strong interactive effect of conspecific density around the natal patch and population trend, so that shorter dispersal distances occurred in birds born in dense but declining populations where more vacancies are available.From a more mechanistic perspective, our results show the importance of the demographic context on the distance moved by dispersers. Contrary to the most general finding of positive density-dependent dispersal patterns in territorial animals59. Adult mortality and territorial extinction create vacant sites in the population which would facilitate individual recruitment closer to the natal territory62. However, contrarily to other demographic processes which may signal habitat degradation such as the quantity and quality of offspring raised by conspecifics63, birds are probably incapable of perceiving changes in habitat quality associated with an increase in anthropogenic adult mortality64. As breeding success in these declining populations is not higher than in stable or increasing ones66, our results suggest that settlement patterns of first breeders could be conditioned at least in part by habitat selection behaviours leading to an incorrect perception of habitat quality . Conspecific attraction may result in this type of maladaptive behaviour if conspecifics are no longer valid indicators of habitat quality69, particularly if coupled with adult site fidelity in what has been called “social inertia”70.This last result does not support the prediction of longer dispersal distances from deteriorating populations, and is probably related to the fact that the main cause of population regression in most Egyptian vulture populations of Western Europe is human-induced adult mortality, with poisoning as the predominant factor32, and in raptors in particular71, supporting a general selective advantage for males to stay closer to their natal sites. Several mostly non-exclusive hypotheses have been proposed to explain these differences, although the resource competition hypothesis proposed by Greenwood31 would be the most supported by data72. Under this hypothesis, males of territorial monogamous birds often acquire and defend local resources, so they would benefit more from being philopatric due to familiarity with the natal area, while females would invest in searching for males in larger areas and eventually disperse further. Moreover, locating and defending a territory is an intensive task that would prohibit males from sampling extensive areas rapidly, while females would be more free to prospect wide areas in search of males73. The fact that conspecific density was particularly influential on the dispersal distance of males, with females being more insensitive to this factor, would support this hypothesis . Contrary to other studies of long-lived birds76, we found evidence that dispersal distance diminishes with recruitment age in Egyptian vultures, particularly in males. Recruitment age could be biased by detection probability, for example if breeders are not detected in the year of recruitment. However, resighting rates of breeders were very high in our populations77, and once recruited Egyptian vultures show extreme fidelity to their territories . Moreover, our findings of a negative relationship between dispersal distance and recruitment age were contrary to what would be expected under distance-decaying resighting rates78. Hence, our estimates are probably very close to reality. Since birds dispersed shorter distances when there were many conspecific breeders in the surroundings, our findings could be related to the simultaneous coexistence of different life-history tactics as to when and where to recruit, two decisions that probably cannot be separated79. Sexually mature birds from dense populations could prefer to delay breeding, gaining skills, experience, and local site dominance while queueing for a territory in the surroundings of the natal territory or, alternatively, try to settle as soon as possible by moving away to seek less competitive environments. This hypothesis would be in accordance with the more pronounced effect of recruitment age on dispersal distance of males, the sex that presumably acquires resources, and with the biased mortality of female breeders observed in Egyptian vultures33, which would relax competition for breeding opportunities in this sex.We also found that birds respond to the natal social environment in different ways depending upon individual traits such as sex, age, and the conditions experienced during the rearing stage. Egyptian vulture females dispersed on average longer distances than males, and indeed in our data set the three birds that recruited in the nest of birth were males, while the three cases of movement distances longer than 500 km corresponded to females. This result is in accordance with the wealth of previous empirical evidence of females being more dispersive than males in birds80, so these females probably decided voluntarily to move further. In addition, body condition may be a prerequisite for not suffering high costs during long-distance movements81, and may affect different aspects of the dispersal process related to landscape exploration, such as speed, tortuosity, and path length82. In late hatched birds, however, body condition did not appear to influence dispersal, which was shaped instead by the density of breeders in the natal population. Although the correlative nature of our data hinders identifying the precise mechanisms involved, our results indicate that the distinct developmental conditions experienced by individuals, interacting with the environmental context, have important effects on dispersal asymmetries later in life.Finally, date of birth and body condition seemed to affect dispersal distances in females. Hatching date interacted with body condition, with females hatched early in the breeding season and with a good body condition dispersing the longer distances. Both variables are usually considered as good proxies of individual quality in birds, and indeed have been related to survival prospects later in life48. Currently, some of the threatening causes have subsided, others continue operating, and new conservation challenges are arising, with the result that the species is recovering in certain areas83 while continues to decline in others84. In this context, relevant questions are how natal dispersal strategies may contribute to local population persistence and dynamics. Our findings suggest that Egyptian vultures, like most raptors, have evolved under conditions selecting for philopatry at a regional scale, probably due to spatial variability but temporal autocorrelation (predictability) in breeding habitat quality71. In these circumstances, social information may provide an efficient and easy way for individuals to assess and select where to settle85. However, drastic changes in adult survival could have decoupled habitat selection and quality (see above), so declining populations still maintaining relatively high densities of conspecifics may become ecological traps for local recruits, probably buffering them from steeper decline86, but reinforcing over time their deceptive appearance of high-quality sites. Inverse density-dependent dispersal also raises concerns about the population viability of sparse populations, which will lose locally-produced individuals via dispersal, increasing extinction probabilities87. Although all these results suggest that dispersal behaviours could depart from which would be ideal for population performance88, more information on the balance between immigration and emigration is needed90.Egyptian vulture populations suffered a dramatic human-induced decline in the past that made the species disappear from many locations of Spain and France91. Our results indicate that dispersal from the natal site (emigration) is inversely related to population density. Recruitment patterns (immigration) also seem to be positively influenced by the presence and abundance of conspecifics, as the spatial distribution of territories explains both territory persistence and the establishment of new pairs92. Thus, Egyptian vultures colonize apparently appropriate empty areas very slowly in spite of being within the frequent range of dispersal distances, so recruits seem to be perceiving them as unsuitable . The fact that recently colonized areas are mostly situated in the proximity of healthy populations agrees with the distance-decaying dispersal distribution reported here, as well as with the higher tendency to emigrate from stable populations. It is also important to highlight that dispersal not only have effects on the spatial dynamics of (meta)populations, but the fitness payoffs of dispersal may be affected by such dynamical properties in an eco-evolutionary feedback loop96. As a consequence, dispersal may be selected against if moving becomes too costly due to habitat fragmentation or if occupied patches become too scarce99. Such a phenomenon could have occurred with the closely related bearded vulture in Spain and France, which was confined to the Pyrenees after intense human persecution and has not been able to leave this mountain range without human assistance despite significant population growth in recent decades100. In this way, if local extinctions continue to fragment Spanish and French populations of Egyptian vultures, evolutionary changes at the individual level could result in a profound discrepancy between dispersal behaviours and the levels of movement needed to maintain metapopulation processes88, thus exacerbating extinction probabilities.If emigration and immigration are governed by the same ‘avoid low density’ strategy, the speed with which the species can shift its range can be greatly reduced13, they only offer a basic description. Dispersal is a behavioural process that has a beginning (emigration from a site), an intermediate stage of movement (transience) and an end (immigration or settlement), and studying these three phases, their interdependence, and the different factors that come into play across them have been remarked as important to understand the complexity of dispersal dynamics17. The transience stage of Egyptian vultures lasts several years, during which birds may wander over long distances visiting several communal roosts as well as territories occupied by breeding pairs . Although the function of these extensive movements is unknown, it is likely that they were used at least in part to gather information on potential mates and settlement areas103, eventually determining natal dispersal distances. Interestingly, theory indicates a great propensity to invest in information acquisition to take informed dispersal decisions when the environment is predictable and prospecting costs are low104. However, Egyptian vultures seem to pay mortality costs just before settling as breeders77, suggesting that prospecting may not be so affordable. Although prospecting length may decrease with mortality risks, even in these circumstances some long-distance dispersal movements are expected to persist105. Indeed, dispersal patterns may reflect different dispersal strategies across stages and switches between movement modes during transience that are likely determined by the way particular phenotypes accumulate experience and respond to environmental conditions on the move107. All these aspects open exciting research avenues that will refine our understanding of dispersal in long-lived territorial birds.Although Euclidean distances are a fundamental characteristic of dispersal108. Egyptian vultures are medium-sized (~ 2 kg) obligate scavengers, which have declined sharply through its range108. They are territorial breeders that actively defend their breeding cliffs from conspecifics. However, during their long pre-adult stage, they lead a nomadic and social lifestyle. Pre-breeders typically roost communally near predictable food sources such as landfills, supplementary feeding stations, and large dumps of dead livestock, often performing large-scale movements between temporary roosting sites109. Median age of first breeding is at 7 years in peninsular Spain33, considerably later than in other raptors with similar size110. As typically occurs in species with a slow pace of life, Egyptian vultures have low fecundity (0–2 fledglings per breeding attempt). Mainland populations from Western Europe are typically long-distance migrants wintering in the sub-Saharan Sahel region111.We analysed natal dispersal distances of Egyptian vultures from six populations with contrasting densities and trends in Spain and France Table , where tBetween 1986 and 2015, we marked 1613 fledglings in six study areas  once birds recruited as breeders112 and from unpublished information for France. We used these data for Spain because there were Egyptian vultures breeding outside our study areas, and therefore we did not have annual information on density within that buffer for all nests from which birds dispersed. When population density was calculated on the basis of the previous Spanish national census carried out in 2000113 our findings were qualitatively similar  hierarchy rank within the brood (three categories: one fledgling and first or second fledgling from two-chick broods); (3) body condition at ringing time, as estimated from the residuals of an OLS regression of log-body mass on log-primary length .At the regional scale, we used as environmental variables local population densities and trends. As an index for natal population density we used the total number of occupied territories within a buffer of 48,000 m of the nest of birth ) with linear models. Prior to fitting the models, we did some exploratory data analyses to visualize the distribution and structure of the data. In this step, we also explored if logarithmic or quadratic effects could potentially produce more robust inference, but linear terms always outperformed their non-linear counterparts. Two sets of candidate models were constructed, one for each spatial scale. Exploratory analyses and graphs suggested that some interactions between predictors could be operating in a sex-specific way at the Ebro valley local scale, so we additionally built linear models for each sex separately at this scale. For the analysis at the regional scale, population identity of origin was initially fitted as the random intercept in linear mixed models to control for multiple observations from the same study plot. However, population ID variance was estimated as zero in some models that included population density as a fixed predictor. Among-group variance was also estimated as zero for all random intercept models with Year identity as a random term, including the null model with no fixed effects. This indicated that all observed variance came from among-observation  variance and virtually none from among-year variation. Thus, we proceeded with linear models without random effects and tested for spatial dependence in model residuals (see below). All combinations of main effects and two-way interactions were fitted, beginning with a global model and trying to reduce model complexity.115. In all cases, values were sufficiently low (e.g. variance inflation factors VIF < 1.2) for collinearity to be of limited concern. We fitted candidate models using maximum likelihood (ML) estimation to allow model comparison. Model selection was based on Akaike’s Information Criterion corrected for sample size (AICc), and the relative fit of each model was ranked according to AICc differences . Following standard procedures, we calculated the Akaike weight for each candidate model (wi) as the relative strength of evidence, i.e., the probability of model i being the best-approximating model from the entire set of candidate models, and evidence ratios of the best models as the ratio of model weights. When there was no clear support for the highest-ranked model (less than 2 AICc points with respect to the second-ranked one), we used model averaging procedures to compute estimates of regression parameters. The relative importance of each predictor (RVI) was assessed by summing up the Akaike weights over the highest-ranked models including that predictor117. We used Moran’s I and semivariograms to evaluate the spatial pattern in the residuals from the top-ranked models118.Before fitting the models, we centred the predictors by subtracting the mean, and assessed multicollinearity by calculating both overall and individual collinearity measures119. Multicollinearity was diagnosed with the package mctest115. For the most parsimonious models derived from AICc values, we inspected the scaled residuals using the package DHARMa120 and used standard methods for model fit diagnosis.We used ArcGIS 10.5  for spatial data management and calculations . All statistical analyses were performed in R 3.5.0.Bird-handling procedures and bird marking were authorized by Centre de Recherches sur la Biologie des Populations d'Oiseaux (CRBPO)—CNRS/MNHN (France), Gobierno de Aragón and Gobierno de Navarra , Diputación Foral de Bizkaia (Bizcaia), Junta de Andalucía , and Gobierno de Castilla y León (Segovia), and following the protocols approved by the Ethic Committee of CSIC (CEBA-EBD-12-56).Supplementary Information


This review describes methodology used in the assessment of the manifestations of exercise-induced hypoalgesia in humans and previous findings in individuals with and without pain. Possible mechanisms and future directions are discussed. Exercise and physical activity is recommended treatment for a wide range of chronic pain conditions. In addition to several well-documented effects on physical and mental health, 8 to 12 weeks of exercise therapy can induce clinically relevant reductions in pain. However, exercise can also induce hypoalgesia after as little as 1 session, which is commonly referred to as exercise-induced hypoalgesia (EIH). In this review, we give a brief introduction to the methodology used in the assessment of EIH in humans followed by an overview of the findings from previous experimental studies investigating the pain response after acute and regular exercise in pain-free individuals and in individuals with different chronic pain conditions. Finally, we discuss potential mechanisms underlying the change in pain after exercise in pain-free individuals and in individuals with different chronic pain conditions, and how this may have implications for clinical exercise prescription as well as for future studies on EIH. This phenomenon is known as exercise-induced hypoalgesia (EIH).195 The first observation of EIH was published 40 years ago by Black et al..14 During the past few decades, the number of studies investigating the effect of exercise on pain has increased dramatically, likely reflecting the increasing burden of pain as well as the recognized role of exercise in the treatment of pain.Exercise is guideline recommended treatment for a range of chronic pain conditions.This article will begin with a brief introduction to the methodology used in the assessment of the manifestations and mechanisms of EIH in humans. The second part of the article will present an overview of the findings from previous experimental studies investigating changes in pain perception after acute and regular exercise in pain-free individuals and in individuals with different chronic pain conditions. Possible mechanisms underlying the response to exercise in pain-free individuals and in individuals with different chronic pain conditions will also be discussed. In the last part of the article, implications for exercise prescription and future EIH studies will be addressed.130 Controlled studies using similar methodology but different designs  have also been conducted.204 The results of these studies, especially those where participants were randomized to exercise or control, or where the order of exercise and control were randomized and counterbalanced for crossover trials, give a less biased estimate of the effect of a single bout of exercise on pain.The effect of a single bout of exercise on pain perception in humans has primarily been investigated experimentally in laboratory settings. The methods used in these investigations are diverse, incorporating different study designs and methods of pain assessment. Most often, EIH has been investigated using a within-group pre-post design, whereby participants' pain is assessed at different exercising and nonexercising body sites before and during/after exercise.23 These tests typically involve the assessment of a person's pain threshold or pain tolerance which are, respectively, the minimum intensity of a stimulus that is perceived as painful and the maximum intensity to a noxious stimulus that the participant is willing to tolerate.116 Ratings of pain intensity and unpleasantness during exposure to various noxious stimuli might also be measured. As an example, pressure may be applied at an increasing intensity over the lower leg using an inflated cuff, with participants asked to rate the point at which this pressure becomes painful (threshold) and then endure it for as long as possible (tolerance) while rating its intensity or unpleasantness. Using this example, EIH could manifest as an increase in pain threshold, an increase in pain tolerance, and/or a reduction in ratings of pain intensity or unpleasantness. These measures are most commonly assessed in the immediate postexercise period , but some studies have measured pain 30 to 60 minutes after exercise cessation to investigate the persistence of EIH.103Pain has been quantified in a variety of ways in studies of EIH, with quantitative sensory testing used most often. Quantitative sensory testing describes a series of tests that measure the perceptual responses to systematically applied and quantifiable sensory stimuli .137 and is considered a behavioural correlate of wind-up—the frequency-dependent increase in C-fibre-evoked responses of dorsal horn neurons after repetitive stimulation at a constant intensity.63 Temporal summation paradigms provide information mostly about facilitatory mechanisms underlying nociceptive processes.23 By contrast, conditioned pain modulation provides an index of the strength of pain inhibition. Conditioned pain modulation  involves the application of 2 noxious stimuli over 2 different areas of the body, with the more pronounced noxious stimulus (conditioning stimulus) subsequently inhibiting the perception of the weaker noxious stimulus (test stimulus).212 Using these paradigms, EIH would manifest as a reduction in temporal summation and/or an increase in conditioned pain modulation, although evidence for the latter is limited.122Methods that assess an individual's ability to modulate pain have been increasingly used in recent studies of EIH. These include temporal summation, spatial summation, conditioned pain modulation, and offset analgesia. Of these paradigms, temporal summation and conditioned pain modulation have been used most often. Temporal summation refers to an increase in pain after repetitive stimulation at the same intensity80 These more complex methods, which include evoked potentials and neuroimaging, may provide greater insight into the mechanisms of EIH compared to more commonly used quantitative sensory tests. Evoked potentials are cortical responses recorded at the scalp using electroencephalography in response to brief and intense stimuli. Evoked potentials are described by their polarities (negative [N] and positive [P]), latencies, and amplitudes, and consist of early, late, and ultra-late components. When analysing pain-related evoked potentials, the peak-to-peak amplitude of the N2P2 is the component most related to nociception, whereby larger N2P2 amplitude is associated with more pain.71 There is evidence that both the sensory-discriminative and affective aspects of pain are captured by this late component of the evoked potential, and studies have shown exercise to reduce the amplitude of this component.145 Neuroimaging is widely used in the study of pain, but to the best of our knowledge, only 2 studies have used neuroimaging to investigate acute EIH.165 In one study, brain responses to noxious thermal stimuli before and after rest and exercise were measured using functional magnetic resonance imaging in women with fibromyalgia and healthy pain-free controls. The results suggested that, in the women with fibromyalgia, exercise-stimulated brain regions involved in descending pain inhibition which, in turn, was associated with lower pain ratings to thermal stimuli.38 In the second study, brain responses to noxious thermal stimuli before and after walking and running exercises were measured using functional magnetic resonance imaging in 20 athletes. The results suggested that running exercise reduced the pain-induced activation in the periaqueductal gray, a key area in descending pain inhibition which, in turn, was associated with lower pain unpleasantness ratings to thermal stimuli.165 Taken together, these results provide evidence that a single bout of exercise can modulate pain-related areas of the nervous system.Although not an assessment of pain per se, techniques that assess the function of the nociceptive pathways have sometimes been used to investigate EIH.130 whereas dynamic resistance exercise has not commonly been used. Within each mode of exercise, the prescription has varied too. For example, aerobic exercise has consisted of cycling, running, and stepping of various durations (30 seconds–30 minutes) and intensities (low to high).195 The same is true of isometric exercise where upper-limb and lower-limb exercise of both short and long duration (<5 seconds—exhaustion) and varied intensity (10%–100% MVC) have been studied.195 Studies of dynamic resistance exercise have typically used whole-body training at moderate intensities.93 Interestingly, EIH is reproducible with each type of exercise, even when modest doses are used.162 This is described in more detail below.In addition to the different study designs and techniques used to quantify pain in investigations of EIH, the exercise protocols have also varied considerably. Aerobic and isometric exercise have been studied most often,200 Increases in pain thresholds can also be observed at nonexercising body areas, although larger hypoalgesic responses are consistently observed in areas closer to the exercising muscles compared with nonexercising muscle areas. The observed EIH response is short-lasting, often with a duration lasting from 5 minutes after exercise69 to 30 minutes after exercise88 and may depend on the modality of the pain test stimulus.As illustrated in Table 195 although EIH differences have been observed,32 but exercise intensity and duration quite consistently affect the EIH response. Exercise intensity affects the EIH response after aerobic exercise.195 For example, in 80 pain-free individuals, it was observed that a moderate-to-high intensity bicycling exercise produced significantly larger EIH responses at the exercising quadriceps muscle, as well as at the nonexercising biceps and trapezius muscles, compared with a low-intensity bicycling exercise.195 Findings on the influence of aerobic exercise duration are more equivocal, with one study observing a dose-response with larger effects after bicycling for 30 minutes compared with 10 minutes,69 and one study observing no difference between bicycling for 10 minutes compared with 20 minutes.195 Moreover, the fact that very short-duration aerobic exercise can elicit EIH162 implies that intensity, or the combination of intensity and duration, may be more important for determining the size of EIH after aerobic exercise than either variable alone.The hypoalgesic responses seem to be similar between exercise types,157 although the results are more inconsistent. In 40 individuals, pressure pain thresholds at the hand were increased and pressure pain intensity was decreased after low-intensity  isometric elbow flexion until exhaustion. However, no hypoalgesia was observed when the contraction was held for only 2 minutes.64 By contrast, hypoalgesia was found after 90 and 180 seconds isometric knee extensions and elbow flexion exercises at 30% MVC and 60%, respectively, in 80 healthy individuals; however, the hypoalgesic responses were not different in magnitude between low-intensity and high-intensity contractions nor between shorter or longer durations.195 The fact that very low doses of isometric exercise  can produce EIH64 lends further support to the lack of clear dose-response, which is further evidenced by a study of 50 individuals where elevations in pain threshold were not different between isometric handgrip exercises at 25% MVC for 1, 3, or 5 minutes.189Exercise intensity and duration may also affect the EIH response after isometric exercises,196 and 20 minutes of aerobic exercise at 55% to 70% of heart rate reserve reduced temporal summation of heat pain132; however, temporal summation of pressure pain was not affected by 15 to 20 minutes of aerobic exercise at 50% to 75% of VO2max.196 However, not all studies have shown exercise to have positive effects on pain mechanisms. For example, Alsouhibani et al. observed a decrease in the CPM response after exercise.2 By contrast, other studies have found exercise to have no effect on CPM122 or offset analgesia,61 suggesting that exercise can, but does not always, influence spinal and supraspinal mechanisms of pain. Exercise can also influence the ability to cope with pain. The perceived pain intensity of a suprathreshold stimulus is consistently reduced by aerobic, isometric, and dynamic resistance exercises,98 and acute exercise can reduce ratings of pain unpleasantness even in the absence of a change in pain intensity.80 In addition, low-intensity nonpainful aerobic and isometric exercises also increase the tolerance to a painful stimulus. A 20% increase in pain tolerance was observed by Vaegter et al.199 after a 3-minute submaximal isometric knee extension exercise, and after a 6-minute walking exercise73 compared with rest in 35 pain-free individuals.As described, robust increases in pressure pain thresholds are observed after exercise, but exercise can also affect spinal and supraspinal mechanisms of pain. Temporal summation of pressure and heat pain was reduced after submaximal isometric exercises at 25% to 40% of MVC for 3 minutes,200 and painful exercises seem to have larger hypoalgesic effects than nonpainful exercises, at least in pain-free individuals,36 but perhaps not in individuals with chronic pain.173Exercise that produces acute hypoalgesia is often perceived as moderately painful with peak pain intensity ratings around 5 or 6 on a 0 to 10 numerical rating scale,81 observed that the hypoalgesic effect after bicycling was slightly increased if positive information about EIH was given before the exercise compared to when no EIH information was given before exercise. Second, a randomized controlled trial by Vaegter et al. comparing positive vs negative pre-exercise information observed a 22% increase in pain thresholds in the positive information group, whereas the negative information group had a 4% decrease  in pain threshold at the exercising muscle . Both studies observed a positive correlation between expectations and hypoalgesia after exercise.Treatment expectations are a well-recognized factor known to modulate treatment outcomes and the information about the effect of exercise given to individuals before exercise influences the magnitude of the EIH response. First, a randomized controlled trial by Jones et al.193 and isometric200 exercise protocols. Across protocols, some individuals consistently show hypoalgesia after exercise, some individuals consistently showed hyperalgesia after exercise, and some individuals had a change in their response from hypoalgesic to hyperalgesic or vice versa between days. Interestingly, the majority of individuals showed hypoalgesia at some point.Despite robust hypoalgesia after exercise on a group level, the response to exercise is not identical across individuals and across days. Several studies have investigated the stability of the EIH response in pain-free individuals across different days using a number of aerobic198 However, Ellingson et al.35 observed lower pain intensity ratings and lower pain unpleasantness ratings to suprathreshold heat pain stimulations in pain-free women who were physically active as defined by the current public health recommendations compared with women who were less physically active than recommended. There is also some evidence that individuals who are more physically fit experience greater EIH.166The effect of regular exercise and physical activity on pain sensitivity has been investigated, albeit less than the effect of a single session of exercise. In pain-free individuals, there have been relatively few studies investigating whether those who are more physically active experience greater EIH. The results of these studies show that EIH is usually similar between inactive and active pain-free individuals irrespective of the type of exercise they regularly perform  and the methods used to assess physical activity .58 observed changes in PPT in the legs after 6 weeks of moderate bicycling exercises (3 times/week) but not after high-intensity interval exercise. In addition, Jones et al.76 observed increases in pressure pain tolerance but not pain threshold after bicycling 30 minutes at 75% of VO2 max 3 times/week for 6 weeks compared with a control condition. These findings suggest that regular exercise in pain-free individuals specifically influences the ability to cope with pain  rather than the level at which pain is first perceived (pain threshold). Similar observations have been found in athletes compared with less active individuals. A systematic review with meta-analysis by Tesarz et al.182 showed consistently higher pain tolerance across different pain modalities  in athletes; however, for pain thresholds, the conclusion was less consistent.Regarding the effect of a longer period of exercise training in pain-free individuals, Hakansson et al.135 Although previous investigations on CPM in athletes have been equivocal because increased CPM52 as well as decreased CPM181 has been observed, the positive effect of regular exercise on CPM may be a potential mechanism underlying the preventive effect of exercise on pain because better CPM capacity has been associated with a reduced risk of chronic pain.211 The preventive effect of regular exercise is supported by a recent systematic review with meta-analysis concluding that regular exercise performed 2 to 3 times/week reduces the risk of low back pain by 33%.169 This is true even in those who are at an increased risk of developing chronic pain.115In addition to the effect on pain tolerance, regular exercise may also affect the ability to inhibit pain as assessed by the CPM paradigm. Naugle et al. observed that pain-free individuals reporting more regular physical activity also had a larger CPM response compared with individuals reporting less regular physical activity.197 shoulder pain,105 patella femoral pain,180 knee osteoarthritis,194 menstrual pain,186 and rheumatoid arthritis.117 However, reduced EIH responses or even hyperalgesia after exercise has often been demonstrated in individuals with whiplash-associated disorder,203 ME/CFS,202 fibromyalgia pain,177 painful diabetic neuropathy,90 chronic musculoskeletal pain,19 and also in a delayed-onset muscular soreness pain model.25 Hyperalgesia after exercise is often observed in individuals with more widespread chronic pain conditions. This was first observed by Kosek et al.100 in 5 individuals with fibromyalgia who showed a decrease in pain thresholds during and after an isometric knee extension exercise. The observation of hypoalgesia after exercise in some groups with chronic pain conditions and the observation of hyperalgesia after exercise in other groups with chronic pain may be influenced by whether the exercise is performed using a painful or nonpainful body area. Lannersten and Kosek107 observed hypoalgesia after a 5-minute submaximal (25% of MVC) isometric exercise in individuals with shoulder myalgia when the exercise was performed by a nonpainful leg muscle but when the exercise was performed by the painful shoulder muscle, no hypoalgesic response was observed. Similarly, Burrows et al.17 observed increases in pressure pain threshold after upper-body but not lower-body resistance exercise in people with knee osteoarthritis. These findings suggest that hypoalgesia can be induced by exercising nonpainful muscles in subjects with chronic pain,191 which may have important implications for exercise prescription in the clinical setting.In individuals with different chronic pain conditions, the response to a single session of exercise is less consistent as hypoalgesia, reduced hypoalgesia, or even hyperalgesia  has been observed. As illustrated in Table 121 often report reduced hypoalgesia after exercise. Vaegter et al.197 observed reduced EIH after submaximal isometric exercise and after bicycling exercise in chronic pain patients with high widespread pain sensitivity compared with patients with low pain sensitivity. In addition, in high pain-sensitive patients, an increase in temporal summation of pain was observed after aerobic exercise197 possibly mimicking the pain flare-up after exercise reported in clinical practice by some individuals with widespread chronic pain.24 Also, Fingleton et al.40 observed reduced pressure pain thresholds  after both aerobic and isometric exercises in individuals with knee osteoarthritis who demonstrated an impaired CPM response. By contrast, pain thresholds increased in knee osteoarthritis individuals with a normal CPM response suggesting that patients with impaired CPM, which is also a common finding in individuals with chronic pain,121 may have less acute hypoalgesic effect from exercise.Individuals with facilitated central pain mechanisms, which are commonly observed in several chronic musculoskeletal pain conditions,136 observed a larger EIH response in individuals with fibromyalgia after 20 minutes of aerobic exercise at a preferred intensity  compared with a prescribed and higher-intensity aerobic exercise . Similarly, Coombes et al.20 showed that isometric exercise above but not below an individual's pain threshold increased pain responses to exercise in people with lateral epicondylalgia. These results could indicate that lower-intensity exercise creates less input to facilitated central pain mechanisms resulting in a net balance of pain inhibition and a reduction in the pain sensitivity after exercise. This may be different for chronic exercise, however, where a small benefit of painful over nonpainful exercise has been observed, albeit for clinical pain at baseline as opposed to experimental pain in the immediate post-exercise period.173 Other possible explanations for reduced EIH include use of opioids and negative expectations about the effect of exercise. Interactions between EIH mechanisms and the use of analgesics may affect the response to exercise. Individuals treated with opioids report less CPM,155 and reduced effects of opioids have been reported in animals after long-term exercise.174 As observed in pain-free individuals, negative expectations are associated with the hypoalgesic response after exercise. Interestingly, most patients with chronic pain referred to multidisciplinary pain treatment do not expect exercises to cause less pain; on the contrary, the majority expects more pain after exercise . In people with fibromyalgia, Umeda et al.187 showed that participants who were more physically active reported a smaller increase in ratings of muscle pain intensity during isometric handgrip exercise. Taken together, these results suggest that being more physically active is associated with reduced pain responses to acute exercise in individuals with chronic pain. These results are consistent with cross-sectional data showing negative associations between fitness and pain  in people with fibromyalgia77 and knee osteoarthritis  as well as longitudinal data showing benefit of longer periods of regular exercise training on reducing pain in individuals with chronic pain.49To the best of our knowledge, only 2 studies have investigated whether habitual physical activity levels predict pain responses to acute exercise in individuals with chronic pain. Coriolano et al.130 suggests that the mechanisms of EIH are disrupted in individuals with chronic pain. That is, some aspect of chronic pain  interferes with the normal hypoalgesic effect of acute exercise. These potential mechanisms will be described in more detail hereafter.There are numerous biological and cognitive factors that contribute to pain, so changes in any one or more of these by acute exercise could account for EIH. It is not clear, however, what these mechanisms are or whether the mechanisms are similar or distinct between healthy individuals and individuals with chronic pain. The contrasting magnitude of EIH between pain-free individuals and individuals with chronic pain184 Exercise also increases the release of endogenous cannabinoids. These opioid and cannabinoid pathways have receptors throughout the peripheral and central nervous systems that can produce analgesia when stimulated.184The most commonly proposed mechanism of EIH is enhanced descending inhibition by activation of the opioid and cannabinoid systems. The contraction of skeletal muscle increases the discharge of mechanosensitive afferents  which, in turn, activates central descending opioid pain pathways.140 Moreover, correlations between EIH and exercise-induced changes in plasma concentrations of beta-endorphins and endocannabinoids are not always observed.165 A limitation of these human investigations is that they are more constrained than rodent studies in their ability to investigate whether opioids and cannabinoids are acting through peripheral and/or central actions to influence pain after exercise; however, there is some evidence that blocking blood flow to a limb during exercise attenuates EIH in pain-free individuals, suggesting that peripheral factors are important.79Human studies investigating the role of opioids and cannabinoids in EIH have yielded equivocal findings. For example, opioid antagonists such as naloxone and naltrexone have been shown to increase, decrease, or have no effect on EIH.149 but another study found that the suppression of exercise-induced growth hormone release by cyproheptadine had no effect on EIH.86 Dexamethasone, a steroid medication, has been shown to attenuate EIH by reducing secretion of adrenocorticotropin88; however, other studies have found no effect of dexamethasone on pain in healthy individuals.209 A small pilot study of 7 healthy individuals showed that exercise-induced changes in neuropeptide Y, allopregnanolone, pregnenolone, and dehydroepiandrosterone were related to EIH.167 However, because concentrations of these substances were only measured in the plasma, it is not clear whether they were acting through peripheral or central mechanisms to influence pain. Moreover, because this was only a small pilot study, more studies are needed to confirm the findings.Exercise-induced hypoalgesia might also be a form of stress-induced analgesia, related to the release of various stress hormones during exercise. However, evidence to support this in humans is mixed. For example, EIH is related to increases in growth hormone during exercise,161 there is currently little evidence that acute changes in blood pressure by exercise are related to EIH.190 Moreover, acute increases in blood pressure by exercise could not account for the persistence of EIH after exercise .Exercise-induced changes in the cardiovascular system have also been proposed as a mechanism of EIH. That is, elevations in blood pressure by exercise are thought to attenuate pain through baroreceptor-related mechanisms . Although it is true that people with high blood pressure are less sensitive to pain ,206 and increase thresholds to elicit the nociceptive withdrawal reflex,55 although there is some evidence contrary to the latter observation.125 These results imply that exercise can reduce pain through reductions in central nervous system sensitivity at spinal and supraspinal levels, but exactly where in the nociceptive pathway these changes occur is not known. Improved efficacy of descending inhibitory pathways by exercise has been studied as a mechanism of EIH as well, but there is little direct evidence to support this. For example, Alsouhibani et al.2 observed a decrease in the CPM response after exercise, Meeus et al. found no effect of aerobic exercise on CPM in healthy individuals,122 and Ellingson et al.36 showed that EIH was comparable for nonpainful and painful exercise, although the latter should have evoked a larger “pain inhibits pain” effect. A few studies have found small positive correlations between conditioned pain modulation and EIH198 suggesting that the 2 may share similar mechanisms; however, EIH is usually somewhat smaller in magnitude but more enduring than conditioned pain modulation so the 2 are likely distinct.195The influence of exercise on reducing the sensitivity of the central nervous system has also been explored as a mechanism of EIH. These studies show that acute exercise can reduce temporal summation80 suggesting that alterations in the appraisal of noxious stimuli contribute to EIH. Cognitive and psychosocial factors including pain self-efficacy, coping strategies, fear of pain, and stress are known to underlie some of the difference in pain between athletes and nonathletes,142 but their relation to EIH is less clear. For example, several studies have shown that individuals with higher levels of catastrophizing experience less EIH,207 although this is not always observed and correlations between EIH and other psychosocial factors  seem negligible.201 Therefore, the contribution of cognitive factors to EIH remains poorly understood but seems limited. More studies are needed to investigate whether these cognitive factors are related to EIH and, more importantly, whether they can be manipulated to augment it.81Changes in pain cognition might also account for some of the effect of acute exercise on pain. It has been shown that exercise can reduce ratings of pain unpleasantness in the absence of a change in ratings of pain intensity,The mechanisms of EIH in individuals with chronic pain are equally if not more unclear. Because exercise has such varying effects on pain within and between individuals with chronic pain, it is difficult to determine whether there is a consistent mechanism that contributes to changes in pain with acute exercise. Moreover, it is not clear if the mechanisms of EIH in individuals with chronic pain are the same as pain-free individuals and are just disrupted, or whether separate mechanisms related to the presence of chronic pain are involved as well.197 However, there are also several demonstrations that exercise with a painful joint or muscle can either diminish EIH compared to when a nonpainful body part is exercised 17 or, worse, can increase pain.177 These results are both opposite to what is normally seen in pain-free individuals where EIH is usually greatest for the exercised body part. Therefore, the results of the above studies provide some evidence that compared to healthy individuals, the mechanisms of EIH in individuals with chronic pain are both similar and distinct. However, because the mechanisms of EIH are still poorly understood in both groups, there is little direct evidence to support this.The fact that EIH can occur at exercised and remote sites in individuals with chronic pain shows that EIH is not always disrupted in these individuals.206 whereas the opposite effect has been observed in individuals with chronic pain.206 By contrast, one of the few studies to combine acute exercise with analgesic medication showed that paracetamol and placebo had comparable effects on temporal summation and conditioned pain modulation after exercise in pain-free individuals and individuals with chronic pain.122 Because paracetamol is a predominantly central acting agent that can affect opioids, cannabinoid and serotonergic pathways,168 this finding provides little support to the notion that exercise reduces pain through central changes in these pathways or that differences in the sensitivity of these pathways through exercise accounts for the greater EIH in pain-free individuals compared to individuals with chronic pain. More studies using drugs with less ubiquitous effects would be useful to further investigate how different substances are involved in EIH in humans and whether these differ between pain-free individuals and individuals with chronic pain.Regarding mechanisms of EIH that may be similar, but disrupted, in individuals with chronic pain compared to pain-free individuals, altered excitability of the central nervous system after exercise is perhaps the most obvious. In pain-free individuals, acute exercise reliably reduces temporal summation,155 and reduced effects of opioids have been reported in animals after long-term exercise.174 This may be explained by opioid-induced hyperalgesia which, paradoxically, leads to a reduction in central opioid receptor availability60 and hence less potential to modulate pain through opioidergic mechanisms  were associated with the observed improvements in pain. Moreover, few of the studies investigated where in the nociceptive pathways  changes might be occurring due to exercise, which could account for the observed reductions in pain. As a result, the precise mechanisms of pain attenuation by exercise training are not known, but several possibilities exist that are likely common to individuals with chronic pain.Regarding regular exercise, despite the large number of studies that have shown exercise training to reduce pain in people with chronic pain,160 Of these possible mediators, improvements in muscle strength are the strongest contributor to the positive effect of physical exercise on improved osteoarthritis symptoms.160Improved structure and function of the musculoskeletal system is one such possibility. In people with knee osteoarthritis, chronic exercise can improve several musculoskeletal factors important in the development and progression of the disease including body mass, joint alignment, proprioception, cartilage structure and function, inflammation, and muscle strength.83 but again it is not clear whether these changes reduce pain due to the peripheral or central actions of these factors. Preliminary evidence shows that exercise can normalise aberrant brain activity in people with fibromyalgia.41 This finding is in agreement with the results of a few cross-sectional studies showing that people with fibromyalgia who are more physically active have more typical brain responses to pain compared to less active individuals.120 However, not all studies have shown chronic exercise to attenuate aberrant brain responses in individuals with chronic pain,126 so the role of changes in brain activity as a mechanism of pain relief by regular exercise remains unclear.Desensitization of the nervous system is another possibility. In humans, exercise-induced changes in biomarkers associated with nociceptive pathways have been reported ,34 Many of these psychosocial factors are positively influenced by exercise,183 so it is plausible that this could result in improvements in pain either directly or indirectly through changes in both the sensory and emotional aspects of pain.Finally, exercise-induced improvements in mood could be another shared mediator of the positive effect of exercise on pain in individuals with chronic pain. The role of both general  and pain-specific  psychosocial processes in the development and maintenance of chronic pain is clear.153 but this is yet to be properly explored in the context of pain responses to a single bout of acute exercise in individuals with chronic pain.Most types of exercise can reduce pain sensitivity at exercising and nonexercising muscles in pain-free individuals, with a larger hypoalgesic response at the exercising muscles. In individuals with chronic pain, the hypoalgesic response after exercise is less consistent; however, in addition to other well-documented physical and mental health benefits related to exercise, exercise can sometimes induce hypoalgesia in individuals with chronic pain. Regarding exercise prescription in clinical settings, it may be worth considering: (1) that exercising nonpainful body areas if possible as well as using low-intensity exercises such as walking may be useful as a first step, (2) that individuals' beliefs, expectations, and exercise preference should be assessed before exercise prescription to minimize the risk of a poor outcome, and (3) that these beliefs and expectations could be modified through education or other interventions to improve pain responses to exercise in people with chronic pain. There is some evidence that combining exercise training and education has superior effects compared to exercise alone in individuals with chronic pain,26 Hence, most studies of EIH probably overestimate the effect of exercise on pain. Consequently, despite the enormous amount of EIH studies to date, the true effect of a single bout of exercise on pain is still unknown. Larger randomized controlled trials, of which there are currently very few, are clearly needed to determine this.In addition to the above-mentioned implications, we also propose several methodological recommendations for future studies of EIH. First, studies should use a randomized controlled design , or at the very least include a control group/condition. This is because the causal effects of exercise on pain are best inferred from randomized controlled trials. As shown in Tables 109 recently outlined several issues in clinical pain research including transparency, underpowered studies, and researcher degrees of freedom. The use of preregistration and registered reports, data sharing, and greater adherence to reporting guidelines were suggested as areas for improvement and we believe that EIH studies would benefit from adopting these recommendations.As evident in Tables The authors have no conflicts of interest to declare.


Motoneurons axotomized by peripheral nerve injuries experience profound changes in their synaptic inputs that are associated with a neuroinflammatory response that includes local microglia and astrocytes. This reaction is conserved across different types of motoneurons, injuries, and species, but also displays many unique features in each particular case. These reactions have been amply studied, but there is still a lack of knowledge on their functional significance and mechanisms. In this review article, we compiled data from many different fields to generate a comprehensive conceptual framework to best interpret past data and spawn new hypotheses and research. We propose that synaptic plasticity around axotomized motoneurons should be divided into two distinct processes. First, a rapid cell-autonomous, microglia-independent shedding of synapses from motoneuron cell bodies and proximal dendrites that is reversible after muscle reinnervation. Second, a slower mechanism that is microglia-dependent and permanently alters spinal cord circuitry by fully eliminating from the ventral horn the axon collaterals of peripherally injured and regenerating sensory Ia afferent proprioceptors. This removes this input from cell bodies and throughout the dendritic tree of axotomized motoneurons as well as from many other spinal neurons, thus reconfiguring ventral horn motor circuitries to function after regeneration without direct sensory feedback from muscle. This process is modulated by injury severity, suggesting a correlation with poor regeneration specificity due to sensory and motor axons targeting errors in the periphery that likely render Ia afferent connectivity in the ventral horn nonadaptive. In contrast, reversible synaptic changes on the cell bodies occur only while motoneurons are regenerating. This cell-autonomous process displays unique features according to motoneuron type and modulation by local microglia and astrocytes and generally results in a transient reduction of fast synaptic activity that is probably replaced by embryonic-like slow GABA depolarizations, proposed to relate to regenerative mechanisms. Peripheral nerve injuries are widely used to study neuronal responses to physical damage and axotomy, as well as the induction of regeneration programs without confounding effects of direct injury to the surrounding CNS or complex neuropathology. Motor and sensory axons injured in peripheral nerves are disconnected from their targets but can regenerate through complex programs initiated in their cell bodies, located in the spinal cord and dorsal root ganglia respectively. However, despite regeneration many patients experience long-term motor dysfunction  undergo plastic changes that differ in mechanism, time-course, significance for regenerative processes, and functional implications after regeneration. Second, the assumption that synapse withdrawal is necessary for motoneurons entering an electrically silent state that favors regeneration. Current evidence, reviewed below, suggests this is not the case. Efficient manipulations to enhance regeneration include electrical stimulation and exercise, both based on increasing motoneuron activation , nerve injury  and species . This diversity introduces high variance in reported results, but comparisons of similarities and differences also provide insights into mechanisms and significance. Importantly, different types of nerve injuries all result in axotomy of the motor axon and induce a regenerative program in the motoneuron; however, they drastically differ in motoneuron preservation and speed and efficiency of regeneration. The goal of this review is to organize this multiplicity of data to allow more precise interpretations of past results and more specific hypotheses moving forward.Removal of synapses from the cell body of motoneurons axotomized following nerve transections was first described in an electron microscopy (EM) analysis of the rat facial nucleus published in a landmark 1968 paper  and a second phase during motoneuron regeneration in which the cell is covered by astrocytes  and later quantified over abducens motoneurons undergoing synaptic stripping induced by botulinum toxin  an increase in uptake of material from the membrane surface that correlates with reduced synaptic bouton adhesion throughout the non-junctional apposition; (2) dissolution of the PSD and PAZ and complete detachment of the synaptic bouton; and (3) coverage of pre and postsynaptic surfaces by glia . Work inProteins that organize PSD neurotransmitter receptor accumulations are downregulated with a slower time course compared to synaptic adhesion proteins. These include PSD95 at excitatory synapses  disruption of the actin cytoskeleton in presynaptic boutons causing their retraction from axotomized motoneurons  and GABA/glycine inhibitory (VGAT/VIAAT) synapses over medial gastrocnemius (MG) spinal motoneurons (a lumbar LMC pool) after tibial nerve transections in which regeneration was allowed (cut and repair) or not (cut and ligation), VGAT/VIAAT were lost to a lesser extent and recovered independently of muscle reinnervation  and Neurotrophin-3 (NT3). Continuous delivery of BDNF in the spinal subarachnoid space after ventral root avulsion did not prevent synaptic stripping evaluated with EM but facilitated synapse recovery in the absence of muscle reinnervation, especially inhibitory synapses  recovered all synapses and synaptic modulation from all inputs, although synaptic gains were abnormally enhanced  using as a model the axotomy of abducens motoneurons. This work draws on extensive knowledge about the synaptic inputs controlling tonic and phasic firing of abducens motoneurons in relation to eye position, eye velocity, and vestibular stimulation  recorded in whole-cell mode ex vivo in slices correlate with in vivo alterations in firing modulation of spinal and brainstem motoneurons by excitatory inputs after axotomy. Hypoglossal motoneurons show decreased firing modulation in response to excitatory inspiratory drive and hypercapnia  demonstrated that this depolarization shift induces the reversal of GABA/glycine synaptic actions and appearance of low frequency spontaneous depolarizing GABA-mediated oscillations that activate NMDA and voltage-gated Ca2+ channels . Changes in these subunits persisted through the last day of the study (60 days after injury) despite 80% re-innervation of muscle at this time point. In contrast, expression of GABAA α2, β1, and β3 subunits was unchanged. Glycine receptor α1 and β subunits were also downregulated, but this was reversed with muscle re-innervation 60 days after injury. These results suggest the disappearance of fast glycinergic currents (and the fast α1 GABA subunit) during regeneration in favor of slower GABAergic synaptic phenotypes. Also, after a transient initial decrease in presynaptic GABA synthetic machinery, these changes are overturned , lamina VII, and IX, where they make synapses on different kinds of interneurons and motoneurons  that “boost” the amplitude of dendritic Ia synaptic currents close to four times, such that they effectively modulate firing at the initial segment  synapses after nerve transection and regeneration was in apparent contradiction to the general assumption that Ia EPSPs recover after muscle re-innervation. This conclusion was first derived from analyses of injuries in 5–8 days old kittens  synapses on motoneurons are the result of the removal of their axons from the ventral horn, not merely detachment of synapses from the membrane of axotomized motoneurons. Intra-axonal fills with neurobiotin of single afferents that regenerated and recovered muscle stretch responses typical of Ia afferents demonstrated that their central projections did not reach lamina IX. They also displayed fewer collaterals than normal in lamina VII, while their density appeared normal in lamina V and VI  synapses from motoneuron cell bodies and dendrites  synapses occurs at specific postnatal critical periods through C1q opsonization  ligand 2 (CCL2) activation of its receptor, CCR2  was found to correlate better with reflex function than Ia EPSP responses elicited by electrical stimulation. Thus, while all regenerated motoneurons display Ia EPSPs evoked by electrical afferent volleys in the nerve, many lack SSPs or these are strongly reduced  show deficits  and affects GABA/glycine and glutamatergic synapses to different levels in different motoneurons according to modulatory influences from neighboring glial, local neurotrophic factors and the intrinsic susceptibility of different inputs to detachment. A second mechanism is microglia-dependent and induces the retraction from the ventral horn of axon collaterals and synapses originating from axons injured in the peripheral nerve. The degree of axon removal is governed by the type and location of the nerve injury and after removal, there is no recovery of these connections. This mechanism affects the ventral horn collaterals of muscle proprioceptors injured in the periphery, and probably also the intraspinal collaterals of motor axons (Havton and Kellerth, FA wrote the manuscript and designed the figures. TR compiled literature regarding synaptic stripping, microglia and provided the primary data on Ia afferent and motor axon plasticity. EA compiled the literature on KCC2 and inhibitory synaptic function after axotomy and provided some of the data on synaptic stripping. AL provided some of the primary data on synaptic stripping after preventing microglia reactions. TR, EA, and AL revised the manuscript. TC and AE were involved in the genesis of some ideas in this review.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.


Amid thecoronavirus disease pandemic, the world is witnessing the greatest naturalexperiment ever, and countries have adopted different response strategies. Anevaluation of the effectiveness of different policies will play a valuable rolein preparing for future public health emergencies. However, controversial issuessuch as the timing and pathways of viral emergence, the effectiveness of socialdistancing and lockdown strategies, and the use of antimalarial drugs as therapyhave still not been fully resolved. This serves as a fertile breeding ground foragnotological strategies, whereby scientific studies are deliberately orunintentionally designed to create distractions or draw conclusions that are notsupported by research findings. Researchers, public health authorities, andhealthcare workers should be equipped to identify such agnotological strategies,distinguish them from scientific fraud, and avoid drawing misleading inferencesbased on an irrational adherence to hypotheses and a lack of criticism ofimplausible results.Two decades ago, Robert Proctor coined the term  On the Sources of Knowledge andIgnoranceth century philosophers of scienceBona fide scientists may focus on one aspect of research sointensively that their methods lack attunement to other relevant informationHow do epistemological disputes concern scientific responses to the coronavirusdisease (COVID-19) pandemic? At this juncture, we must recall Robert Proctor’s (born1954) concept of evidence (as used by the Cochrane Collaboration) will emerge inthe near futureFrom a researcher’s perspective, the world is witnessing the greatest naturalexperiment ever. Different countries have adopted varied strategies to prepare forand respond to the COVID-19 pandemicrd death and the following 10 days. These datasets andBox-Jenkins modelsIn an ecological study, IzouletSeveral factors underscore the active agnotological strategies used by this author.Although scientific documents typically carry a dispassionate tone, enthusiasticwords such as “excellent model,” “very effective,” and “highly predictive” abound inthe article. The article also contains a “study limitations” section, which subtlyaddresses the potential role of confounding variables and the limits of theforecasting models. However, there is not even a single reference to the ecologicalfallacy . This is nota minor issue. Even if ecological studies are an appropriate means of assessingcollective public policiesThe debate surrounding the effectiveness of chloroquine and hydroxychloroquine stillremains contentious and politically charged, even though randomized controlledtrials (RCTs) have yielded no strong evidence of their benefits, and their severeadverse effects have caused agencies  to contraindicate their useAt present, it is assumed that severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) emerged in Hubei province in China in late 2019https://brazilian.report/power/2020/07/08/new-study-gives-china-opportunity-blame-brazil-covid-19-virus/).If groundbreaking scientific information that can change our entire understanding ofthe epidemiology of COVID-19 exists, it deserves much more attention from theinternational scientific community than it has actually received. The authors muststrengthen their findings if they wish to address justifiable widespread skepticism.As researchers, they deserve the benefit of the doubt. Nevertheless, theagnotological issues involved in this study pertain to semantics. The authors havestated that their results “show that SARS-CoV-2 has been circulating in Brazil sincelate November 2019.” Circulate is an ambiguous term that is notindexed in the International Epidemiological Association’s Dictionary ofEpidemiologycirculation. Even ifthe findings prove to be true, the epidemiological inferences embedded in theconclusion will remain agnotological.My objective is not to refute these findings but to articulate why they should beinterpreted with due caution. First, and contrary to the previous example, they arepresented concisely . Nevertheless,it has received substantial attention from the national press and has beenconsidered as a potential source of conspiracy theories  andothers posited that only knowledge grounded in observation and/or experimentation isvalidscience. The incorporation of the concepts of empiricism intomedical practice  can betraced back to the late 18th or early 19th centuryRationalism introduced RCTs, based on Ronald Fisher’s (1890-1962) prior experience withrandomizing territories for agronomic research,,Except for research on therapeutic options and vaccines, the EBM hierarchy regardingthe strength of evidence is not readily applicable to the COVID-19 responsequasi-experimental studies, natural experiments, and evencomputational modeling) play a very valuable role in guiding public healthpoliciesIt is noteworthy that even some of Hill’s criteria for causality ,,,invitro or animal experimental findings to clinical practice among humanbeings. It is noteworthy that two of the aforementioned studies,As mentioned earlier, calls for further evidence are a classic agnotological strategyused by the tobacco industry and climate deniers,,Isearly treatment an option that can prevent the recession caused by socialdistancing protocols? The fact that well-designed studies that comparethe two strategies are both ethically and operationally unfeasible in the short termhas facilitated the emergence of several agnotological strategies based onsurveillance data or modeling. For example, on the Brazilian COVID-19 surveillancehomepage (https://covid.saude.gov.br/), the number of cured individuals isprominently displayed in a large font in a green box, whereas the numbers of casesand deaths are discreetly presented in a smaller font. Even though it is ratherobvious to epidemiologists that the high number of cured individuals is a directconsequence of the high number of cases, this message may not be easily comprehendedby the general public. Therefore, emphasizing the number of cured persons instead ofthe number of reported cases is not an innocent decision. Instead, it exemplifies agovernmental agnotological strategy during the pandemic era.The promotion of scientific ignorance for political purposes has been studiedextensively. Most authors have examined the issue of climate denialism in the UnitedStates and Europebonafide errors based on a strong adherence to a hypothesis or a lack ofcriticism of implausible results). Virtuous ignorance is an ethical choice and must,therefore, be guided by human, social, and cultural values. In accordance with thesecond (but not less important) objective, I have underscored the limited value ofevidence that has not been submitted to rational filters,,,This review aimed to introduce different agnotological strategies to researchers andhealthcare workers so that they can identify active construct strategies (deliberateproduction of ignorance) and avoid passive construct strategies (,,,A network of mutual criticism that combines rationality and empiricism should be thebasis of any scientific endeavor, including our response to the COVID-19pandemic


Sickle cell disease (SCD) is an inherited disorder that occurs due to point mutation in the beta-globin chain resulting in the production of hemoglobin S that tends to become rigid and sickle-shaped under low oxygen concentration. These sickle-shaped red blood cells (RBCs) obstruct the blood vessels leading to reduced blood flow to the organs, causing ischemia and tissue fibrosis. These sickle RBCs being abnormal in shape are frequently sequestered by the spleen, creating a state of chronic anemia in the body. This chronic anemia leads to a high cardiac output state causing cardiac remodeling. To tackle chronic anemia, patients are frequently treated with blood transfusions that makes them more prone to the risk of iron overload (from newly transfused RBCs and iron release from the RBCs that just got sequestered as well as from volume overload) and volume overload causing left ventricular (LV) dilation. The above-mentioned mechanism of cardiac hypertrophy, along with LV dilation together, makes SCD-related cardiomyopathy unique cardiomyopathy with features of restrictive cardiomyopathy with LV dilation. It is interesting to note here that even though there is a presence of LV dilatation, Systolic dysfunction is very uncommon in SCD-related cardiomyopathy. Complications of sickle cell disease (SCD) represent the significant health care burden in developed countries and cardiovascular (CV) complications being the highest causes of mortality . SCD is Chronic inflammation in SCDChronic inflammation has been said to play an essential role in the pathogenesis of SCD, reactive oxygen species (ROS) generated by leukocytes, endothelial cells, plasma enzymes, and sickle red blood cells being its important component . Human aPathophysiology of SCD-related cardiomyopathy and its complicationsSCD, which originated from Sub-Saharan Africa, Southeast Asia and India, has been known to be the most common inherited hemoglobinopathy worldwide due to increasing migration in the modern world. Prolonged exposure to high cardiac output state from chronic anemia in SCD leads to significant dilatation of LV which, over time, adapts to increased wall stress by developing eccentric LV hypertrophy, as shown in Figure Myocardial fibrosis in SCDIntravascular hemolysis causing nitric scavenging, along with repeated vaso-occlusion by sickle RBC can contribute to microvascular dysfunction, which has been identified to cause cardiac dysfunction in SCD patients Figure  9,10]. ,10. 9,10Myocardial iron overload uncommon in SCDChronic blood transfusion-related iron overload cardiomyopathy is a major cause of death in patients with chronic anemia, such as in thalassemia or SCD . High moDiastolic dysfunction in SCDMany studies identified diastolic dysfunction in SCD as an independent risk factor for premature death -20. FactPulmonary hypertension in SCDPathophysiology of pulmonary hypertension (PH) in SCD is complex and is a significant cause of mortality and morbidity in patients -25. A stPreventive measures to cope with complicationsBy diluting the load of sickle red blood cells in the circulation, chronic blood transfusion may reduce the risk of vaso-occlusion and stroke . HoweverThis study was conducted to demonstrate the pathophysiology of cardiomyopathy occurring in patients with SCD. It aimed to study the cause behind the restrictive nature of SCD-related cardiomyopathy and the impact of chronic anemia on the heart and its long-term complications in patients. It was very interesting to note that the patients who had diastolic dysfunction did not have myocyte iron overload, as confirmed by CMR, which means iron overload was not the cause of restrictive cardiomyopathy in patients. Instead, it occurs due to myocardial fibrosis from vaso-occlusion as well as from ventricular hypertrophy caused by chronic anemia. This restrictive cardiomyopathy, along with LV dilation from the hyperdynamic state in the body together, makes SCD-related cardiomyopathy unique cardiomyopathy. This paper is crucial as it explains the complicated nature of cardiomyopathy related to SCD, which will help clinicians to understand the pathophysiology of SCD-related cardiomyopathy and will help them with treatment plans for patients. It will also help to educate patients about their disease. During our literature search, we realized that even though frequent transfusions are required to treat chronic anemia and to dilute sickle cells in the blood, it has its side effects too. We encourage future researchers to study the consequences of frequent transfusions in order to lay down strict guidelines for its early management and prevent various complications arising from volume overload.