Food availability and associated sensory cues such as olfaction are known to trigger a range of hormonal and behavioural responses. When food availability is predictable these physiological and behavioural responses can become entrained to set times and occur in anticipation of food rather than being dependent on the food-related cues. Here we summarise the range of physiological and behavioural responses to food when the time of its availability is unpredictable, and consider the potential to manipulate feeding patterns for benefit in metabolic and mental health. Typically in modern society, eating behaviour is focused around meals, and the number and frequency of meals eaten is influenced by a number of factors, many of them cultural . Here wei.e., eating disorders and addiction, is the development of anxiety-related behaviours, manifested in rodent models as behaviour in the elevated plus maze (EPM) [i.e., binge-first or diet-first), but patients in both categories have similar psychiatric symptoms, with more than a third presenting with anxiety disorders and over 60% having some form of mood disorder [Feeding behaviours such as binge eating have been suggested to be the result of behavioural disinhibition following repeated periods of dieting or caloric restriction . In lineze (EPM) ,15. Thisze (EPM) . The difze (EPM) . Binge edisorder . TherefoAnother condition associated with the timing of meals is night eating. In humans this is characterised by the skipping of morning meals and the consumption of more than 50% of daily food intake in the evening, including appreciable intake after the evening meal, leading to metabolic consequences such as disruption of circadian patterns of melatonin, leptin, insulin and glucose ,20. ThesAn increase in total activity is often an indicator of an anorexia-like phenotype in rodents , and intSome of the characteristics of human food-related disorders including binge eating disorder, night eating syndrome, anorexia and bulimia can be replicated in animal models by manipulating the time of food availability. However, we still have only limited information about how such feeding schedules affect physiology and behaviour, whether disruption of feeding can lead to increased risk of such eating disorders, and whether feeding schedules could be manipulated to develop an optimum routine which prevents the development of, or aids the recover from, such conditions. Here we examine the varied feeding schedules employed with animal models. Food-related behaviour is compared and contrasted on the basis of whether the imposed meal schedules are predictable, and thereby allow entrainment, or otherwise, before the likely mechanistic basis of these behavioural responses is considered.ad lib. high fat fed animals [In general, a typical schedule of 2 h of access to a highly palatable diet provided daily in a predictable manner, with chow diet available for the remaining 22 h, is not sufficient to cause an increased body weight ,28. Intr animals , but cerad lib., this regime may lead to a deteriorating metabolic state, since blood glucose levels immediately prior to a 2 h scheduled feed were elevated on high fat pellet diets and had similar trends for sucrose and Ensure liquid supplements [ad lib. or in scheduled meals with chow available for the remainder of the light:dark cycle had impaired glucose tolerance regardless of access schedule [ad lib. fed animals, prevented high fat induced changes to insulin levels or glucose control [Despite the ability of animals to regulate weight on schedule fed palatable diets with chow available plements . Rats onschedule . However control .There is very limited information available on the use of unpredictable meal schedules and their effect on basic elements of metabolism and energy regulation. While it has been suggested that randomising the time of a meal reduces body weight compared to a fixed feeding schedule , this haFood anticipatory activity (FAA), the elevated locomotor activity occurring 2 h prior to a predicted meal in laboratory rodents, is relatively well defined for a variety of similar dietary manipulations based around predictable meal feeding. FAA in response to scheduled food access, or limited availability of a more palatable alternative food, is a proxy for a range of behaviours that are temporally dynamic, as well as psychological and cognitive processes such as perception, motivation, memory and decision making . These pLearning when food will be available, for example, in the studies described above, is likely to involve inputs from both light- and food-entrainable oscillators as well as interval timers tracking light/dark periods and inter-meal intervals . Whereasad lib. but provided with additional timed access to a palatable diet, such as a high fat pellet or chocolate, frequently induce increased total energy intake. For logistical simplicity, the palatable diet is usually provided at the same time each day, allowing the “treat” to be anticipated by the animal using environmental and biological cues. For example, a study that combined twice weekly caloric restriction with a refeeding schedule the following day that included 2 h access to a sweetened fat diet produced a substantial binge-like feeding episode [ad lib. chow access [Experimental feeding schedules where animals are fed  episode . This anw access .ad lib. fed rats entrains anticipatory activity, albeit at a lower level than in rats held on a 2 h restricted access chow schedule [ad lib. chow with predictable access to chocolate for 2 h in the light phase increased their activity levels relative to those fed ad lib. chow, but not relative to rats on a predictable restricted chow schedule [ad lib. fed rats [ad lib. fed chow, less than half the rats tested exhibited FAA, whereas rats fed Ensure only for just 2 h a day showed robust FAA beginning 2–3 h before scheduled feeding [ad lib. However, a slight increase in locomotor activity was detected in these mice in response to a high fat chow snack [Delivery of palatable chocolate treats at a fixed time of day to schedule . FAA wasschedule . Similarschedule . In anotschedule . This cofed rats . However feeding . Similarow snack , and resow snack . Interesow snack . This roow snack  and addiow snack ,42. As iScheduled feeding of standard chow or food of increased palatability has not only been shown to induce binge-like consumption but to also impact on circadian patterns . While aIn addition to effects on locomotor activity and energy balance, food restriction can influence consumption of, and response to, drugs of abuse. These relationships were shown to intertwine in a study examining the interaction between feeding schedules under restriction conditions and locomotor responses to methamphetamine. Mice were food restricted to one of two body weight levels (8% or 16% weight loss) and fed in either one or 3 meals . At the Another shared characteristic of addiction and eating disorders is an increase in anxiety-related behaviours. The prevalences of a spectrum of anxiety-related conditions are positively correlated with eating disorders , and expi.e., non-circadian) schedule. This implies that the predictability of a meal may be determined by its timing relative to the circadian cycle rather than the interval between meals, with consequent effects on activity levels. The use of behavioural software to measure FAA also raises the question of which behaviours are contributing to FAA—increases in locomotor activity or an accumulation of micro-behaviours such as rearing or grooming, which may provide insight into disorders such as anxiety.Unpredictable meal provision is less well studied than scheduled delivery, at least in part due to logistical considerations. While FAA is reliably induced under predictable feeding schedules, it was not evident when rats were fed a 2 h meal at an unpredictable time in the light phase, although there was increased activity in phase with the previous meal, as well as immediately following food delivery . An inveThe elevated activity levels associated with food availability in a scheduled access paradigm will contribute to overall energy expenditure, so that the duration of FAA on a given day, but more importantly in the long term, is likely to impact on energy homeostasis. By contrast, mice that were intermittently and randomly food restricted by 50% or that had food completely removed showed significant reductions in physical activity both on days when the restriction was applied but also on subsequent days . This woad lib. for short periods of time  in order to create a background of restriction and refeeding similar to what is observed when dieting is undertaken (and fails) in humans, there was no effect in the standard anxiety tests, open field or elevated plus maze [ad lib. access to chow, 3 of which also provided additional palatable food, presumably makes it difficult for animals to precisely foresee access to the palatable diet. Although a history of intermittent feeding on this schedule caused a generalised trend towards increased anhedonia, central changes in serotonin and dopamine were observed only when a history of caloric restriction was accompanied by intermittent access to cookies and not by ad lib. chow or daily access to palatable cookies [In a feeding schedule where palatable food (Oreo cookies) was given lus maze . This ma cookies . This su cookies . Anxiety cookies .In combination, these studies suggest that intermittent access may be less anxiogenic than predictable access to palatable food, however, it is likely that the different timings and design of unpredictable feeding schedules will impact on their metabolic and anxiolytic properties. Further research and optimisation of these timings may allow them to be applied in a manner which could positively impact on the anxiety-related characteristics of eating disorders as well as other mental health conditions. Currently, therapeutic strategies to tackle binge eating disorder, for example, recommend normalisation of eating patterns through adherence to regular meals and snacks.ad lib. However, increased PER1 positive cell numbers in the arcuate nucleus (ARC) and perifornical area are seen only with a restricted feeding schedule, while cells of the prefrontal cortex respond only to chocolate [ad lib. chow but there were indicators of central effects of supplementary treats as numbers of Fos positive cells were increased in both the hypothalamus and the forebrain [ad lib. fed chow controls. Under disruptive light conditions, food can be used to reset circadian rhythms since mice fed or fasted on alternate days were able to maintain normal circadian expression in clock genes regardless of manipulation of the light/dark cycle to 8 h  [Rhythms in biology are generally thought of as being underpinned by central mechanisms driven through the suprachiasmatic nucleus (SCN). The SCN is part of a central clock system located within the hypothalamus which under normal conditions uses light to generate and regulate daily cycles in behaviours such as sleeping and eating (for review ). Many bhocolate . PER2 exorebrain . When Ench 24 h) .While hypothalamic clocks primarily in the SCN are clearly factors in the regulation of feeding patterns, other regions of the brain, for example, traditional feeding centers such as the arcuate nucleus (ARC) are likely to play a role, as well as interacting with the SCN to generate a feedback loop . There iTo date, a critical neuroanatomical/neurochemical basis for food related rhythms and behaviours has proved elusive. While the anticipation of, and response to, food is thought to be regulated by multiple signal systems distributed throughout the body, which may be modulated by peripheral hormones such as leptin and ghrelin , these hRestricted access to food may be a stressor, and in a standard feeding schedule where calorically-restricted rats expect limited access to a palatable food or chow they have significantly elevated plasma corticosterone . In contBoth FAA and anxiety behaviours induced by palatable meals and/or intermittent feeding could be regulated by homeostatic feeding pathways or central reward systems. However, establishing the mechanisms behind intermittent feeding and reward of palatable meals is complicated by the feeding schedules themselves which may enforce an element of food restriction and negative energy balance that also directly impacts on energy balance and reward systems. Activation of pathways regulating reward and energy homeostasis is suggested by observations made with a 2 h restricted feeding protocol. Here, c-Fos positive cells were increased in the ARC and DMH 25 h after the start of the last meal regardless of whether the meal was predictable or unpredictable . In addiad lib. Rats fed palatable supplements for 2 h a day in addition to chow responded differently to different solid or liquid palatable foods. Rats with 2 h access to sucrose had reduced ARC expression of the homeostatic neuropeptides, cocaine and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC), and of suppressor of cytokine signalling-3 (SOCS3), compared to rats given ad lib. access to sucrose solution. A similar relationship was not observed when high fat pellets were schedule-fed, although neuropeptide Y (NPY) was upregulated by scheduled feeding of a 60% high fat pellet. Schedule-fed liquid chocolate Ensure reduced leptin receptor and SOCS3 expression but not that of the energy balance neuropeptides [et al. [How intermittent feeding schedules can mediate energy balance and behaviour is not well understood. However, the potential role of the hypothalamus and feeding pathways was highlighted in similar studies where gene expression was analysed prior to anticipated palatable food availability with chow available peptides . By comppeptides . Both st [et al.  quantifi [et al.  and whil [et al. , this suThe hypothalamus may also play a role in regulating the behavioural response to feeding times by integrating signalling from peripheral hormones such as ghrelin. In an electrophysiological study, rats were held on a randomised single meal feeding schedule where the approaching meal, fed at a different time of the dark active phase, was signalled by a light cue . The ligad lib. or in a 2 h period following restriction to induce bingeing [In terms of reward pathways, animals fed a palatable high fat-high sugar diet had suppressed expression of µ opioid receptors in the brainstem (nucleus of the solitary tract) and this was true both in rats fed the palatable diet option bingeing . µ opioibingeing . This woThis review aimed to integrate a varied and dispersed literature derived from imposed disrupted feeding regimes. Research in this area could have implications for our understanding of mood and eating disorders and their treatment. The increased impulsivity associated with obesity, and probably with binge eating disorder also , as wellAnimals tend to binge and display clear FAA that may be combined with disruption of circadian activity when palatable food is provided in a predictable manner alongside unrestricted access to chow. Animals are likely to experience anxiolytic symptoms as a result of such schedules but opposing anxiogenic effects during withdrawal. On the other hand, irregular feeding has a less robust effect on anxiety which may reflect reduced ability to predict the meal and to display FAA. Candidate molecules and neuroanatomical substrates from circadian, reward and energy regulating pathways and circuits have all been implicated in mediating the effects of meal timing but interpretation of results from these studies is complicated by the confounding component of food restriction in the feeding schedules with the consequence that the strongest contenders are those which directly affect FAA such as NPY.The range of feeding studies discussed here includes regimes of starvation, restriction, refeeding and intermittent access, but it is worth noting that in the different studies these phrases are sometimes used interchangeably depending on the focus of the respective research group. Similarly, these feeding schedules have been used in a range of studies to address research outcomes that do not necessarily include the effect of the schedule on the animal itself in terms of food intake or feeding-related behaviour. In addition, there is a paucity of information on behavioural consequences other than FAA during such regimes, and effects on later feeding behaviour and specifically other mood-related behaviours such as anxiety. Where the feeding schedule was the primary manipulation, the main focus of current literature has been on effects following withdrawal of feeding schedules of palatable food, and subsequent effects on intake, rather than the potential of feeding schedules to mediate metabolic or mood disorders associated with eating disorders. Studies of feeding behaviour following the termination of intermittent or irregular feeding patterns do, however, highlight the importance of dietary history as well as current eating regime on mood and behaviour outcomes. Our aim in integrating this varied body of research was to highlight that apparently simple manipulations of food availability have the potential to impact on more widely relevant behaviours with application in the study of eating disorders.While feeding behaviour and FAA are clearly influenced by diet availability and the predictability of meals, effects on other food-related behaviours such as anxiety are less well reported. Mental health conditions are closely associated with eating disorders and it is not surprising, therefore, that disrupting feeding patterns in animal models may impact on behaviour. More emphasis should be placed on monitoring such behaviours in situations where food intake is manipulated for other reasons. A better understanding of the behavioural consequences of disruption to normal eating patterns may be important in improving both clinical diagnostic criteria and therapies for eating disorders such as binge eating disorder which is characterised by intake of irregular high calorie meals. A more detailed characterisation of pre-clinical models may further our understanding of how such conditions impact on people’s mood, behaviour and daily lives.Changes in availability of the main dietary energy source may have a larger impact on circadian and metabolic rhythms, and FAA, than palatable treat foods ,39, but It is apparent that there has been only limited research into the direct effects of feeding schedules on behaviour. Consequently, establishing the potential for intermittent feeding schedules to generate behavioural responses beyond classical feeding and activity responses will require further investigation. The combination of changes in energy intake and anxiety-associated behaviours may link animal models of intermittent feeding with human eating disorders, and allow the development of models to promote our understanding of underlying endocrine and neurobiological mechanisms, and facilitate the identification of therapeutic targets. The relationship between food predictability and the anxiolytic/anxiogenic properties of a particular diet suggests that habitual dietary manipulations may be useful as indicators of eating disorders and traditional addictions, whereas dietary strategies may have a therapeutic benefit in addressing behaviours associated with such conditions.


Neural networks provide candidate substrates for the spread of proteinopathies causing neurodegeneration, and emerging data suggest that macroscopic signatures of network disintegration differentiate diseases. However, how do protein abnormalities produce network signatures? The answer may lie with ‘molecular nexopathies’: specific, coherent conjunctions of pathogenic protein and intrinsic network characteristics that define network signatures of neurodegenerative pathologies. Key features of the paradigm that we propose here include differential intrinsic network vulnerability to propagating protein abnormalities, in part reflecting developmental structural and functional factors; differential vulnerability of neural connection types  to particular pathogenic proteins; and differential impact of molecular effects  on gradients of network damage. The paradigm has implications for understanding and predicting neurodegenerative disease biology. Neural networks are a key theme in contemporary neuroscience To date, work in neurodegenerative disease has mainly focussed on linking clinical phenotypes to network alterations. However, it remains unclear how molecular (protein) abnormalities translate to network damage and, thus, clinical phenotypes; and whether pathological substrates can be predicted reliably from macroscopic network signatures. Recent advances in genetics and histopathology have enabled the detailed mapping of neurodegenerative clinico-anatomical phenotypes onto specific proteinopathies, transcending broad categories such as ‘tauopathy’ or ‘ubiquitinopathy’. Histopathological patterns of protein deposition reflect underlying molecular  characteristics in a range of neurodegenerative diseases, most strikingly in the FTLD spectrum nectere, tie) to refer to a coherent conjunction of pathogenic protein and intrinsic neural network characteristics expressed as a macroanatomical signature of brain network disintegration. We argue that improved understanding of the molecular mechanisms of network disintegration will constitute a new paradigm of neurodegenerative disease. The essential features of the paradigm that we propose are presented in Here, we address this problem. We propose the term ‘molecular nexopathy’  characteristics . AlthougAn important theoretical motivation for applying the network information-processing framework to the neurodegenerative proteinopathies is the rich taxonomy of network activity patterns that follow from relatively simple starting assumptions when modelling the evolution of artificial neural networks Relevant network and protein characteristics have yet to be worked out in detail for neurodegenerative proteinopathies. However, it has been shown that brain networks have ‘small-world’ properties expressed as a high degree of clustering among network elements and short average path lengths between clusters The degree of macroanatomical asymmetry of network damage within and between cerebral hemispheres appears to be a further partitioning characteristic of many neurodegenerative diseases , althouga priori that any set of neuronal or neural network features would confer vulnerability uniquely to a single molecular species. However, further specificity in the profile of network involvement  may be driven, in part, by functional characteristics of the pathogenic protein itself.It is unlikely Across the spectrum of potentially pathogenic proteins, there is a basic distinction between toxic-gain-of-function (deleterious effects of protein accumulation) and loss-of-function  molecular effects We envisage that, within an affected network, an overall toxic gain of function will spread relatively uniformly, whereas an overall loss-of-function effect will establish a gradient of tissue loss due to attenuation of ‘downstream’ synaptic inputs. Such polarising network-level effects of loss-of-function proteinopathies would be in line with a net ‘inhibitory’ action on damaged connections, because selective inhibition of network elements can generate highly polarised network structures and self-amplifying network activity patterns in computational models Although it is unlikely that polarised protein effects operate in pure form in the brain A critical feature of neurodegenerative molecular nexopathies is likely to be their pattern of evolution in time as well as spatially within the brain. The rapidity of network breakdown might depend on the relative proportions of connection types affected by the pathological process, the predominant involvement of longer-range connections corresponding to rapid spread and involvement of clustered connections corresponding to slower spread, respectively. This would fit with available data for certain neurodegenerative disorders. For example, patients with MAPT mutations and relatively focal anterior temporal lobe damage have, on average, slower rates of overall brain atrophy and survive substantially longer compared with patients with GRN mutations associated with widespread intrahemispheric damage The temporal evolution of atrophy profiles associated with a particular proteinopathy may reveal a characteristic signature of network involvement that unites apparently disparate phenotypes . For exaThis concept of the differential involvement of a core vulnerable network (with increasingly complete involvement of the network over time) suggests one possible solution to the apparent paradox of individual phenotypic variation associated with particular proteinopathies The effects of a particular proteinopathy need not and generally will not be restricted to a single vulnerable large-scale network . Rather,As a final important caveat on the differentiation of nexopathies, it is unlikely that complete specificity will apply across the entire gamut of pathogenic proteins implicated in neurodegenerative disease. Rather, we envisage a taxonomy of predictable profiles of network disintegration: within the taxonomy, particular profiles of nexopathy might be common to different pathogenic proteins to the extent that those proteins share key properties that promote network damage or dysfunction. Different proteins might, for example, participate in a common, multicomponent pathogenic cascade  approaches, including synthetic and


Transformation of wild species into elite cultivars through “domestication” entails evolutionary responses in which plant populations adapt to selection. Domestication is a process characterized by the occurrence of key mutations in morphological, phenological, or utility genes, which leads to the increased adaptation and use of the plant; however, this process followed by modern plant breeding practices has presumably narrowed the genetic diversity in crop plants. The reduction of genetic diversity could result in “broad susceptibility” to newly emerging herbivores and pathogens, thereby threatening long-term crop retention. Different QTLs influencing herbivore resistance have also been identified, which overlap with other genes of small effect regulating resistance indicating the presence of pleiotropism or linkage between such genes. However, this reduction in genetic variability could be remunerated by introgression of novel traits from wild perhaps with antifeedant and antinutritional toxic components. Thus it is strongly believed that transgenic technologies may provide a radical and promising solution to combat herbivory as these avoid linkage drag and also the antifeedant angle. Here, important questions related to the temporal dynamics of resistance to herbivory and intricate genetic phenomenon with their impact on crop evolution are addressed and at times hypothesized for future validation. During speciation in crop plants, many morphological changes evolved in response to continuous selection pressure. Such characters are largely governed by genetic and epigenetic changes or are modulated according to ecological adaptations. The transition of wild progenitor species into modern elite cultivars through “domestication” entails evolutionary responses in which plant populations adapt to human selection. In response to this selection most plant species exhibit marked changes in a variety of phenotypes, most noticeably in traits consciously under selection  . As DarwAn example of how this concept has transformed our understanding is the realization that natural selection pressure, as well as adaptation under human selection, often led to unexpected and unexplained departures from predicted phenotypes. This mainly includes traits such as enhanced yield, enhanced apical dominance, reduced seed dormancy, perennial to annual habit, and relative susceptibility to pathogens, disease, and insect pests , 4. HoweRegardless of these rapidly accumulating insights, important questions remain about every stage of agricultural development. How did individual crop plants evolve from wild species and acquire agriculturally important traits? How do contemporary plant forms achieve diverse evolutionary trajectories separate from those of their progenitor(s)? How do recently formed elite accessions of crop plants become compromised of different resistance traits? To what degree has crop evolution via the process of domestication and concurrent breeding practices provided a stimulus for sustainable agriculture? Despite the domestication events followed by breeding practices across plant taxa, we do not know why agricultural evolution is so prevalent or conversely, why crop evolution is not universal if it confers some adaptive advantages and promotes species diversification. Nor do we understand the dynamics that underlie the transformation of wild forms to domesticated forms in cryptic crops such as cotton and corn.Cajanus, reduced levels of resistance have been reported against herbivores [in general more “successful” than their wild progenitors? This is an exceedingly difficult question to answer, in large part because “success” is an ill-defined term that can refer to anything from short-term proliferation of individuals to long-term effects on lineage diversification. The susceptible nature of modern crop plant varieties in comparison to their wild progenitors could be one of the most apparent consequences of such a megaevent. Or accelerated mutational activity in coresident genomes (in case of polyploid crops) in early generations led to a downgrade in the pathogenic and herbivore resistance of domesticated plant species. Answering these and other questions will require comparisons of wild and domesticated forms by researchers from diverse disciplines such as ecology, population biology, and physiology. Unfortunately, these important areas of biology have received far less attention than the genetics and genomics of selection [It has been assumed that several agriculturally important traits such as resistance to abiotic and biotic stress conditions decreased significantly during evolution. For example, in domesticated accessions of the genus rbivores , 13, bacrbivores , and funrbivores . Among selection , 16–18. A primary concern of agricultural evolution biology is to investigate where, when, and how crop plants originated. Vavilov's center of domestication  has beenVigna [The term “domestication” is often used to describe the process by which wild becomes stabilized. From the standpoint of morphological transformation, domesticated forms are by definition wild species with certain traits highlighted under human selection , showingVigna ; an incrVigna , 25; chaVigna ; increasVigna , 8; and Oryza, Hordeum), and even if their respective wild progenitors were identified, the multiple origins of domesticated forms and their formation would mostly remain unknown. It has also been assumed that almost all crop plants have experienced repeated polyploidization of genomes in their evolutionary history with multiple-fold duplication of ancestral angiosperm (flowering plant) genes [The domestication process and introgression under modern breeding programs must have served as effective means to increase the genetic diversity of elite cultivars especially following the initial domestication bottleneck, and to produce cultivars adaptive to climatic conditions . But is t) genes . Polyplot) genes , 39. In sh4) is responsible for the reduction of grain shattering in the wild rice [Domestication could, therefore, include all responses to plant evolution, including genetic and epigenetic effects, as reviewed recently , 26. Whaild rice  and a loild rice ; and a Qild rice . Accordiild rice , 43.Regarding the magnitude of the changes that occurred throughout crop formation, it appears that breeding activities of crop plants are relatively of less radical change than the conversion of wild forms to the domesticated forms. If so, will the modern elite varieties derived through hybridization of two similar domesticated varieties/forms have less evolutionary resolution than those derived through hybridization with their wild progenitor species? This is definitely an affirmative assertion and has also been validated across plant taxa with reduced genetic diversity in the breeding programs. Thus, what may be the potential risks involved with such radical loss in the genetic diversity among elite cultivars? It may also develop the weedy competitors of crop plants as well as their susceptibility to the diseases, pathogens, and herbivores leading to severe crop losses. But is there any correlation between operative stress condition and the niche of any plant population? Are there sufficient pieces of evidence for relatively less epidemic of any particular pathogen or pest population? The bewildering possibility of such prevalence may destabilize the crop productivity as well as subsequent evolution. For example, despite low crop diversity among cereals initially, successful introgression of resistance to abiotic stress conditions, pathogens, and herbivores was deployed to maintain yield. In this scenario, what is the deadline for such incorporation of resistance traits in crops for sustainable agriculture? The answer is still unclear but it may only be possible if (i) domestication, (ii) change from traditional landraces to modern breeding varieties, and (iii) their over and above decade field adaptation can work indefinitely; for example, maize hybrids in the United States now have a useful lifetime of about 4 years, half of what it was 30 years ago .Triticum tauschii to the landraces and subsequently to the elite germplasm [sh4, responsible for the reduction of grain shattering.The advent of genomics has brought a bonafide improvement to the study of such regulatory regions and generation of molecular and expression data, knowledge, and tools which could be applied in modern breeding programs for exploitation of genes from tertiary gene pool . To furtermplasm . Though ermplasm , with thCicer microphyllum, C. canariense, and C. macracanthus exhibiting significant reduction in leaf feeding, larval survival, and larval weight of neonate larvae of Helicoverpa armigera in comparison to domesticated perennial accessions. The extent of suppression of damage is impressive in wild accessions as compared to the domesticated chickpeas. Herbivores (insect pests) are the major factor responsible for destabilizing crop productivity in agricultural ecosystems. Herbivores have been recognized as a major constraint to crop production causing significant yield loss and quality degradation. In response to herbivory, plants have acquired inherent resistance against such pests; however, the intensity of this resistance varies enormously between wild and domesticated forms. So, what could be the rationale for such large variations in the resistance levels? It is believed that the alterations in herbivory resistance are a prominent outcome of genetic reduction within and between crop species. Several studies have shown that massive expression changes accompany crop evolution (under domestication and breeding practices). The magnitude of expression changes varied greatly between species influencing genetic diversity and resistance levels tremendously. However, do enough data exist at present to reveal general trends of reduced resistance to herbivory among domesticated forms across taxa? It is evident in three wild relatives of chickpeas that are, Gossypium barbadense has specifically addressed the transcriptional effects of domestication during development. Several important genes and their functional categories related to resistance genes have been identified as downregulated in the domesticated form than its counterpart wild form supporting the assumption of reduced resistance properties of a plant species [G. barbadense with their diploid progenitors  revealed significant transcriptional downregulation of resistance-related genes in the expression phenotype of the domesticated form. This is a clear indication of reduction in herbivore resistance traits during the domestication of an allopolyploid crop. Since cotton allopolyploid species carry “A” and “D” genomes, derived from their diploid progenitors [Also, a comparison of global gene expression profiles in the wild and domesticated allotetraploid cotton  species . Furthergenitors , it may genitors , but insThis lack of additivity in gene expression levels in most polyploid crop plants raises several fundamental questions on the consequences of the evolutionary dynamics of resistance gene expression following domestication. From a mechanistic standpoint, what is responsible for nonadditivity in gene expression, and why does this vary so much among resistance genes and between different genomic combinations? Why do such important genes from two diploid genomes demonstrate such a large disparity in the degree of suppression of the gene expression phenotype? Also from an evolutionary point of view, how does genomic evolution impact resistance gene expression variation during agricultural evolution (domestication followed by the breeding practices), and what are the potential phenotypic effects of each of these sources of variation?Arabidopsis known to regulate the glucosinolate-myrosinase system controlling the generalist herbivore Trichoplusia ni than specialist feeding insect Plutella xylostella [Arabidopsis known to regulate the glucosinolate-myrosinase system controlling the generalist herbivore Trichoplusia ni than specialist feeding insect Plutella xylostella. This demonstration of the higher levels of genetic variation for resistance to the generalist and specialist herbivores has been further verified and expanded in several subsequent studies, including one in which several QTLs from consistent resistance sources for leaf feeding insects SWCB and FAW were mapped on and observed to be located on chromosomes 6, 7, and 9 in corn. Given the resistance to both of these insects, candidate genes were identified as mir cysteine proteinase gene family [Glossly15 gene controlling adult to juvenile transition [x resistant hybrids; however, with some exceptions those could probably be addressed later with the help of soybean insect resistance QTL database. Will the contemporary catalogues of genome-sequencing projects across plant systems support the identification of important herbivory resistance loci? In result, it may definitely be assumed that future analyses based on whole-genome sequencing data will emphasize insect resistant (IR) QTLs/IR genes identified earlier through marker-assisted selection. This will substantially reduce the time utilized for their adaptive inheritance through classical or precision breeding. Until relatively recently, family-based QTL mapping and association mapping were the primary means of searching genes involved in crop evolution [One of the most recent and spectacular revelations in crop plants is the identification of a number of molecular markers, and how these markers could be applied to identify and track target genes in a marker-assisted breeding program –56. Molelostella  identifie family  and the ansition . Also inansition , 65. Thuansition , 66. RFLansition , 67, andansition . The hervolution . Considevolution , 69. Thevolution , 69. So,The domestication process increased a number of important traits required for agricultural innovations, though with few subsides. For example, the nascent “crop-form” (representative from independent domestication events) is more susceptible to herbivores as a result of having few important resistance loci, of which most were identified from their wild progenitor species. Is such phenotypic transformation under domestication universally advantageous or has accompanied with the loss of an “additional” benefit? What is the spectrum of consequences of having a set of important genomic loci selected under human selection? Are the answers to these questions consistent among plant lineages and/or between independent and parallel domestication events within a single species?Traditional views maintain that domestication followed by breeding promoted the fixation of resistance loci, referred to as fixed heterozygosity –72. It wAnalysis of a large number of loci underlying resistance to herbivory in soybean showed that resistance is an outcome of a mixture of major and minor gene effects and is not random. Some loci responsible for acquiring resistance to herbivory were underlying within regions having loci for the resistance against cyst nematode . ClassifUnder classical models, plant resistance to herbivory and pathogens is proposed to be a primary phenotype mostly available in the wild ancestors. For instance, plant introductions (PIs) in soybean with low agronomic quality have been demonstrated to be resistant against number of defoliating insects , 13. SucG. soja), and even appear to undergo significant change in the allele frequency [If artificial selection prevails all through generations at the genomic level, is the operation of such selection global or localized? It may be argued that the evolutionary event such as domestication can affect the sequence variation at wide-reaching loci within a crop plant. In that scenario, what could be the limiting factors responsible for such proposed “genetic erosion” in an elite germplasm? One explanation could be that selection in modern breeding programs instead acts on selected important loci controlling a variety of traits, concluding that selection in either case would significantly reduce species-wide polymorphism and make it more vulnerable to the stressful conditions . Besidesrequency . Could irequency , 17, 57.requency . Those irequency , 85. MorBacillus thuringiensis (Bt), resistant to corn rootworm, was first commercialized in the USA in 2003 [Bt cotton [Bt cotton, equivalent to 8.7% of the total area under cotton cultivation in India. The corresponding adoption rate of biotech cotton has also been increased globally from 15.5 mHa to 16.1 mHa in the year 2009 [Introduction of novel foreign genes into crop plants helps breeders to extend their germplasm with novel phenotypic traits. Such required traits are often related to the control of abiotic and biotic stresses, increasing the crop yield and improving the product quality, which were hitherto difficult or not possible to breed using a conventional approach , 87. Giv in 2003  and succ in 2003 . Howevert cotton , which ht cotton , though ear 2009 . For soyear 2009 . These eear 2009 . The latBacillus spp.), and in codon usage [Bt cry1Ac gene in comparison to the wild-type gene from bacterial origin. Subsequently, by modifying codon usage, removing polyadenylation sequences [Bt genes, a number of plants have been transformed against their target pests [What controls the level of a foreign gene expression in genetically modified plants? Any or all of the molecular mechanisms associated with cellular gene expression machinery could be involved. Such a definition encompasses an array of molecular mechanisms at the transcriptional level including DNA methylation, mRNA decay, and small RNA-mediated gene silencing or at translational level having protein misfolding, degradation or other modification, and nuclear/chromosomal context with respect to genomic location of transgene often referred to as “position effect.” It is generally assumed that because genes of prokaryotic origin are expressed poorly in higher organisms, such as plants , 97, cerequences , and othet pests , 99. Butet pests , 101 sucUnder field conditions, reverse effects of transgenics were also recorded with (i) harmful effect on nontarget insects and (ii) target insect to develop resistance against insecticidal genes used. The first risk could be addressed by designing the synthetic genes to target the hypervariable regions of target insect genes, thereby avoiding their lethal effects on nontarget insect population. However, in the latter case, the potential hazard could only be equilibrated through achieving very high transgene expression in the transgenics through the system-specific codon usage modification of a gene, use of high strength constitutive promoters, “position effect-” based screening of large transgenic population, and following refuge strategy to delay the acquired resistance in the pest population. If transgenic technologies are so promising and successful over conventional breeding, what are the major constraints that delayed the worldwide cultivation of genetically modified (GM) crops? Here, one of the likely explanations may be the inappropriate resistance management strategies deployed so far for the commercially important crop plants. For rice, assessment of agricultural fields for productivity and health effects in China emphasized such issues and highlighted key concerns on policy implementation and resolution of trade barriers , which mBt genes (one to control the European corn borer complex and the other to control rootworm) and herbicide tolerance  and continued to grow in 2009 [Oryza indica), incorporation of two Bt genes and one lectin gene showed the control of three major herbivores: rice leaf folder , yellow stemborer (Scirpophaga incertulas), and the brown planthopper (Nilaparvata lugens), respectively [Bt gene-transgenic cotton showed enhanced protection against Helicoverpa zea in comparison to the single gene transgenics with any of the two genes studied [Bt genes targeting two different lepidopteran insects shows significant improvement in the resistance trait against individual insects than do the respective single gene transgenics . This indicates that the gene combinations may have played a strong role in reserving a durable resistance phenotype. Even without knowing the comprehensive specific mechanism(s) involved, there is clearly some association between the observation of high levels of protection against herbivores and the presence of multiple genes.Transgenic technologies are undoubtedly important for plant defense against stresses, and it has also been argued that they are useful for the incorporation of novel phenotypes into crop plants. Existing single gene biotech crop studies may be extrapolated to a hypothetical case where full coverage of all target herbivores and plant diseases would be available in a genetic stock. As mentioned previously, biotech maize in USA is the best example of the deployment of stacked multiple traits including  in 2009 . Howeverectively . This in studied . EvidencGalanthus nivalis agglutinin (GNA), with Bt genes is very promising for increased insect resistance, with the ability of GNA to serve as carrier protein for the delivery of insecticidal proteins (in most cases Bt toxins)[However, for any particular trait such as resistance to herbivores, can only genes from similar origin be tagged for synergistic activity? Can it be assumed that genes from distant origin be grouped together for increased resistance phenotype? The answer lies with the gut anatomy of phytophagous herbivore, which has different binding sites for toxic proteins that determine the spectrum of different lethal protein(s) activity and severity and provide clues for the use of diverse toxic genes to introgress herbivory resistance phenotype. The use of lectins, for example, t toxins).Bacillus thuringiensis during its vegetative growth along with Bt crystal proteins. Unlike Bt crystal proteins known as δ-endotoxins, VIPs are not parasporal and are secreted from the bacterial cell during vegetative growth. The full-length toxin gets activated proteolytically to a core toxin by proteases in the lepidopteran gut juice [Bt toxins in the insect gut epithelium, their use as potential insecticidal proteins for gene staking is very promising. Transgenic cotton expressing two insecticidal proteins Vip3A and Cry1Ab is estimated to be highly effective against two cotton herbivores, Helicoverpa armigera and Heliothis virescens [Bt cry1Ac and snowdrop lectin GNA were also tested in cotton and showed resistance against insect pests Heliothis armigera and Aphis gossypii [Bt toxin tobacco transgenics and two gene transgenics having the Bt gene and the cowpea trypsin inhibitor (CpTi) gene showed the dominance of two gene products with enhanced insecticidal efficacy against cotton bollworm (Helicoverpa armigera) [Bt-CpTi fusion protein was performed in Brassica oleracea to study the insecticidal effect of this fusion protein on cabbage worm, which showed high activity of trypsin inhibitor, and the overall strong resistance to the common cabbage worm [Bt genes in the mid-gut of herbivores, novel combinations of such genes have been considered good to be deployed in delaying the evolution of resistant herbivores [Spodoptera litura resulted in extreme toxicity to all developmental stages of larval development [Bt gene using truncated cry1Ba gene as a scaffold and inserted part of the second domain of cryIIa gene conferring resistance to both coleopteran and lepidopteran pests. These studies support the assumption that such a novel strategy may provide new avenues for resistance management studies involving multiple transgenes in crop plants [What should be the major selection criteria for insecticidal proteins when used for gene pyramiding? This may entail (i) toxic activity against wide spectrum of herbivores and (ii) nonhomology between or among concurrent toxins used. A well-studied example in second-generation insect-resistant transgenic plants is the use of novel vegetative insecticidal proteins (VIPs), which are produced by ut juice , 107. Siirescens . Hence, gossypii . Also, trmigera) . Furtherage worm . The synrbivores . Since mrbivores , 114, itrbivores , 116. Trelopment  construcp plants .The pyramiding technology has been noted to provide excellent control of a broad range of herbivores and reinforces the argument that developed resistance in selected herbivores against one toxin will still be fully susceptible to other toxin molecules present in the plants (reviewed by ). If so,Bt genes [Bt genes to the target herbivores due to high specificity of Bt toxins, (ii) the potential cross-resistance leading to the evolution of resistant herbivores and (iii) the restricted use of possible novel combinations of Bt genes. A possible solution to the aforementioned problems may be either pyramiding of Bt genes with another transgene having a different mode of action, as also discussed earlier [Bt transgenes ? Genetic modification of cotton with the Btcry1Ab transgene with high terpenoid levels showed more resistance to tobacco budworm than transgenics with low terpenoid levels [Btcry3A gene against Colorado potato beetle larvae exhibit higher or at least similar mortality in the target herbivores as in the resistant potato line with leptine glycoalkaloids [Bt genes along with the exploitation of native resistance through marker-assisted breeding will comprise complementary additive effects ameliorating the deployment of resistance management practices in the field.As mentioned above, one strategy to delay the evolution of resistant herbivores is the stacking of multiple Bt genes , 121. Ho earlier –110, or iewed in ). In refiewed in  identifid levels . Howeverlkaloids . In the lkaloids , 123. Thlkaloids . Thus, sper se, or is domestication, artificial selection, just as important? In the opinion of a crop breeder, the end product is warranted by both. Plant breeding of independently selected domesticated forms began almost ten thousand years ago. Gene mutations occurred during selection, polyploidy, or artificial or natural hybridization and brought remarkable genetic variations. For management of stress conditions in crops, do parallel breeding efforts share similar genomic modifications or is it system/event specific, given the likelihood that different features of human-mediated selection may predominate among various lineages? What are the key evolutionary attributes that make the conversion of wild germplasm to “crop” such a prevalent phenomenon? Are the most important evolutionary properties of modern crop plants due to contemporary breeding efforts Very important successes during domestication in terms of crop yield and quality with other agronomic aspects have been achieved, but with compromised resistance to the herbivores and diseases. All modern crop plants are protected against herbivores by using synthetic toxic chemicals, as has been the case for many years, and this often leads to the development of resistance in herbivores against such frequently used chemicals. To circumvent this problem, introgression of important traits from the wild gene pool has been performed through classical breeding, but has met limited success due to incompatibility and numerous genetic and genomic differences among plant forms. Such principal distinctions may be critical, in that the interactions established by the initial conditions propagate from the time of initial origin through periods of stabilization and long-term evolutionary outcome.Based on the limited number of available examples, when gene transfer occurred in the nascent interspecific crosses, genetic engineering techniques had proven useful to overcome such problems. Two potential benefits of genetic modification are precise transfer of foreign gene sequences and the evolution of adaptive transgressive traits. Two potential benefits of genetic modification are precise transfer of foreign gene sequences and the evolution of adaptive transgressive traits. Classic plant breeding programs are reinstated for heterozygosity and therefore may be more likely to experience locus-specific linkage with its evolutionary consequences. In contrast, a transgenic crop plant possesses a greater insertion of multiple alien genic sequences with immediate phenotypic effect and genetic novelty. Indeed, experimental analysis of genetically modified crops for multiple traits suggests that pyramiding of favorable genes for individual trait may yield a “super-crop” with high returns. Thus, the breadth of recurrently selected traits in the domesticated plants and the genetic transformation system together has a major effect on the creation and retention of evolutionary novelty in the crop system.


Background: While it is known that increasing surgeon experience is correlated with improved efficiency and safety in the reduction mammaplasty procedure, it is unclear whether these improvements lead to an erosion in patient satisfaction. Methods: The authors distributed the Breast-Q questionnaire to all patients who underwent bilateral reduction mammaplasty at their institution between 1995 and 2007. Univariate and multivariate analyses were performed to assess the relationship between postoperative patient satisfaction scores and surgeon experience, as well as to characterize those patients with particularly high or low satisfaction scores, in general. Results: A total of 279 (26.1%) completed surveys were analyzed. No statistically significant erosion in either Satisfaction with Breasts (SWB) or Satisfaction with Outcomes (SWO) scores were witnessed with increasing surgeon experience or efficiency. Patients older than 40 years demonstrated significantly higher SWB scores than younger patients (P = .004), while patients who suffered postoperative soft tissue necrosis demonstrated significantly lower SWB (P = .003) and SWO (P = .010) scores. Conclusions: Gains in operative efficiency with increasing surgeon experience do not appear to come at the expense of patient satisfaction in the reduction mammaplasty procedure. Younger patients and those who experience postoperative soft tissue necrosis appear to be at higher risk for reporting lower postoperative patient satisfaction scores. Our prior investigation into the dynamics underlying the reduction mammaplasty procedural learning curve revealed the primacy of surgeon experience with regard to performance improvement.In seeking to further refine this new approach to performance improvement, however, we have given serious consideration to the lack of metrics related to patient satisfaction and esthetic outcomes in our learning curve analysis. It is well-recognized that the reduction mammaplasty procedure serves both functional and esthetic aims, and that effective fulfillment of both priorities is vital to this intervention's success.The purpose of this study was to supplement the findings of our prior investigation through a thoughtful consideration of patient satisfaction trends over the course of the reduction mammaplasty learning curve. In particular, our focus was to elucidate whether increasing surgeon efficiency over time resulted in a concomitant erosion in patient satisfaction. A secondary goal was to determine those factors most readily associated with improved or diminished patient satisfaction.The generation of our core patient database has been described in detail elsewhere.4P values were 2-sided. To assess the representativeness of the population who completed the satisfaction survey, characteristics were compared between responders and nonresponders. Chi-squared or Fisher exact tests were used, as appropriate, to compare categorical variables, whereas the Student t test was employed to compare continuous variables.Statistical analyses were then conducted using SAS 9.2 , for which mean confidence intervals were set at 95% (CI 95%) and Among the responders, nonparametric analyses were performed to identify variables potentially associated with scoring of 2 cardinal satisfaction domains: “Satisfaction with Breasts” (SWB) and “Satisfaction with Outcomes” (SWO). A Kruskal-Wallis test or Mann-Whitney Wilcoxon test was used to compare satisfaction scores between groups. Correlation between satisfaction scores and surgeon experience, as well as operative time, was also tested using the Spearman's rank correlation test. For every variable of interest, mean value or percentage was computed with corresponding 95% CI according to stratification on tertiles of SWB and SWO scores. Last, multivariate analyses for potential associations between these covariates and patient satisfaction were performed using generalized estimating equations, accounting for clustering of patients by surgeon.A total of 1068 breast-reduction procedures were performed during the study period; of these, 279 (26.1%) completed the satisfaction survey. No significant differences were observed between responder and nonresponder characteristics except for patient's age and the year of procedure; younger patients or those who underwent operation prior to 1998 completed the survey less frequently (Table P = .145) or SWO , nor between operative time and SWB  or SWO . Postoperative necrosis was the only factor associated with both SWB and SWO domains: the mean SWB score was lower among patients experiencing postoperative necrosis  compared with those who did not , with a similar reduction witnessed in mean SWO scores . Higher SWB scores were also linked with increasing patient age. These results were recapitulated in additional analyses of SWB and SWO scores stratified by quartiles; patients having high SWB scores were generally older than lower scoring patients (P = .004), and postoperative necrosis was never witnessed among patients with high SWB or SWO scores  As in the univariate analyses, multivariate analyses were notable for a statistically significant association between increasing patient age and SWB. On the basis of composite outcomes, a nonsignificant trend was also observed between the occurrence of complications and SWO. No relationship was found between satisfaction scores and surgeon's experience or operative time, respectively Table .,surgeon-reported outcomes measurement tool has been achieved.Applying a uniform standard to the evaluation of breast esthetics—particularly in the postoperative period—is not a straightforward task. The plastic surgery literature includes attempts by multiple investigators to determine a universally acceptable, independent system for the assessment of breast cosmesis, including expositions on the potential virtues of subjective ratings scales,6patient-reported outcomes measurement tools to assess a variety of esthetic, functional, and psychological parameters related to breast procedures. A review of the literature demonstrates a veritable cornucopia of patient satisfaction questionnaires that have been applied to the assessment of breast surgery outcomes, in general, and reduction mammaplasty, in particular, including the Short Form 36,8,15-21Perhaps in response, attention has increasingly turned instead to the employment of ,25(p1826)However, a major criticism of utilizing patient-reported outcomes measurement tools in the assessment of reduction mammaplasty patients is that these ad hoc questionnaires tend to lack validity, reliability, and specificity.23very dissatisfied) to 100 (very satisfied).4In accordance with these guidelines, Pusic et alWe selected the BREAST-Q as our analytic instrument because of its documented validity, reliability, and specificity for reduction mammaplasty patients. To our knowledge, our study represents the largest cohort of BREAST-Q responses for this procedure reported to date. We focused our analysis principally on 2 of the 10 possible satisfaction categories—SWB and SWO—in accordance with our stated intent to preferentially concentrate on the esthetic components of the procedure; our analyses therefore pertain to a subset of the patient-reported responses derived from our use of the BREAST-Q.Our results suggest that patient assessments of esthetics and overall outcomes following reduction mammaplasty do not appear to decline with increasing operative efficiency. In fact, patient satisfaction in these 2 categories seems to exhibit essential stability over the course of the procedural learning curve, with some hint of slow but gradual ongoing improvement with increasing surgeon experience. This improvement may be attributable to declining complication rates witnessed in the later phases of the reduction mammaplasty learning curve, as evidenced in the association noted between postoperative skin necrosis and reduced satisfaction scores. Interestingly, this finding runs counter to that of other investigators such as Cunningham et al,These findings support the hypothesis that efficiency gains achieved over the course of the reduction mammaplasty learning curve do not appear to come at the expense of patient satisfaction with regard to postoperative esthetics or overall outcome. In fact, the benefits realized though diminished operative time and operative time variance with increasing surgeon experience may be accompanied concomitantly not only by improved safety as reflected in diminishing complication rates but also by stable patient satisfaction scores with ongoing maturation of the operative surgeon Figs  and 2. TA curious finding of our study is that patient satisfaction scores appear to plateau very early for attending-level surgeons and remain largely constant over the course of the reduction mammaplasty learning curve. This contrasts starkly with the ongoing improvement witnessed in efficiency and safety outcomes over the same interval that we have previously reported. The reasons underlying this dynamic remain unclear; perhaps the development of social proficiency precedes the development of technical proficiency by many years, with the most marked gains in the former witnessed over the course of residency training . Why this evolution would occur over a different interval than that observed for efficiency and safety improvements is open to speculation and is a potentially fertile area for additional research.While the primary intent of our investigation was to determine whether patient satisfaction erodes with increasing surgeon efficiency in reduction mammaplasty, a secondary goal of our study was to elucidate those factors that may contribute to either exceptionally high or exceptionally low patient satisfaction scores in this procedure, in general. Our analyses of patient satisfaction scores stratified by score quartile suggest that patient age appears to correlate with procedural satisfaction, with increased age (particularly >40 years) associated with increased satisfaction. As referenced previously, this may be a reflection of lower or more realistic expectations on the part of older patients; alternately, it may evidence that older patients have lived with the negative sequelae of macromastia for a longer duration and, therefore, find a greater degree of relief both functionally and esthetically after undergoing reduction mammaplasty. This finding suggests that additional care should be taken when setting postoperative expectations in the preoperative setting in patients younger than 40 years. In addition, lower satisfaction scores seem to be reported among patients who suffer postoperative complications; this finding is particularly evident among patients who experience postoperative skin necrosis—likely due to the fact that treatment in this population generally consists of prolonged conservative wound care with an increased likelihood of subsequent prominent scarring. This finding provides credence to the well-established notion of limiting tension along closure lines and counseling patients to avoid agents known to contribute to poor wound healing, such as tobacco exposure.,28Our study represents a retrospective, cross-sectional survey, and therefore falls prey to the limitations generally witnessed in this study design. In addition, our lack of prospective data collection did not permit an assessment of respondents' preoperative satisfaction levels; we are therefore making an implicit assumption that all respondents demonstrated an approximately equivalent baseline level of satisfaction. Furthermore, despite the absence of marked differences between the responder and nonresponder subgroups, it is unclear whether those patients who completed questionnaires may exhibit either a positive or negative bias with regard to their outcomes. Last, the lack of longitudinal satisfaction tracking of individual patients does not permit us to comment on the durability of patient assessments over time. However, other published studies concerning long-term patient satisfaction and reduction mammaplasty suggest that satisfaction scores tend to improve steadily over the course of the first postoperative year, then stabilize and remain essentially constant thereafter.27,30Our reliance on patient-reported measures for esthetic outcome assumes an implicit equivalency between these metrics and objective, third-party assessments commonly employed in other studies. This assumption, however, is not unfounded; several reports by other investigators have noted patient evaluations to be a reliable index of esthetic outcome following reduction mammaplasty, often identical in scale to evaluations provided by expert, objective observers.29Our results are based on an assessment of dynamics witnessed in a multiple-member faculty practice in a large academic medical center. It is uncertain to what degree our findings may be generalized to other academic environments, or to either the group private practice or solo practitioner model.There are several limitations to the present study that warrant mention:The improvements typically witnessed with regard to increasing efficiency and safety over the course of the reduction mammaplasty procedural learning curve do not appear to come at the expense of esthetic outcomes, as assessed through patient-reported satisfaction metrics. This finding is particularly relevant to the reduction mammaplasty procedure, which includes both functional and esthetic components that must be considered equally when assessing surgical success.


There has been a great deal of interest in understanding how the human brain processes appetitive food cues, and knowing how such cues elicit craving responses is particularly relevant when current eating behavior trends within Westernized societies are considered. One substance that holds a special place with regard to food preference is chocolate, and studies that used functional magnetic resonance imaging (fMRI) and event-related potentials (ERPs) have identified neural regions and electrical signatures that are elicited by chocolate cue presentations. This review will examine fMRI and ERP findings from studies that used high-caloric food and chocolate cues as stimuli, with a focus on responses observed in samples of healthy participants, as opposed to those with eating-related pathology. The utility of using high-caloric and chocolate stimuli as a means of understanding the human reward system will also be highlighted, as these findings may be particularly important for understanding processes related to pathological overeating and addiction to illicit substances. Finally, research from our own lab that focused on chocolate stimulus processing in chocolate cravers and non-cravers will be discussed, as the approach used may help bridge fMRI and ERP findings so that a more complete understanding of appetitive stimulus processing in the temporal and spatial domains may be established. Scientific attention towards understanding how people process appetitive food cues has seen a major raise over the course of the last decade, partly due to the increased interest that has been devoted to understanding disordered eating. Researchers who use neuroimaging techniques have attempted to identify the neural correlates of appetitive food processing, and by using functional neuroimaging and electroencephalography (EEG), brain activations elicited by presentations of highly appetitive food cues have been identified in the temporal and spatial domains.i.e., what cognitive processes are recruited within 200–300 ms after a chocolate image is presented?). Additionally, it is very expensive to acquire, operate, and maintain fMRI equipment, thereby limiting the number of studies that could be conducted within a given period of time. On the other hand, ERPs have very high temporal resolution and can be used to document changes in brain electrical activity recorded over the scalp on a millisecond-by-millisecond basis due to the fact electrical responses travel at nearly the speed of light and reach external sensors rapidly. Because of this property, the technique is especially well suited for identifying the bottom–up processes that underlie phenomena such as reward valuation and decision making, as well as subconscious processes that may underlie various automatically generated behaviors . Also, the equipment is relatively inexpensive and does not require the large amount of space needed for fMRI data collection. However, the spatial resolution of scalp-recorded EEG is less precise because electrical signals generated inside the brain reach the scalp though volume conduction, which reduces and smears the signal as distance from the source increases. In addition, distinct tissues  conduct electricity at different rates, further complicating the precise localization of generators inside the brain. Brain source localization relies on complex source modeling techniques which attempt to identify where electrical signatures detected at the scalp come from by solving the so-called inverse problem. These have historically produced biased estimates that favor sources closer to the cortical surface, and have also had difficulty identifying activations that are produced in deeper brain tissue. One further methodological issue that is pertinent to the investigation of food cue processing in the brain relates to stimulus presentation techniques that can be utilized during a study. Using fMRI, it is possible to have a participant consume various foods while they complete a given task, as the small movements that are made within the scanner can be corrected during data processing. Unfortunately, these same movements create more serious artifacts when the ERP technique is used, therefore contaminating experimental trials within the research paradigm and affecting data quality. Despite the advantages and disadvantages inherent in the utilization of these methods, some researchers are now trying to compare and combine ERP and fMRI findings so that neural structures and cognitive processes implicated in various aspects of appetitive food stimulus processing can be identified and better understood.Collectively, a large number of studies have been carried out using functional magnetic resonance imaging (fMRI) and event-related potentials . Both of these techniques have inherent advantages and disadvantages, with fMRI providing excellent spatial resolution due to its measurement of BOLD (blood oxygen level-dependent) changes within key regions of the brain during experimental tasks. However, because such effects happen over a matter of seconds, the fMRI technique is thought to have relatively poor temporal resolution. Ultimately, this limitation restricts the method’s ability to address certain research questions . FurtThis review will summarize findings that were reported by researchers who presented high-caloric food stimuli to samples of healthy participants. Findings that were obtained using fMRI and ERPs will be highlighted, and different sections of the paper will also specifically discuss fMRI and ERP effects discovered using multimodal presentations of chocolate stimuli. Finally, we will attempt to bridge these two areas of research by showcasing findings we obtained when we conducted an ERP study of chocolate stimulus processing that utilized a source localization technique . Before the relevant research is examined in detail, we will briefly review the neuroanatomy of the human gustatory and olfactory systems and the proposed functions for some neural areas that process stimuli presented through these sensory streams.Researchers have made great advances in understanding how human beings process gustatory and olfactory cues. Advances in brain sciences have granted us unparalleled access into the inner workings of our nervous systems, and the pathways that process tastes and smells have been described in intricate detail. We will review some of the basic research that has been done in this area to provide a context for understanding results that were obtained in studies that specifically assessed reactivity to food cues that were presented to various sensory modalities.Taste signals begin when specialized chemosensory cells (taste buds) located in regions of the oral cavity (tongue and epithelium) are activated by a taste stimulus. These specialized cells respond preferentially to sweet, sour, bitter, salty, and umami stimulation (the five basic tastes) . Once acOlfactory stimulation is first received by olfactory receptor neurons in the main olfactory epithelium, which transmit chemosensory signals to the olfactory bulb via their axonal projections. The reception of odor signals by olfactory receptor neurons differs from that seen with the reception of chemosensory stimulation by taste buds, as different odorants can be processed by the same olfactory neurons  . Once thA number of studies have used both high-caloric and low-caloric foods as stimulus categories in attempts to understand how the brain responds to highly salient, craving-inducing stimuli. Findings from fMRI research indicate that a neural network is involved in the processing of such stimuli, and ERP research indicates that these cues recruit different nuclei during the early and late stages of stimulus processing.i.e., [Perhaps not surprisingly, the majority of research done using high-caloric food stimuli in experimental paradigms with healthy participants has utilized fMRI. Although a large number of studies have looked at food stimulus processing in a general sense , only a i.e., ,20). Theversus non-food objects), and were also found to be predictive of future snack consumption [Research using high-caloric food images in conjunction with fMRI has been accomplished with a variety of experimental manipulations see . High-casumption  and weigsumption . A recensumption . Other rsumption . InteresLooking at this body of research collectively, highly appetitive and/or high-caloric food cues appear to activate brain regions that are implicated in the appraisal of rewards and reward-based learning , top-down regulation , affect , decision making , interoceptive awareness and hedonic evaluation (insula) and homeostasis  when they are viewed. Furthermore, it appears that activations observed within some of these regions are sensitive to subject-specific factors such as hunger level and dietary conscientiousness induced by exercise, with brain activations to the sight of this stimulus type being moderated by the coded value of externally and internally generated stimuli. By working in concert, these individual brain regions appear to enable a representation of stimulus value, which are presumably related to observable behavior. It is also significant that brain activations to the sight of these cues successfully predicted future weight gain and snack consumption. Future research in this direction could be extremely useful for researchers interested in clinical aspects of abnormal eating behavior, as well as those working in private industry who wish to better understand consumer populations.i.e., [i.e., the nucleus accumbens, pallidum, thalamus) and prefrontal/limbic regions  [et al. (2009) found that there was greater activation in the ventral striatum, bilateral insula, medial and lateral OFC, and amygdala when participants who fasted overnight viewed high-caloric foods relative to a “fed” condition  [i.e., [Given that neural structures implicated in reward processing are consistently activated by the sight of appetitive food cues when healthy participants view them  . Goldstorewards) . Severalrewards) . Studies) [i.e., ,38), cha) [i.e., . Importa) [i.e., . Regardi) [i.e., . Althoug) [i.e., . Althoug) [i.e., .i.e., [Taken together, a great deal of research has identified brain structures that are activated by the sight of appetitive foods when healthy participants are satiated as well as when they are in fasted states, and these structures are believed to play a central role in reward processing. Many of these structures are also found to be active when patients suffering from substance abuse pathologies view drug stimuli , and fuAlthough a great deal of research has been conducted using fMRI, there have been far fewer reports about the processing of high-caloric food cues by healthy participants using EEG/ERP technology see . Althougversus low-fat pictures, and its estimated source generator was found to localize to the ventromedial PFC in addition to dorsal and lateral prefrontal areas in the right hemisphere , and in bilateral inferior frontal cortex . Importahniques; ). These hniques; . Researchniques; . Severalhniques; . Finallyhniques; . Importaversus global features as measured by reaction times (RT) were also successfully predicted by LPP voltages, suggesting that the stimulus was highly salient and that it received special processing. This component has also been elicited to a greater degree when appetitive foods were presented to participants in a deprived state [versus unrestrained eaters who were told that certain foods would be available or unavailable to them. In the latter case, restrained eaters showed less of an LPP response to available food cues, which may have reflected a mobilization of cognitive control strategies by members of this group [Other research that looked at late-occurring ERP components found that a potential called the Late Positive Potential (LPP) increased in amplitude after presentations of highly appetitive pictures relative to neutral control stimuli . Additioed state  and whenis group .versus unrestrained eating style. In addition to using the classic approach of reporting the topographic location of the ERP components at the level of the scalp, recent research has also implemented source localization procedures in an effort to estimate the neural generators of these electrical potentials, with their solutions appearing similar to those results obtained using fMRI tasks that assessed neural responses to high-caloric foods. The utility of using ERPs to study normal and abnormal processing of highly appetitive food cues is an area of research that is still developing, but it has great potential for informing scientists about how human beings process these biologically relevant cues in real time, as well as how this processing maps on to classic descriptions of sensory processing streams identified by neuroanatomy.Taken together, ERP research has consistently identified both early and late-occurring effects in response to high-caloric food cues, and the amplitude and polarity of some of these components are modulated by within-subjects factors such as hunger state or restrained Although this discussion has focused on high-caloric food cues up until the current point, special mention should be made about the unique effects reported by researchers who have used chocolate stimuli as a target of interest. Chocolate is unique in the sense that it is commonly used as a positive reinforcer for desirable behaviour by parents during their offspring’s early life and adolescent years, and this is especially true in Westernized societies. Some earlier scientific work that utilized the positron emission tomography (PET) technique focused on changes in regional cerebral blood flow within the brain as the hedonic value of chocolate decreased as a function of increased consumption, where reductions in bilateral insula activation were observed when chocolate became less rewarding . By looki.e., [versus a tasteless solution [i.e., anhedonia) which also involve abnormalities in patients responding to appetitive stimuli .In summary, a diversity of fMRI research has been conducted using chocolate stimuli and healthy participants, with studies ranging from investigations of its effects on mood states to its ability to engage neural regions implicated in reward processing and conditioning. This research has facilitated insights into the neural basis of learning, satiety, mood regulation, reward, and also allows us to make inferences about the neural correlates of pathological conditions , in an effort to show the utility of using chocolate stimuli and the ERP technique in tandem, as well as how ERP findings can be interpreted in light of fMRI findings regarding chocolate and the brain.One study attempted to describe the differential processing of chocolate odors in a sample of restrained eaters relative to a control group . While pBefore concluding this section, we would like to summarize a recent ERP study we conducted that explored chocolate stimulus processing among samples of participants who were either high or low in trait chocolate craving . In thisAlthough this review has focused on research that attempts to highlight neural responses to high-caloric food and chocolate stimuli, it is important to note that many factors may influence observations seen using either fMRI or ERP food-cue paradigms. As can be seen in the preceding text, many factors including (but not limited to) affective state , discretHow the brain responds to highly appetitive foods has been a fascinating research area for many scientists, and, over the course of the last decade, there has been tremendous advances in understanding the neural correlates of appetitive food cue processing. Given the special status of chocolate in Western culture, studies have also been conducted using this stimulus as a target, and its presentation has been found to activate many of the same brain regions that are activated by high-caloric foods and other reward stimuli. Electrophysiology research has also found a number of ERP components that seem to be elicited specifically by high-caloric food pictures and chocolate stimuli, although more research will need to be done in order to fully understand the processing of these stimuli in the temporal domain. As a result of advances in computer technology, sophisticated source localization procedures can now be used to localize electrical activity recorded at the scalp, therefore facilitating comparisons with fMRI results. Using chocolate and high-caloric stimuli may provide useful information about pathological and normal brain processes, and understanding how chocolate consumption affects cognition is still in its infancy. Although this list of potential research directions is not exhaustive, it nonetheless conveys the notion that there is still much to be learned regarding the human processing of appetitive stimuli while highlighting the converging findings that have been obtained through multiple methodologies that will enrich our knowledge regarding this universal human neurocognitive response.