Alternative Frameworks for Advancing the Study of Eating Disorders
Authors: Sarah A. Stern, Cynthia M. Bulik
Journal: Trends in Neurosciences (2020)

Eating disorders are complex disorders with a strong biological component, but are understudied by basic scientists.Improved genome-wide association studies (GWAS) and pluripotent stem cells provide the first insights into genes with a role in the etiology of anorexia nervosa (AN).Neuroimaging studies of individuals with AN point to conserved behavioral features and underlying brain regions that can be translated to animal models and neural circuit-based research.Studies of neuroimmune diseases with restrictive feeding components may also provide important biological insights into mechanisms underlying eating disorders.We identify promising avenues for researchers to pursue in the study of eating disorders that will inform tailored and improved prevention and treatment interventions. Eating disorders are life-interrupting psychiatric conditions with high morbidity and mortality, yet the basic mechanisms underlying these conditions are understudied compared with other psychiatric disorders. In this opinion, we suggest that recent knowledge gleaned from genomic and neuroimaging investigations of eating disorders in humans presents a rich opportunity to sharpen animal models of eating disorders and to identify neural mechanisms that contribute to the risk and maintenance of these conditions. Our article reflects the state of the science, with a primary focus on anorexia nervosa (AN) and binge-eating behavior, and encourages further study of all conditions categorized under feeding and eating disorders. Eating disorders are life-interrupting psychiatric conditions with high morbidity and mortality, yet the basic mechanisms underlying these conditions are understudied compared with other psychiatric disorders. In this opinion, we suggest that recent knowledge gleaned from genomic and neuroimaging investigations of eating disorders in humans presents a rich opportunity to sharpen animal models of eating disorders and to identify neural mechanisms that contribute to the risk and maintenance of these conditions. Our article reflects the state of the science, with a primary focus on anorexia nervosa (AN) and binge-eating behavior, and encourages further study of all conditions categorized under feeding and eating disorders. Basic research on eating disorders, especially food-restricting disorders, such as anorexia nervosa (AN), has lagged behind other psychiatric illnesses. AN is characterized by extreme low weight coupled with fears of, and behaviors to prevent, weight gain [1.American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders.5th edn. American Psychiatric Association, 2013Crossref Google Scholar]. Current conceptualizations implicate both genetic and environmental etiological factors [2.Yilmaz Z. et al.Genetics and epigenetics of eating disorders.Adv. Genom. Genet. 2015; 5: 131-150PubMed Google Scholar]. Mortality is high and impacts on other aspects of health (e.g., osteoporosis, amenorrhea, cardiac function, and anemia) are extensive [3.Treasure J. et al.Anorexia nervosa.Nat. Rev. Dis. Primers. 2015; 115074Crossref PubMed Scopus (125) Google Scholar]. Bulimia nervosa (BN) and binge-eating disorder (BED) are primarily characterized by binge eating (eating an unusually large amount of food coupled with a sense of loss of control). They are differentiated by the presence of recurrent compensatory behaviors (e.g., self-induced vomiting or laxative abuse), which is seen in BN but not in BED [1.American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders.5th edn. American Psychiatric Association, 2013Crossref Google Scholar]. The high co-occurrence of all eating disorders with other psychiatric illnesses, such as anxiety disorders, major depressive disorder (MDD), and obsessive-compulsive disorder (OCD) (between 40% and 90%) [4.Herpertz-Dahlmann B. Adolescent eating disorders: update on definitions, symptomatology, epidemiology, and comorbidity.Child Adolesc. Psychiatr. Clin. N. Am. 2015; 24: 177-196Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar], and their intersection with weight and appetite regulation mechanisms tells us that building the eating disorders knowledge base has the potential to illuminate factors that also influence other related psychiatric and somatic conditions and traits. Research into the etiology and pathogenesis of eating disorders is in search of refined paths forward. Discovery has been slow due to the lack of tractable models and genetic leads. Importantly, moderate to high twin-based heritability estimates [2.Yilmaz Z. et al.Genetics and epigenetics of eating disorders.Adv. Genom. Genet. 2015; 5: 131-150PubMed Google Scholar] (on par with other major psychiatric traits [5.Polderman T.J.C. et al.Meta-analysis of the heritability of human traits based on fifty years of twin studies.Nat. Genet. 2015; 47: 702-709Crossref PubMed Scopus (848) Google Scholar]) imply that strong biological mechanisms are implicated that have yet to be discovered. We discuss how recent research provides insights into the mechanisms underlying restrictive eating disorders, which have the potential to direct basic science researchers toward testable science. AN is perplexing, with affected individuals defying, failing to respond to, or not experiencing biological drives central to survival (i.e., hunger) and claiming to feel better while doing so. Coined a paradoxical response to negative energy balance [6.Bulik C.M. Towards a science of eating disorders: replacing myths with realities: the fourth Birgit Olsson lecture.Nord. J. Psychiatry. 2016; : 224-230Crossref PubMed Scopus (11) Google Scholar] (see Glossary), this core feature of AN directly opposes a global trend toward positive energy balance and progressive weight gain [7.NCD Risk Factor CollaborationTrends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants.Lancet. 2016; 387: 1377-1396Abstract Full Text Full Text PDF PubMed Scopus (2388) Google Scholar]. The core features of AN are packaged within cultural or psychological epiphenomena, such as religiosity of the Middle Ages [8.Espi Forcen F. Espi Forcen C. The practice of holy fasting in the late middle ages: a psychiatric approach.J. Nerv. Ment. Dis. 2015; 203: 650-653Crossref PubMed Scopus (6) Google Scholar] or the contemporary societal drive for thinness [9.Striegel-Moore R. et al.Toward an understanding of risk factors for bulimia.Am. Psychologist. 1986; 41: 246-263Crossref PubMed Scopus (875) Google Scholar], which can obscure the central features of restricting food intake and/or increasing energy output to achieve and maintain negative energy balance. We acknowledge the importance of cultural and psychological factors, and suggest that a more concerted focus on the core biology could be key to unlocking mechanisms underlying eating disorders. Individuals with BN or BED display dysregulated eating in the opposite direction by overriding or failing to experience typical satiety signals during binge episodes [10.Sysko R. et al.Rigor and reproducibility via laboratory studies of eating behavior: a focused update and conceptual review.Int. J. Eat Disord. 2018; 51: 608-616Crossref PubMed Scopus (12) Google Scholar]. Individuals with BN tend to be in the normal to overweight range, whereas individuals with BED, often, but not always, maintain a positive energy balance and fall within the overweight or obese range [11.Schaumberg K. et al.The science behind the Academy for Eating Disorders' Nine Truths About Eating Disorders.Eur. Eat. Disord. Rev. 2017; 25: 432-450Crossref PubMed Scopus (69) Google Scholar]. Animal models are an important research tool for many psychiatric disorders. Although animal behaviors cannot fully recapitulate human diseases, the core behavioral features of many diseases can be modeled in animals to gain insight into underlying neural circuits and mechanisms. Examples include fear conditioning in the study of anxiety [12.Jovanovic T. et al.Translational neuroscience measures of fear conditioning across development: applications to high-risk children and adolescents.Biol. Mood Anxiety Disord. 2013; 3: 17Crossref PubMed Google Scholar] and post-traumatic stress disorder [13.Careaga M.B.L. et al.Understanding posttraumatic stress disorder through fear conditioning, extinction and reconsolidation.Neurosci. Biobehav. Rev. 2016; 71: 48-57Crossref PubMed Scopus (53) Google Scholar], social defeat for depression [14.Hollis F. Kabbaj M. Social defeat as an animal model for depression.ILAR J. 2014; 55: 221-232Crossref PubMed Scopus (113) Google Scholar], and grooming or reversal learning for obsessive-compulsive behaviors [15.Ahmari S.E. Using mice to model obsessive compulsive disorder: from genes to circuits.Neurosci. 2016; 321: 121-137Crossref PubMed Scopus (31) Google Scholar]. The intention is clearly not to perfectly recapitulate the target disorder, but rather to model foundational behavioral aspects of the disease that isolate implicated neural underpinnings [16.Monteggia L.M. et al.Meeting Report: can we make animal models of human mental illness?.Biol. Psychiatry. 2018; 84: 542-545Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar]. A comparison of AN with OCD is informative, given their strong shared genetic basis [17.Yilmaz Z. et al.Examination of the shared genetic basis of anorexia nervosa and obsessive–compulsive disorder.Mol. Psychiatry. 2018; 25: 2036-2046Crossref PubMed Scopus (29) Google Scholar]. Animal models of OCD never claim to study obsessive cognitions, which are impossible to assess in rodents, but rather compulsive behaviors, which can be observed and quantified [15.Ahmari S.E. Using mice to model obsessive compulsive disorder: from genes to circuits.Neurosci. 2016; 321: 121-137Crossref PubMed Scopus (31) Google Scholar]. Similarly, it is impossible (and even humorous) to propose to observe obsessions with thinness in rodents, but it is feasible to observe and quantify voluntary food restriction. Several animal models have been advanced to study AN [18.Mequinion M. et al.The use of animal models to decipher physiological and neurobiological alterations of anorexia nervosa patients.Front Endocrinol. (Lausanne). 2015; 6: 68PubMed Google Scholar,19.Zeltser L.M. Madra M. A framework for elucidating causes and consequences of malnutrition in anorexia nervosa.in: Sangha S. Foti D. Neurobiology of Abnormal Emotion and Motivated Behaviors. Elsevier, 2018: 92-118Crossref Scopus (1) Google Scholar] and binge-eating behavior (Box 1). Early models of AN tended not to recapitulate core features of the disease (e.g., experimenter-imposed food restriction has little to do with the psychiatric condition of AN) and may have fueled skepticism about the utility of animal models. Several animal models of binge-eating behavior exist, but cannot fully capture the syndromes of BN or BED. For example, a complete model of BN would include both binge eating and compensatory behaviors. Animal models can capture excessive consumption, but cannot model the psychological criterion of 'feeling out of control'. Moreover, mice and rats, commonly used for behavioral neuroscience studies, are physiologically unable to vomit, rendering animal models of BN only partially attainable. Similarly, BED often co-occurs with obesity and shares numerous features, complicating the ability of animal models to differentiate between the two. In addition to these practical limitations, the historical focus on sociocultural aspects of eating disorders [20.Culbert K.M. et al.Research Review: what we have learned about the causes of eating disorders - a synthesis of sociocultural, psychological, and biological research.J. Child Psychol. Psychiatry. 2015; 56: 1141-1164Crossref PubMed Scopus (227) Google Scholar] may have contributed to a systemic bias against animal models. However, as the science of eating disorders matures, we anticipate a greater acceptance of the relevance of animal models for studying both restrictive eating disorders and other patterns of dysregulated eating.Box 1Animal Models Relevant for Eating DisordersNumerous animal models have been proposed to study AN and binge eating, and are variably useful depending on which aspects of the disease one is trying to model. Early models that used simple food restriction or deprivation paradigms [18.Mequinion M. et al.The use of animal models to decipher physiological and neurobiological alterations of anorexia nervosa patients.Front Endocrinol. (Lausanne). 2015; 6: 68PubMed Google Scholar] to lower body weight have been mostly discarded because they do not involve voluntary food restriction [18.Mequinion M. et al.The use of animal models to decipher physiological and neurobiological alterations of anorexia nervosa patients.Front Endocrinol. (Lausanne). 2015; 6: 68PubMed Google Scholar,19.Zeltser L.M. Madra M. A framework for elucidating causes and consequences of malnutrition in anorexia nervosa.in: Sangha S. Foti D. Neurobiology of Abnormal Emotion and Motivated Behaviors. Elsevier, 2018: 92-118Crossref Scopus (1) Google Scholar,66.Donohoe T.P. Stress-induced anorexia: implications for anorexia nervosa.Life Sci. 1984; 34: 203-218Crossref PubMed Scopus (63) Google Scholar] and appear to mainly reflect energy balance changes. Similarly, sham feeding (i.e., draining liquid food before entering the intestinal tract) serves as a model for binge eating in which rodents get positive orosensory feedback from consumption with negative intestinal feedback, although the behavior is not self initiated [76.Corwin R.L. Buda-Levin A. Behavioral models of binge-type eating.Physiol. Behav. 2004; 82: 123-130Crossref PubMed Scopus (145) Google Scholar]. Binge-like behavior of palatable foods can be induced under limited access conditions, but this access schedule is also experimenter initiated.Genetic mutations that lead to catastrophic weight loss, from which mice die soon after birth, such as the anx/anx mutation [77.Nilsson I.A. The anx/anx mouse–a valuable resource in anorexia nervosa research.Front. Neurosci. 2019; 13: 59Crossref PubMed Scopus (10) Google Scholar], are intriguing and informative, although significant phenotypic differences, including timing of neurodevelopmental onset, differ from that seen in AN. Similarly, ob/ob mice engage in severe hyperphagia, but this is likely due to a perceived sensation of starvation due to the lack of circulating leptin, which is not characteristic of binge-like behavior. These mice exhibit other unrelated phenotypes, such as hypothermia, reduced fertility, and decreased bone mass [78.Friedman J.M. Leptin and the endocrine control of energy balance.Nat. Metab. 2019; 1: 754-764Crossref PubMed Scopus (75) Google Scholar].Simple stress models, such as restraint stress or social isolation stress, can induce reduction in body weight and/or food intake in the absence of imposed food restriction, but other chronic stress models, including after footshock, can induce hyperphagia [79.Hagan M.M. et al.A new animal model of binge eating: key synergistic role of past caloric restriction and stress.Physiol. Behav. 2002; 77: 45-54Crossref PubMed Scopus (163) Google Scholar], highlighting the importance of dissecting out these competing mechanisms. However, these models may preferentially reflect energy balance changes over food intake changes and may also more closely model the type of food restriction or increase that occurs during simple hypothalamic–pituitary–adrenal (HPA) axis activation.More sophisticated animal models of eating disorders incorporate multiple parameters. For binge eating, cue-mediated overconsumption is a model that incorporates learning about food cues with restriction/refeeding, which induces overconsumption in the sated state when prompted by the cue [80.Petrovich G.D. Forebrain networks and the control of feeding by environmental learned cues.Physiol. Behav. 2013; 121: 10-18Crossref PubMed Scopus (71) Google Scholar]. The most popular animal model of AN currently in use is activity-based anorexia (ABA) [18.Mequinion M. et al.The use of animal models to decipher physiological and neurobiological alterations of anorexia nervosa patients.Front Endocrinol. (Lausanne). 2015; 6: 68PubMed Google Scholar], which combines moderate food restriction (usually 1 h a day of food access) in combination with access to a running wheel. This model leads to severe food restriction compared with control groups that are also food restricted but do not have access to a running wheel. The ABA model also successfully models hyperactivity, a pernicious and often intractable symptom of AN. Despite this, the model requires a food restriction paradigm for the duration of the experiment to maintain voluntary food restriction, which contrasts with the voluntary food restriction seen in patients with AN despite all efforts to encourage consumption. Another recent gene × environment × diet (GED) model incorporates moderate food restriction for 11 days, genetic predisposition to anxiety (BDNFVal66Met gene variant), and social isolation stress in adolescent mice [19.Zeltser L.M. Madra M. A framework for elucidating causes and consequences of malnutrition in anorexia nervosa.in: Sangha S. Foti D. Neurobiology of Abnormal Emotion and Motivated Behaviors. Elsevier, 2018: 92-118Crossref Scopus (1) Google Scholar]. Compared with ABA, the GED model imposes food restriction for only a short period of time and, therefore, may more accurately model the type of voluntary food restriction seen in patients with AN following initial dieting. It is notably the only model proposed to date that incorporates gene, environment, and diet changes to produce anorexia-like behaviors. Numerous animal models have been proposed to study AN and binge eating, and are variably useful depending on which aspects of the disease one is trying to model. Early models that used simple food restriction or deprivation paradigms [18.Mequinion M. et al.The use of animal models to decipher physiological and neurobiological alterations of anorexia nervosa patients.Front Endocrinol. (Lausanne). 2015; 6: 68PubMed Google Scholar] to lower body weight have been mostly discarded because they do not involve voluntary food restriction [18.Mequinion M. et al.The use of animal models to decipher physiological and neurobiological alterations of anorexia nervosa patients.Front Endocrinol. (Lausanne). 2015; 6: 68PubMed Google Scholar,19.Zeltser L.M. Madra M. A framework for elucidating causes and consequences of malnutrition in anorexia nervosa.in: Sangha S. Foti D. Neurobiology of Abnormal Emotion and Motivated Behaviors. Elsevier, 2018: 92-118Crossref Scopus (1) Google Scholar,66.Donohoe T.P. Stress-induced anorexia: implications for anorexia nervosa.Life Sci. 1984; 34: 203-218Crossref PubMed Scopus (63) Google Scholar] and appear to mainly reflect energy balance changes. Similarly, sham feeding (i.e., draining liquid food before entering the intestinal tract) serves as a model for binge eating in which rodents get positive orosensory feedback from consumption with negative intestinal feedback, although the behavior is not self initiated [76.Corwin R.L. Buda-Levin A. Behavioral models of binge-type eating.Physiol. Behav. 2004; 82: 123-130Crossref PubMed Scopus (145) Google Scholar]. Binge-like behavior of palatable foods can be induced under limited access conditions, but this access schedule is also experimenter initiated. Genetic mutations that lead to catastrophic weight loss, from which mice die soon after birth, such as the anx/anx mutation [77.Nilsson I.A. The anx/anx mouse–a valuable resource in anorexia nervosa research.Front. Neurosci. 2019; 13: 59Crossref PubMed Scopus (10) Google Scholar], are intriguing and informative, although significant phenotypic differences, including timing of neurodevelopmental onset, differ from that seen in AN. Similarly, ob/ob mice engage in severe hyperphagia, but this is likely due to a perceived sensation of starvation due to the lack of circulating leptin, which is not characteristic of binge-like behavior. These mice exhibit other unrelated phenotypes, such as hypothermia, reduced fertility, and decreased bone mass [78.Friedman J.M. Leptin and the endocrine control of energy balance.Nat. Metab. 2019; 1: 754-764Crossref PubMed Scopus (75) Google Scholar]. Simple stress models, such as restraint stress or social isolation stress, can induce reduction in body weight and/or food intake in the absence of imposed food restriction, but other chronic stress models, including after footshock, can induce hyperphagia [79.Hagan M.M. et al.A new animal model of binge eating: key synergistic role of past caloric restriction and stress.Physiol. Behav. 2002; 77: 45-54Crossref PubMed Scopus (163) Google Scholar], highlighting the importance of dissecting out these competing mechanisms. However, these models may preferentially reflect energy balance changes over food intake changes and may also more closely model the type of food restriction or increase that occurs during simple hypothalamic–pituitary–adrenal (HPA) axis activation. More sophisticated animal models of eating disorders incorporate multiple parameters. For binge eating, cue-mediated overconsumption is a model that incorporates learning about food cues with restriction/refeeding, which induces overconsumption in the sated state when prompted by the cue [80.Petrovich G.D. Forebrain networks and the control of feeding by environmental learned cues.Physiol. Behav. 2013; 121: 10-18Crossref PubMed Scopus (71) Google Scholar]. The most popular animal model of AN currently in use is activity-based anorexia (ABA) [18.Mequinion M. et al.The use of animal models to decipher physiological and neurobiological alterations of anorexia nervosa patients.Front Endocrinol. (Lausanne). 2015; 6: 68PubMed Google Scholar], which combines moderate food restriction (usually 1 h a day of food access) in combination with access to a running wheel. This model leads to severe food restriction compared with control groups that are also food restricted but do not have access to a running wheel. The ABA model also successfully models hyperactivity, a pernicious and often intractable symptom of AN. Despite this, the model requires a food restriction paradigm for the duration of the experiment to maintain voluntary food restriction, which contrasts with the voluntary food restriction seen in patients with AN despite all efforts to encourage consumption. Another recent gene × environment × diet (GED) model incorporates moderate food restriction for 11 days, genetic predisposition to anxiety (BDNFVal66Met gene variant), and social isolation stress in adolescent mice [19.Zeltser L.M. Madra M. A framework for elucidating causes and consequences of malnutrition in anorexia nervosa.in: Sangha S. Foti D. Neurobiology of Abnormal Emotion and Motivated Behaviors. Elsevier, 2018: 92-118Crossref Scopus (1) Google Scholar]. Compared with ABA, the GED model imposes food restriction for only a short period of time and, therefore, may more accurately model the type of voluntary food restriction seen in patients with AN following initial dieting. It is notably the only model proposed to date that incorporates gene, environment, and diet changes to produce anorexia-like behaviors. Here, we outline research developments into the biological mechanisms underlying eating disorders and discuss how they will enable an updated framework for future research in this area (Figure 1). Encouraging science related to restrictive eating disorders has emerged from genome-wide association studies (GWAS). The largest published GWAS (~17 000 cases and 55 000 controls), yielded eight significant loci with clearest evidence for the single gene loci that intersected with CADM1, MGMT, FOXP1, and PTBP2, suggesting that these genes have a role in AN etiology. Moreover, we observed expected positive SNP-based genetic correlations with other psychiatric illnesses (such as OCD, MDD, anxiety, and schizophrenia) and intriguing negative genetic correlations with metabolic and anthropometric traits, fueling a reconceptualization of AN as a metabo-psychiatric illness [21.Watson H. et al.Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa.Nat. Genet. 2019; 51: 1207-1214Crossref PubMed Scopus (190) Google Scholar]. Moreover, positive genetic correlations with educational attainment and measured physical activity suggested that features previously believed to be driven by family pressure (academic achievement) or treatment resistance (driven physical activity) have their roots in underlying shared genetic factors. One significant biological pathway emerged, positive regulation of embryonic development, tentatively pointing to a role of developmental processes in AN etiology. In addition, genes associated with AN were enriched for expression in most brain regions and, at a finer resolution in 24 brain cell types, significant enrichment was found for striatal medium spiny neurons and pyramidal neurons from hippocampal CA1. Notably, striatum and hippocampus have been associated with feeding behaviors, including food motivation and reward [22.Kim J. et al.Basolateral to central amygdala neural circuits for appetitive behaviors.Neuron. 2017; 93: 1464-1479Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar,23.O'Connor E.C. et al.Accumbal D1R neurons projecting to lateral hypothalamus authorize feeding.Neuron. 2015; 88: 553-564Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar]. The genetic data were used to estimate gene expression levels (using PrediXcan), and 36 genes were predicted to be differentially expressed, most notably with the expression of MGMT predicted to be downregulated in the caudate. Although the sample sizes analyzed to date are still insufficient, these are the first indications of specific pathways, tissues, and cell types that may mediate genetic risk for AN [21.Watson H. et al.Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa.Nat. Genet. 2019; 51: 1207-1214Crossref PubMed Scopus (190) Google Scholar]. No GWAS has yet been published for other eating disorders, but global efforts are underway. As the genetic research evolves and sample sizes increase, we anticipate that more robust results will yield insight into underlying biological pathways that will inform animal models and guide drug repositioning or development toward compounds that target dysregulated biology. Neuroimaging provides insight into the neuropsychological processes that underlie certain aspects of eating disorders [24.McGuire P.K. Matsumoto K. Functional neuroimaging in mental disorders.World Psychiatry. 2004; 3: 6-11PubMed Google Scholar]. A full review of the eating disorders imaging literature is beyond our scope here and, thus, we focus on how recent studies have pinpointed central mechanisms underlying behavioral changes in AN and binge eating, and how these findings may translate into focusing basic research on core systems. Initial findings of altered gray matter volume and cortical thickness in AN were intriguing, although most studies indicate that brain structure is modified strongly by food intake (or lack thereof), and that these abnormalities resolve when eating is restored [25.King J.A. et al.Structural neuroimaging of anorexia nervosa: future directions in the quest for mechanisms underlying dynamic alterations.Biol. Psychiatry. 2018; 83: 224-234Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar]. Functional connectivity studies have been more consistent, pointing to dysfunction in the 'salience network' (anterior cingulate, insula, and orbitofrontal cortex), as well as altered connectivity between ventral striatum and the prefrontal cortex [26.Frank G.K.W. et al.The neurobiology of eating disorders.Child Adolesc. Psychiatr. Clin. N. Am. 2019; 28: 629-640Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar]. A third approach correlates specific task performances (e.g., attention, reward, perception, and decision-making) with alterations in brain activity using functional MRI (fMRI) in patients with AN versus healthy controls. Using food images as cues, studies of AN consistently report alterations in pleasure derived from (e.g., liking) and motivation to consume (e.g., wanting) high-calorie foods, as well as implicit liking of neutral stimuli following food images [27.Lloyd E.C. Steinglass J.E. What can food-image tasks teach us about anorexia nervosa? A systematic review.J. Eat. Disord. 2018; 6: 31Crossref PubMed Scopus (28) Google Scholar]. Neuroimaging studies utilizing these tasks also support a role of the brain reward system in AN [25.King J.A. et al.Structural neuroimaging of anorexia nervosa: future directions in the quest for mechanisms underlying dynamic alterations.Biol. Psychiatry. 2018; 83: 224-234Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar]. By contrast, there is no clear consensus as to whether individuals with AN display attentional biases toward or against food images, and no perceptual deficits have been identified. Imaging studies also support the role of both trait and state anxiety during food-related tasks and consumption in patients with AN [27.Lloyd E.C. Steinglass J.E. What can food-image tasks teach us about anorexia nervosa? A systematic review.J. Eat. Disord. 2018; 6: 31Crossref PubMed Scopus (28) Google Scholar]. Other neuroimaging studies have examined regional activation during passive viewing of food, interoception [28.Jacquemot A.M.M.C. Park R. The role of interoception in the pathogenesis and