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Physiology & Behavior 206 (2019) 185-190 Contents lists available at ScienceDisect Physiology & Behavior journal homepage: www.clsevier.com/locate/physbeh Review Motivation to eat and not to eat - The psycho-biological conflict in anorexia nervosa ons Guido K.W. Frank’’’, Marisa C. DeGuzman’, Megan E. Shott” *pxparnet of Paci, Univer of Clade Ans: Maal Campus Sh of Mele, Aa, CO, USA “pip of euros, Uno of Clr Ant Mesa Carus, Sol of Mehra, CO, USA Keynes “Anorexia nervosa ica severe psychiatreillness with high mortality. Brain imaging research has indies altered reward cris in the disorder. Here we propose disease model for snorexa ners, supported by reent ste, that imegrates poychologeal and biological factors. In that mode, we propose that theresa confit becween the conscious motivation to restrict food, anda bed -homeostasis driven modvation to approach food in response to weight oss. These opposing motivations tigger anxiety, which maitans the vclous eyce af “ongoing energy restriction and weigh as. 1. Introduetion At the 2018 annual meeting ofthe Society forthe Study of Ingestive Behaviors in Bonita Springs, we presented recent data from ove group ‘on brain reward processing in anorexia nervosa (AN). Here we provide a background co those studles and presenta model forthe viefous cycle ‘of food restrietion and weight loss that occurs in AN despite being underweight. 2. Clinical presentation of AN [AN isthe third most common cheonie illness among adolescent fe males. Ithas the highest morality rate among the psychiatric disorders ‘with most deaths occurring between the ages of 16 and 29 years {1-2 [AN is associated with severe emaciation from restriction of food intake, ‘and a pereeption of being overweight despite severe underweight (41 ‘The disorder shows a complex interplay between neurobiological, psychological and environmental factors [5], and itis a chronic dis: ‘order with frequent relapse, high treatment costs and severe disease burden [6,7] Treatment effectiveness is limited [8], and no medication has been approved for AN [9] Yet, lite is known about the patho: physiology oF brain biomarkers that characterize AN (10). Increasing ‘efforts to identity biologie mechanisms that affect behavior in AN is of ‘central importance in gaining a more complete understanding of the «disorder, and to develop pharmacological treatments (1 ,12J- 5. The core conflict in AN “The spectrum of individuals who develop AN is broad. This may range from adolescents who simply exercise more to be mote compe- tive in sports or ty to eat healthier, o individuals who have been ‘traumatized and have ha lifelong body image problems, and y all develop AN with the same core features. Whi come from different paths to develop AN, they all have in common a discrepancy between their conscious motivation for how much they want to at - or rather restrict food intake - versus the body's need to stay ata healthy and sustainable body weight. Here we will summarize recent research from our group that is Investigating motivational pro cesses of food intake in AN together with other human and basic re search o develop a psycho-biological model for how core AN behaviors develop and contribute to a continuous cycle of weightloss. Central to this model is the conflict between a conscious motivation to restrict eating and the unconscious messages from the body-homeostasis ‘maintaining mechanisms including reward circuits and neuroendocrine systems to seek out food and to preserve a healthy body weight. This is a data-driven model that integrates empirically studied brain biology With measured behavior and weight gain observed in treatment. 4. AN is associated with altered neuroendocrine and brain reward cireuit function During the course of AN, a multitude of changes happen in appetite * Coresponding author at: Departments of Psychiatry and Neurosience, Developmental ain Reseach Program University of Colorado Anschutz Medical Campus; ‘Childrens Hospital Colorado, Gary Pavilion AU36/8-120, 12123 East 6th Avenue, Aurora, CO 80045, USA. ‘mall ree: Guido Pronkaredenvee ed (GALW. Fran). hnup://d.og/10.1016/.physbeh.2019.04.007 Received 31 October 2018; Received in revised form 9 Apel 2019; Accepted 9 April 2019 ‘Available online 10 April 2019 ‘003193847 © 2019 The Authors. Published by Elsevier ne. Thi is an apen sees ar (ott /eretivecommons.ongienses/BY-NCND/4.0/). ander the OC BY.NCND license GA W Protea regulating circuits. While the results are not all uniform, leptin as a marker of body fat is low, the appetite stimulating hormone ghrelin is ‘levated as are the stress markers eortsol and corticotropin releasing factor, and the level ofthe appetite reducing oxytocin is low in AN [13]. ‘While those hormones and peptides that take part in regulating body homeostasis adapt to the acute nutritional state and typically normalize with weight recovery, they may have important roles inthe modulation ‘of the brain reward citcuitry [14] ‘The brain reward system is a well-studied circuitry that has been hypothesized to hold promise as a target for future treatment inter ventions in eating disorders including AN [1]. Especially important co ‘ating and food reward isthe taste pathway that projects inputs from the tongue taste receptors via the thalamus to the insula, which con- tains the primary taste cortex [15]. The reward system receives further {input from frontal cortical regions about desires to consume foods, and it is connected with the hypothalamus to integrate signals from the body periphery such as blood sugar levels to regulate food intake and maintain energy homeostasis of the body {16]. The taste perception leads to leared associations betwcen taste and subjective hedonie ex Periences to create an internal cognitive and emotional representation ‘of food stimuli that gets activated when we see, smell or taste food [17]. ‘Those associations provide dopamine mediated learning signals (0 higher order brain regions to compare the current (food) experience ‘with past experience and store new, or update previously stored, in formation on how much we value a particular food stimulus. This isto support the decision-making process for what type and amount of food ‘we would like to eatin the fature [18,19}. The above described ci. ‘euitry to motivate food intake is interrelated with the interoceptive signal of satiety, and a variery of gut hormones and neuropeptides to ‘gether with specific brain regions contribute to this signal to regulate ‘eating (20,211 ‘An increasing number of funetional brain imaging studies have in cated altered activation in reward:processing brain regions in AN. It ‘as hypothesized that such abnormalities together with anxious traits ‘could contribute to AN-specifc brain pathophysiology and drive ex: tremes of food restriction [22]. Brain reward studies in AN have applied various paradigms using for instance food images to study emotional or hormonal response (23) Our lab has focused on brain dopamine function to study altered reward cieuits in AN. The dopamine pathways are a neuromodulatory system that arises from cells in the midbrain [24], These midbai neurons release dopamine, which acts on cortical and subcortical do- ppamine receptors. Dopamine function contributes to the modulation of motor activity (25), feeding behaviors [26], and reinforcement and reward learning [27]. The dopamine system is particularly interesting to study as we know relatively more about the neuronal dynamics ofits ‘setivation compared to other neurotransmitter systems and mathem tical models have been developed to predict dopaminergic neuron re sponse during presentation of rewarding or salient stim [28,29] ‘The dopamine system adapts in opposite directions to extremes of food! Intake 90-33]. Animal models have shown enhanced neuronal ‘dopamine activation following food restrietion [34,35], which led (0 the hypothesis that brain dopamine circuits sensitize in AN in during food restriction and weight loss and are part ofits specific pathophy- siology 14,221, Food restriction sensitizes both dopamine D1 and D2/ 13 receptors in animal studies, which is suggestive of being the derlying mechanism for enhanced dopamine neuron activation in re sponse to weight loss [35,971 the past, low cerebrospinal uid homovanilic acid, the major dopamine metabolite in ill AN [38], and elevated dopamine D2/3 re ‘ceptor availability after recovery [99], suggested directly altered do ppamine function in AN, although a group currently ill wth AN showed normal dopamine D2/3 receptor distribution [40]. Those receptor studies, however, could not inform on brain function in response 0 oF during behavior. Dopamine related brain function can be studied in humans Pye & tar 2062019) 185-190, Indirectly using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (EMR) and prediction error model tasks ‘The predietion error model is @ model for how dopamine neurons re spond {o environmental stimuli and drive motivation to approach re wards and lear from rewarding or salient stimuli [41]. Dopamine neurons exhibit a phasic burst of activation in response to presentation ofan unexpected rewarding stimulus, and a decreas in tonic dopamine neuron activity in response to unexpected omission of an expected re ward stimulus [42]. This mode was fis validated in rodents [43] and later adapted for human brain imaging [44,45]. Those circuits are critically associated with providing signals regarding the presence and amplitude of rewards (16,281, and eode the value of reward stimuli, including the metabolic value of food [46-4]. In earlier studies, adults with AN showed elevated prediction error response (stronger postive response to unexpected receipt and stronger negative response t0 un: expected omission) to sucrose taste stimuli versus control [50,51]. This elevation in both directions was interpreted asa general sensitization of the dopamine neuronal response in AN. This was in contrast to obese individuals who shoved lower prediction error response compared to controls, further supporting the adaptation of the dopamine system to the amount of food intake and consistent with basic science [32,91]. A smaller elevation in prediction error response in long term recovered AN suggested a gradual normalization of brain response with illness recovery (52. In summary, those studies suggested that dapamine-e- lated reward processing is altered in AN and this led us to expand those studies to integrate behavior and treatment response with brain circuit activation. 5. A model for competing motivations to eat and not to eat in AN Recently we published a study ina Targe group of adolescents with AN (n= 56), and an age-matched control group (nt = 52) [5° fs that study we applied a taste prediction error task a above. We also studied dynamic effective brain connectivity, that is what brain region drives ‘another during sugar tasting. The prediction ervor signal derived from "unexpected omission or receipt of suerose taste reward resulted in heightened response in insula, striatum and orbitofrontal cortex in AN versus controls. This confirmed our previously found elevated predic tion error response in AN. Orbitofontal cortex prediction exor signal in the AN group was signifiantly positively correlated with harm avoid- ance, a measure for an anxiety trait, which in turn was positively cor elated with drive for thinness and body dissatisfaction (Pig. 1.) In addition, the prediction error signal correlated negatively with increase in body mass index (BMI, weight in kg/height in m*) during treatment. Salivary cortisol was elevated in AN, consistent with other studies, and showed positive correlation with prediction error response. IC was therefore hypothesized that stress and associated cortisol inerease may directly contribute to elevation in prediction error brain response in AN. Lasly, prediction error response in AN was positively correlated with dynamic effective connectivity from ventral striatum to hypotha- lamus, an anxiety driven circuit that quickly inhibits food intake (54). An additional smaller study in adolescent AN using a monerary reward prediction ertor task aso showed elevated prediction error brain re: sponse together with negative correlation with BMI increase during treatment [55]. Ths suggested that enhanced prediction error response could be a illness state biomarker and independent from the stills ‘ype. Based on those empirial data we propose @ model for the con- tinuous cycle of energy restriction in AN that integrates cognitive ‘emotional factors such as drive for thinness, body dissatisfaction and fear of weight gain, with the body's adaptations to weight los that finchide neuroendocrine factors as well as the changes inthe brain do: amine system that occur with food restriction and weight loss (Pi. 2.) GA W Protea Same, Body Disaatistacton ele Increase in Age Adjusted Bue During Treatment Fig. 1. rovios studies have shown that prediction eror bra response (PE) ‘was posively corelated with harm avoidance as # measure fr anxious te perament in adolescents with anoreala nervosa (AN), whieh coredated pos! tively with core AN behaviors drive food thinness and body dissatisfaction, but repstivly with weigh gain in treatment; PE wa also postively elated tothe “dynamic eflesve connectivity from ventral strat to hypothalams adapted fiom Frank el, JAMA Psjehaty, 2018); OFC, orbtofonal cortex. 5.1. Initiation of AN behavior AN fs characterized by weight loss for various reasons, This can range from losing weight in the context of increased exercise 10 get fitter, fo eating “healthier” (leaving out certain high calorie foods from the diet as for instance often discussed in mide setoo! health clas, co ‘overweight individuals who decidedly want to lose weight, to in ividals who were maybe abused and alter their eating in that context, ‘and variations in between. This “conscious motivation” to ehange ‘eating or exercise behavior is then followed by weight los. Weight loss is subsequently learned to be associated wit the original goal of eating (Creumsianes that "Tigers Desire to ‘Nervosa Core Behaviors Precsposi ‘Conscious Motivation” iom ‘Neuroendocrine Changes = Gut Hormone Changes ‘Signal tho Need to Eat ‘Anxiaty Activates Dopamine Mediated Food Intake Control Circuitry Ventral Satu Hypothalamus + Facitatod by Sonstized Dopamine D1 Receptors - +Food Reston Unconscious Motivation” 10 Stimulate Eating Weight Loss Success Reinforces the ‘Conscious Motivation and Later Anorexia ‘Anorexia Nervosa - Drive for Thinness t + Body Dissatstaction 1 - Faro Losing Contal¢ = Ansty Worsens ~ Low Sex Hormone Levels Impair Behavior Chango + Ongoing Food Resticton = Micious Cycie" Pye & tar 2062019) 185-190, healthier, being Ater or thinner, and weight gain then may be per ceived asa threat to that gol 5.2. Underlying cogntive-emotional mechanisms Not everyone who dies, or exercises more, develops AN. There are reports on specific underlying cogniive-cmotional dynamics, fo in stance feeling in control that drive food restriction in AN, but to what extent those have developed as part of the illness or have been there premorbidly is not known [56]. What is known is that individuals who develop AN tend to have anxious temperaments, biological trafts such as high harm avoidance and perfectionism, which may facilitate de velopment and maintenance of AN cote behaviors [57]. Those traits that drive the desire to do things correctly are strong motivators of bbchavior in general, including eating disorder behaviors. Weight loss as ‘an indicator of suecess then becomes a conditioned reward and cogni tive reinforcer of the behavior, AN runs in families and we postulate a {enetic predisposition for this transition from the initial motivation to change eating to core AN behaviors and excessive weight los. We be: lieve that brain changes occur that drive the extreme preoccupation with food and weight and shape. What the underlying biologie me chanisms may be is unclear. Recent genetic research has shown an overlap between AN and obsessive compulsive disorder genes and the {wo disorders might share biological mechanisms that drive excessive bbehavior perpetuation [58]. Habit leaning has also been hypothesized to be part of ANs pathophysiology and itis possible that high habit strength (the connection between stimuls and behavior response to: gether with heightened frontostriatal brain connectivity contribute to ongoing AN behaviors [59-61]. 5.3. Physiological response to weight loss ‘Animal models have shown that the body’s normal response to woight loss is an activation of the feeding system, including. many adaptation of gut hormones and neuropeptides that signal to the hy’ pothalamus the bodys nutritional needs, as wel as a sensitization of the dopamine system to support fond approach [1,16]. Food restriction is Fig, 2. schematic model that integrates dhe ex itl fadings from Fig. 1 with previous esearch neuroendocrine faction in human ses a sn ‘mal models fr the effects of food rextrlction. After ecing to change eating behavior and ose weight, fenocrine changes occur that signal the need 0 eat the dopamine spstem ges activated to support the ‘motivation to seck out fod: perfectionism and high anulety mediate the transition to developing AN cote Uchaviors while the original conseious motivation sustained. Weight loss briefly alleviates anxiety and reinforces fod restriction. However, gut hormones fand dopamine that simulate fod seeking, elevate Snaiety and subsequendy elevate AN core behaviors. [Anse triggers afd conta ieltry fm vent striatum to hypothalams that depends on dopamine DI receptors, which have been sensitized in the tatet of food setition. Anlety gels further ele ‘ted i the lines proces de to the possibilty of los of control and weight gain and this becomes seléscnforcing proces. Ongoing food restriction and weight loss perpetuate the eee.

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