Therapeutic ketogenic diet as treatment for anorexia nervosa.

Anorexia nervosa (AN) is a severe psychiatric disorder. However, we lack neurobiological models and interventions to explain and treat the core characteristics of food restriction, feeling fat, and body size overestimation. Research has made progress in understanding brain function involved in the pathophysiology of AN, but translating those results into biological therapies has been challenging. Studies have suggested that metabolic factors could contribute to developing and maintaining AN pathophysiology. Here, we describe a neurobiological model for why using a therapeutic ketogenic diet could address key alterations in brain function in AN and prevent the desire for weight loss and associated eating disorder-specific symptoms. This translational model is based on animal studies and human data and integrates behavioral traits, brain neural energy metabolism, and neurotransmitter function. Pilot data indicate that the intervention can dramatically reduce eating and body-related fears, although larger studies across illness stages still need to be conducted.

Food Avoidance and Aversive Goal Value Computation in Anorexia Nervosa.

Anorexia nervosa (AN) is associated with food restriction and significantly low body weight, but the neurobiology of food avoidance in AN is unknown. Animal research suggests that food avoidance can be triggered by conditioned fear that engages the anterior cingulate and nucleus accumbens. We hypothesized that the neural activation during food avoidance in AN could be modeled based on aversive goal value processing. Nineteen females with AN and thirty healthy controls matched for age underwent functional magnetic resonance brain imaging while conducting a food avoidance task. During active control free-bid and computer-generated forced-bid trials, participants bid money to avoid eating food items. Brain activation was parametrically modulated with the trial-by-trial placed bids. During free-bid trials, the AN group engaged the caudate nucleus, nucleus accumbens, ventral anterior cingulate, and inferior and medial orbitofrontal cortex more than the control group. High- versus low-bid trials in the AN group were associated with higher caudate nucleus response. Emotion dysregulation and intolerance of uncertainty scores were inversely associated with nucleus accumbens free-bid trial brain response in AN. This study supports the idea that food avoidance behavior in AN involves aversive goal value computation in the nucleus accumbens, caudate nucleus, anterior cingulate, and orbitofrontal cortex.

Parental styles are associated with eating disorder symptoms, anxiety, interpersonal difficulties, and nucleus accumbens response.

OBJECTIVES: Eating disorders (EDs) typically emerge during adolescence. Parental bonding has a lasting impact on a child's mental health during those developmentally critical years. There remains uncertainty over whether parental bonding is a risk factor for developing or maintaining specifically EDs or, rather, general psychopathology and the associated underlying brain function. METHODS: Forty-one young adult healthy control individuals (HC, 26.6 ± 3.5 years) and 46 individuals with EDs (25 with anorexia nervosa, AN, 22.8 ± 6.4 years, and 21 with bulimia nervosa, BN, 23.5 ± 4.2 years) completed the parental bonding instrument (PBI), assessments for anxiety, depression, and ED behaviors, and underwent a conditioning paradigm during brain imaging. RESULTS: In both groups, perceived parental care and overprotection were correlated with state and trait anxiety and interpersonal alienation, and in HC only, with body dissatisfaction and drive for thinness. Individuals with an ED reported lower self-perceived parental care, but higher overprotection compared to the HC group. Nucleus accumbens (NAc) response was related to bonding measures in both groups and right NAc response mediated the relationship between maternal care and trait anxiety in HC. CONCLUSIONS: Perceived parental bonding is associated with general psychopathology, including elevated anxiety and interpersonal difficulties across HC and ED groups. Lower perceived parental care and higher overprotection could predispose healthy individuals to develop problems with body shape or weight; however, other, maybe biological factors may determine whether a person will develop an ED. The link between perceived parental bonding, NAc valence processing and anxiety implicates dopaminergic circuits that should be studied further. LEVEL OF EVIDENCE: Level III: Case-control analytic study.

Why Don't You Just Eat? Neuroscience and the Enigma of Eating Disorders.

Eating disorders are severe psychiatric illnesses that are associated with high mortality. Research has identified environmental, psychological, and biological risk factors that could contribute to the psychopathology of eating disorders. Nevertheless, the patterns of self-starvation, binge eating, and purging behaviors are difficult to reconcile with the typical mechanisms that regulate appetite, hunger, and satiety. Here, the authors present a neuroscience and human brain imaging-based model to help explain the detrimental and often persistent behavioral patterns seen in individuals with eating disorders and why it is so difficult to overcome them. This model incorporates individual motivations to change eating, fear conditioning, biological adaptations of the brain and body, and the development of a vicious cycle that drives the individual to perpetuate those behaviors. This knowledge helps to explain these illnesses to patients and their families, and to develop more effective treatments, including biological interventions.

Perceptual Dysfunction in Eating Disorders.

Eating disorders (EDs) are characterized by abnormal responses to food and weight-related stimuli and are associated with significant distress, impairment, and poor outcomes. Because many of the cardinal symptoms of EDs involve disturbances in perception of one's body or abnormal affective or cognitive reactions to food intake and how that affects one's size, there has been longstanding interest in characterizing alterations in sensory perception among differing ED diagnostic groups. Within the current review, we aimed to critically assess the existing research on exteroceptive and interoceptive perception and how sensory perception may influence ED behavior. Overall, existing research is most consistent regarding alterations in taste, visual, tactile, and gastric-specific interoceptive processing in EDs, with emerging work indicating elevated respiratory and cardiovascular sensitivity. However, this work is far from conclusive, with most studies unable to speak to the precise etiology of observed perceptual differences in these domains and disentangle these effects from affective and cognitive processes observed within EDs. Further, existing knowledge regarding perceptual disturbances in EDs is limited by heterogeneity in methodology, lack of multimodal assessment protocols, and inconsistent attention to different ED diagnoses. We propose several new avenues for improving neurobiology-informed research on sensory processing to generate actionable knowledge that can inform the development of innovative interventions for these serious disorders.

Weight gained during treatment predicts 6-month body mass index in a large sample of patients with anorexia nervosa using ensemble machine learning.

OBJECTIVE: This study used machine learning methods to analyze data on treatment outcomes from individuals with anorexia nervosa admitted to a specialized eating disorders treatment program. METHODS: Of 368 individuals with anorexia nervosa (209 adolescents and 159 adults), 160 individuals had data available for a 6-month follow-up analysis. Participants were treated in a 6-day-per-week partial-hospital program. Participants were assessed for eating disorder-specific and non-specific psychopathology. The analyses used established machine learning procedures combined in an ensemble model from support vector machine learning, random forest prediction, and the elastic net regularized regression with an exploration (training; 75%) and confirmation (test; 25%) split of the data. RESULTS: The models predicting body mass index (BMI) at 6-month follow-up explained a 28.6% variance in the training set (n = 120). The model had good performance in predicting 6-month BMI in the test dataset (n = 40), with predicted BMI significantly correlating with actual BMI (r = .51, p = 0.01). The change in BMI from admission to discharge was the most important predictor, strongly correlating with reported BMI at 6-month follow-up (r = .55). Behavioral variables were much less predictive of BMI outcome. Results were similar for z-transformed BMI in the adolescent-only group. Length of stay was most predictive of weight gain in treatment (r = .56) but did not predict longer-term BMI. CONCLUSIONS: This study, using an agnostic ensemble machine learning approach in the largest to-date sample of individuals with anorexia nervosa, suggests that achieving weight gain goals in treatment predicts longer-term weight-related outcomes. Other potential predictors, personality, mood, or eating disorder-specific symptoms were relatively much less predictive. PUBLIC SIGNIFICANCE: The results from this study indicate that the amount of weight gained during treatment predicts BMI 6 months after discharge from a high level of care. This suggests that patients require sufficient time in a higher level of care treatment to meet their specific weight goals and be able to maintain normal weight.

Adverse childhood experiences, low self-esteem, and salient stimulus response in eating disorders.

BACKGROUND: Adverse childhood experiences (ACEs) are elevated in individuals with eating disorders (EDs), but how the neurobiology of EDs and ACEs interact is unclear. METHODS: Women 18-45 years old with anorexia nervosa (AN, n = 38), bulimia nervosa (BN, n = 32), or healthy controls (n = 60) were assessed for ACEs and ED behaviours and performed a taste-conditioning task during brain imaging. Mediation analyses tested relationships between ACE score, self-esteem, and ED behaviours. RESULTS: ACE scores were elevated in EDs and correlated positively with body mass index (p = 0.001), drive for thinness (p = 0.001), and body dissatisfaction (p = 0.032); low self-esteem mediated the relationship between ACEs and body dissatisfaction, drive for thinness, and bulimia severity. ACE scores correlated negatively (FDR-corrected) with unexpected, salient stimulus receipt in AN (substantia nigra) and BN (anterior cingulate, frontal and insular cortex, ventral striatum, and substantia nigra). When ACE scores were included in the model, unexpected stimulus receipt brain response was elevated in EDs in the anterior cingulate and ventral striatum. CONCLUSIONS: ACEs attenuate unexpected salient stimulus receipt response, which may be a biological marker for altered valence or hedonic tone perception in EDs. Low self-esteem mediates the relationships between ACEs and ED behaviours. Adverse childhood experiences should be assessed in biological studies, and their effects targeted in treatment.

Neural Response to Expecting a Caloric Sweet Taste Stimulus Predicts Body Mass Index Longitudinally Among Young Adult Women With Anorexia Nervosa.

BACKGROUND: Anorexia nervosa (AN) is an often-chronic illness, and we lack biomarkers to predict long-term outcome. Recent neuroimaging studies using caloric taste stimuli suggest that paradigms that have tested conditioned neural responses to expectation or salient stimulus receipt may underpin behaviors. However, whether activation of those neural circuits can predict long-term outcome has not been studied. METHODS: We followed women treated for AN (n = 35, mean age [SD] = 23 [7] years) and tested whether functional imaging brain response during a taste conditioning paradigm could predict posttreatment body mass index (BMI). We anticipated greater neural activity relative to caloric stimulus expectation and that dopamine-related receipt conditions would predict lower posttreatment BMI, indicating fear-associated arousal. RESULTS: Follow-up occurred at mean (SD) = 1648 (1216) days after imaging. Stimulus expectation in orbitofrontal and striatal regions and BMI and BMI change at follow-up were negatively correlated, and these correlations remained significant for the right superior orbitofrontal cortex and BMI change after multiple comparison correction (r = -0.484, p = .003). This relationship remained significant after including time between brain scanning and follow-up in the model. Reward prediction error response did not predict long-term BMI. CONCLUSIONS: The orbitofrontal cortex is involved in learning and conditioning, and these data implicate this region in learned caloric stimulus expectation and long-term prediction of weight outcomes in AN. Thus, conditioned elevated brain response to the anticipation of receiving a caloric stimulus may drive food avoidance, suggesting that breaking such associations is central for long-term recovery from AN.

Noradrenergic control of neurobehavior in human binge-eating disorder and obesity (NOBEAD): A smartphone-supported behavioral emotion regulation intervention study protocol integrating molecular brain imaging.

OBJECTIVE: The neurobehavioral underpinnings of binge-eating disorder (BED), co-occurring with obesity (OB), are largely unknown. This research project conceptualizes BED as a disorder with dysfunctional emotion regulation (ER) linked with changes in central noradrenaline (NA) transmission and NA-modulated neuronal networks. METHODS: We expect abnormalities in NA activity in both BED and OB, but most pronounced in BED. We expect these abnormalities to be modifiable through state-of-the-art ER intervention, specifically in BED. To assess the role of NA transmission, we will quantify changes in NA transporter (NAT) availability using the highly NAT-specific [11 C]methylreboxetin (MRB) and positron emission tomography-magnetic resonance imaging (PET-MRI) that allows measuring molecular and neuronal changes before and after an ER intervention. Individual 12-session smartphone-supported acceptance-based behavioral therapy will be conducted to improve ER. Thirty individuals with OB and BED (OB + BED), 30 individuals with OB without BED (OB - BED), and 20 individuals with normal weight will undergo assessments of NAT availability and neuronal network activity under rest and stimulated conditions, clinical interviews, self-report questionnaires on eating behavior, ER, mental and physical health, and quality of life, and neuropsychological tests on executive function. Afterwards, in an experimental randomized-controlled design, individuals with OB + BED and OB - BED will be allocated to smartphone-supported ER intervention versus a waitlist and re-assessed after 10 weeks. DISCUSSION: By obtaining biological and behavioral markers, the proposed study will disentangle the involvement of NAT and the central NA system in the modulation of emotion-supporting neuronal networks that influence eating behavior. Neurobehavioral mechanisms of change during an ER intervention will be determined. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00029367. PUBLIC SIGNIFICANCE: This study investigates the central noradrenaline system by using hybrid brain imaging in conjunction with emotion regulation as a putative core biological mechanism in individuals with obesity with or without binge-eating disorder that is targeted by emotion regulation intervention. The results will provide a molecular signature beyond functional imaging biomarkers as a predictive biomarker toward precision medicine for tailoring treatments for individuals with binge-eating disorders and obesity.

Examining anxious temperament in anorexia nervosa: Behavioural inhibition and intolerance of uncertainty and their contribution to trait anxiety in adolescents with anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is a serious and complex psychiatric disorder yet treatment results are suboptimal. Insight into the etiology of this illness is much needed. Research highlights the implication of anxiety-related traits in the development and maintenance of AN. This study investigates firstly, behavioural inhibition and intolerance for uncertainty (IU) in adolescents with and without AN, and secondly relations between these traits. METHODS: In a cross-sectional study, 165 adolescent girls (AN = 94, HC = 71) completed questionnaires measuring behavioural inhibition, IU and trait anxiety. ANOVAs tested differences between AN and HC groups, and mediation models with IU as a mediator between behavioural inhibition and trait anxiety were run. RESULTS: AN adolescents reported significantly higher levels of behavioural inhibition, IU and trait anxiety compared to their peers. In both AN and HC, a direct and a total effect of behavioural inhibition on trait anxiety was found. However, only in the AN group IU partially mediated the relation between behavioural inhibition and trait anxiety. LIMITATIONS: Data is cross-sectional and longitudinal studies are required. A mean illness duration of nearly 2 years may mean early effects of malnourishment and habituation and future studies should include patients with shorter illness duration. CONCLUSIONS: Results highlight that behavioural inhibition and IU may contribute to anxiety in AN whilst their peers may have developed better executive and social-emotional skills to manage uncertainty. Adolescents with AN may benefit from interventions targeting behavioural inhibition and IU.