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.

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.

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.

Brain reward response in adolescents and young adults with anorexia nervosa is moderated by changes in body weight and sweetness perception.

OBJECTIVE: Anorexia nervosa (AN) is a severe psychiatric illness with complex etiology. Recently, we found elevated striatal brain response to sweet taste stimuli in adolescents and young adults with AN. Here, we tested the hypothesis that nutritional rehabilitation normalizes prediction error activation, a measure for dopamine-related reward circuit response, to salient caloric taste stimuli in AN. METHODS: A total of 28 individuals with AN (age = 16 ± 2 years; body mass index [BMI] = 16 ± 1) who previously underwent brain imaging while performing a taste prediction error task using sucrose as salient caloric stimulus, participated in a second brain imaging scan (BMI = 18 ± 1) after intensive specialized eating disorder treatment (41 ± 15 days). A total of 31 healthy controls (age = 16 ± 3 years; BMI = 21 ± 2) were also studied on two occasions. RESULTS: At baseline, individuals with AN demonstrated an elevated salience response in bilateral caudate head and nucleus accumbens, and right ventral striatum. At the second scan, elevated response was only found in the right nucleus accumbens. A moderator analysis indicated that greater increase in BMI and greater decrease in sweetness perception predicted lesser prediction error response at the second scan in AN. CONCLUSION: Consistent with the previously reported monetary stimulus-response, elevated taste prediction error response in AN was largely absent after weight restoration. This study indicates that changes in BMI and sweet taste perception are independent moderators of change of brain salience response in adolescents and young adults with AN. The study points toward dynamic changes in the brain reward circuitry in AN and highlights the importance of nutrition and weight restoration in that process. PUBLIC SIGNIFICANCE STATEMENT: AN is a severe psychiatric illness. Biological factors that integrate neurobiology and behavior could become important targets to improve treatment outcome. This study highlights the importance of weight normalization and taste perception the normalization of brain function, and food type or taste-specific interventions could help in the recovery process. Furthermore, the study suggests that food-related and nonfood-related reward processing adapts to illness state in AN.

The potential role of stimulants in treating eating disorders.

BACKGROUND: Many individuals with eating disorders remain symptomatic after a course of psychotherapy and pharmacotherapy; therefore, the development of innovative treatments is essential. METHOD: To learn more about the current evidence for treating eating disorders with stimulants, we searched for original articles and reviews published up to April 29, 2021 in PubMed and MEDLINE using the following search terms: eating disorders, anorexia, bulimia, binge eating, stimulants, amphetamine, lisdexamfetamine, methylphenidate, and phentermine. RESULTS: We propose that stimulant medications represent a novel avenue for future research based on the following: (a) the relationship between eating disorders and attention deficit/hyperactivity disorder (ADHD); (b) a neurobiological rationale; and (c) the current (but limited) evidence for stimulants as treatments for some eating disorders. Despite the possible benefits of such medications, there are also risks to consider such as medication misuse, adverse cardiovascular events, and reduction of appetite and pathological weight loss. With those risks in mind, we propose several directions for future research including: (a) randomized controlled trials to study stimulant treatment in those with bulimia nervosa (with guidance on strategies to mitigate risk); (b) examining stimulant treatment in conjunction with psychotherapy; (c) investigating the impact of stimulants on "loss of control" eating in youth with ADHD; and (d) exploring relevant neurobiological mechanisms. We also propose specific directions for exploring mediators and moderators in future clinical trials. DISCUSSION: Although this line of investigation may be viewed as controversial by some in the field, we believe that the topic warrants careful consideration for future research.

I know I am not out of control, but I just cannot shake the feeling: exploring feeling out of control in eating disorders.

PURPOSE: Individuals with anorexia (AN) or bulimia nervosa (BN) often present with fear of loss of control in the context of eating. It is unclear whether this fear of loss of control, which has been associated with fear of failure and a sense of not being in charge of one's own life in eating disorders, can be distinguished from self-perceived maintained control over food intake in AN. Further, anxious traits are elevated across eating disorders and could contribute to this fear of loss of control. METHODS: We recruited 113 adult women: restricting type AN (n = 26), BN (n = 28), and healthy controls (CW, n = 59). Participants completed the Eating Expectancies Inventory (EEI), which assesses learned expectations on the effects of eating, including whether Eating Leads to Feeling out of Control, and the Trait Food Craving Questionnaire (FCQ-T), which measures food craving and the ability to withstand those cravings, including self-perceived Lack of Control Over Eating. RESULTS: Eating Leads to Feeling out of Control was elevated in AN and BN compared to CW. Lack of Control Over Eating was similar between AN and CW but elevated in BN. Intolerance of uncertainty correlated with those measures in CW only. CONCLUSION: Individuals with restricting-type AN experience feeling out of control when eating while maintaining self-perceived control over eating. The EEI's eating leads to feeling out of control is associated with negative self-improvement expectations. Targeting self-improvement through more functional strategies could be an important aspect in psychotherapy in AN and reduce the perceived need to restrict food intake. LEVEL OF EVIDENCE: Level III, Evidence obtained from well-designed cohort or case-control analytic studies.

Ketogenic diet and ketamine infusion treatment to target chronic persistent eating disorder psychopathology in anorexia nervosa: a pilot study.

PURPOSE: Anorexia nervosa (AN) is a severe psychiatric disorder, and shape and weight concerns are often chronic despite weight normalization. No specific treatments exist for those preoccupations that interfere with recovery and trigger relapse. A case study using a ketogenic diet followed by ketamine infusions led to sustained remission in one patient with chronic AN. Here we conducted an open-label trial to test whether this response could be replicated. METHODS: Five adults weight recovered from AN but with persistent eating disorder thoughts and behaviors adopted a therapeutic ketogenic diet (TKD) aimed at maintaining weight. After sustaining nutritional ketosis, participants received six ketamine infusions and were followed over 6 months. RESULTS: All participants completed the study protocol without significant adverse effects. Two participants maintained TKD for 8 weeks prior to ketamine infusions due to good behavioral response and remained on TKD. Three participants received TKD for 4 weeks prior to and during ketamine, then tapered off after the final infusion. The group showed significant improvements on the Clinical Impairment Assessment (p = 0.008), Eating Disorder Examination Questionnaire (EDEQ) Global score (p = 0.006), EDEQ-Eating Concerns (p = 0.005), EDEQ-Shape Concerns (p = 0.016), EDEQ-Weight Concerns (p = 0.032), Eating Disorders Recovery Questionnaire (EDRQ) Acceptance of Self and Body (0.027) and EDRQ-Social and Emotional Connection (p = 0.001). Weight remained stable, except for one participant who relapsed 4 months after treatment and off TKD. CONCLUSION: This novel treatment appears to be safe and effective for adults with chronic AN-related psychopathology. The results from this open trial support that there are specific neurobiological underpinnings of AN that can be normalized using TKD and ketamine. LEVEL OF EVIDENCE: Level IV, multiple time series with intervention.

Open science practices for eating disorders research.

This editorial seeks to encourage the increased application of three open science practices in eating disorders research: Preregistration, Registered Reports, and the sharing of materials, data, and code. For each of these practices, we introduce updated International Journal of Eating Disorders author and reviewer guidance. Updates include the introduction of open science badges; specific instructions about how to improve transparency; and the introduction of Registered Reports of systematic or meta-analytical reviews. The editorial also seeks to encourage the study of open science practices. Open science practices pose considerable time and other resource burdens. Therefore, research is needed to help determine the value of these added burdens and to identify efficient strategies for implementing open science practices.

Eye blink and reward prediction error response in anorexia nervosa.

BACKGROUND: Functional brain imaging has been used to study brain reward function and behavioral traits in anorexia nervosa (AN). Here we tested whether eye blink relates to behavior and brain imaging response as a method that is less costly and more accessible. METHOD: We recruited 26 women with AN and 50 healthy matched controls. All underwent a reward-learning prediction error task during functional magnetic resonance imaging. In addition, eye blink was measured for spontaneous blink rate, baseline blink amplitude, and startle response to an auditory stimulus. RESULTS: Baseline blink rate, amplitude and startle response were similar between groups. In AN, there were significant positive correlations between spontaneous blink rate and bulimia symptoms, and baseline blink amplitude and prediction error response in right-sided caudate, insula, and nucleus accumbens. Correlations between eye blink measures and body dissatisfaction or harm avoidance were no longer significant after multiple comparison adjustments. DISCUSSION: This study provides evidence that measures of eye blink response can be related to brain prediction error response and eating disorder behavior in AN. The catecholamine dopamine contributes to both eye blink and prediction error response providing indirect evidence that it could be a neurobiological correlate that contributes to behaviors relevant to AN.

Editorial to the virtual issue highlighting neuroscience based research in eating disorders to mark the 49th Society for Neuroscience Annual Meeting.

OBJECTIVE: This virtual issue of the International Journal of Eating Disorders highlights recently published research that is based on neuroscience concepts, to mark the 49th Society for Neuroscience Annual Meeting in Chicago, IL, in November 2019. METHODS AND RESULTS: The collection of articles includes research published between 2018 and 2019 that fall within the broader field of clinical neuroscience. Those articles span a broad range of themes, including food intake regulation and reward circuitry, taste perception, decision-making, cognitive and emotional bias, and targeting altered brain circuits using novel therapeutic methods. DISCUSSION: The eating disorders field as a whole is increasingly incorporating neuroscience-based concepts when studying those disorders and developing disease models. We hope that this virtual issue will further stimulate discussion and research that is focused on brain circuits and neurobiology to study etiology and pathophysiology of eating disorders to develop more effective treatments.

Toward valid and reliable brain imaging results in eating disorders.

Human brain imaging can help improve our understanding of mechanisms underlying brain function and how they drive behavior in health and disease. Such knowledge may eventually help us to devise better treatments for psychiatric disorders. However, the brain imaging literature in psychiatry and especially eating disorders has been inconsistent, and studies are often difficult to replicate. The extent or severity of extremes of eating and state of illness, which are often associated with differences in, for instance hormonal status, comorbidity, and medication use, commonly differ between studies and likely add to variation across study results. Those effects are in addition to the well-described problems arising from differences in task designs, data quality control procedures, image data preprocessing and analysis or statistical thresholds applied across studies. Which of those factors are most relevant to improve reproducibility is still a question for debate and further research. Here we propose guidelines for brain imaging research in eating disorders to acquire valid results that are more reliable and clinically useful.

Cortical thickness patterns as state biomarker of anorexia nervosa.

OBJECTIVE: Only few studies have investigated cortical thickness in anorexia nervosa (AN), and it is unclear whether patterns of altered cortical thickness can be identified as biomarkers for AN. METHOD: Cortical thickness was measured in 19 adult women with restricting-type AN, 24 individuals recovered from restricting-type AN (REC-AN) and 24 healthy controls. Those individuals with current or recovered from AN had previously shown altered regional cortical volumes across orbitofrontal cortex and insula. A linear relevance vector machine-learning algorithm estimated patterns of regional thickness across 24 subdivisions of those regions. RESULTS: Region-based analysis showed higher cortical thickness in AN and REC-AN, compared to controls, in the right medial orbital (olfactory) sulcus, and greater cortical thickness for short insular gyri in REC-AN versus controls bilaterally. The machine-learning algorithm identified a pattern of relatively higher right orbital, right insular and left middle frontal cortical thickness, but lower left orbital, right middle and inferior frontal, and bilateral superior frontal cortical thickness specific to AN versus controls (74% specificity and 74% sensitivity, χ2 p < .004); predicted probabilities differed significantly between AN and controls (p < .023). No pattern significantly distinguished the REC-AN group from controls. CONCLUSIONS: Higher cortical thickness in medial orbitofrontal cortex and insula probably contributes to higher gray matter volume in AN in those regions. The machine-learning algorithm identified a mixed pattern of mostly higher orbital and insular, but relatively lower superior frontal cortical thickness in individuals with current AN. These novel results suggest that regional cortical thickness patterns could be state markers for AN.

The partial dopamine D2 receptor agonist aripiprazole is associated with weight gain in adolescent anorexia nervosa.

OBJECTIVE: Finding medication to support treatment of anorexia nervosa has been difficult. Neuroscience-based approaches may help in this effort. Recent brain imaging studies in adults and adolescents with anorexia nervosa suggest that dopamine-related reward circuits are hypersensitive and could provide a treatment target. METHODS: Here, we present a retrospective chart review of 106 adolescents with anorexia nervosa some of whom were treated with the dopamine D2 receptor partial agonist aripiprazole during treatment in a specialized eating disorder program. RESULTS: The results show that aripiprazole treatment was associated with greater increase in body mass index (BMI) during treatment. DISCUSSION: The use of dopamine receptor agonists may support treatment success in anorexia nervosa and should be further investigated.

Prediction error and somatosensory insula activation in women recovered from anorexia nervosa.

BACKGROUND: Previous research in patients with anorexia nervosa showed heightened brain response during a taste reward conditioning task and heightened sensitivity to rewarding and punishing stimuli. Here we tested the hypothesis that individuals recovered from anorexia nervosa would also experience greater brain activation during this task as well as higher sensitivity to salient stimuli than controls. METHODS: Women recovered from restricting-type anorexia nervosa and healthy control women underwent fMRI during application of a prediction error taste reward learning paradigm. RESULTS: Twenty-four women recovered from anorexia nervosa (mean age 30.3 ± 8.1 yr) and 24 control women (mean age 27.4 ± 6.3 yr) took part in this study. The recovered anorexia nervosa group showed greater left posterior insula activation for the prediction error model analysis than the control group (family-wise error- and small volume-corrected p < 0.05). A group × condition analysis found greater posterior insula response in women recovered from anorexia nervosa than controls for unexpected stimulus omission, but not for unexpected receipt. Sensitivity to punishment was elevated in women recovered from anorexia nervosa. LIMITATIONS: This was a cross-sectional study, and the sample size was modest. CONCLUSION: Anorexia nervosa after recovery is associated with heightened prediction error-related brain response in the posterior insula as well as greater response to unexpected reward stimulus omission. This finding, together with behaviourally increased sensitivity to punishment, could indicate that individuals recovered from anorexia nervosa are particularly responsive to punishment. The posterior insula processes somatosensory stimuli, including unexpected bodily states, and greater response could indicate altered perception or integration of unexpected or maybe unwanted bodily feelings. Whether those findings develop during the ill state or whether they are biological traits requires further study.

Aripiprazole, a partial dopamine agonist to improve adolescent anorexia nervosa-A case series.

Anorexia nervosa (AN) is a severe and complex psychiatric disorder and no medication has been approved for its treatment. This case series in youth with severe, recurrent AN supports the hypothesis that dopamine receptor agonists could be helpful in supporting fear extinction during eating disorder focused psychotherapy and therefore support recovery from AN. © 2015 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:529-533).

Extremes of eating are associated with reduced neural taste discrimination.

OBJECTIVE: Eating disorders are severe psychiatric disorders of unknown etiology. Understanding how neuronal function affects food choices could help personalize treatment based on brain function. Here we wanted to determine whether disordered eating behavior is associated with alterations in the primary taste cortex's ability to classify taste stimuli, which could interfere with taste reward processing. METHOD: One-hundred and six women, 27 healthy comparison (age 26.15 ± 6.95 years), 21 with restricting-type anorexia nervosa (AN; age 23.10 ± 6.14 years), 19 recovered from restricting-type AN (recovered AN; age 26.95 ± 5.31 years), 20 with bulimia nervosa (BN; age 25.15 ± 5.31 years), and 19 with obesity (age 28.16 ± 8.13 years), received sucrose, control solution or no taste stimulation during functional magnetic resonance brain imaging. Multivariate Bayesian pattern analysis (decoding) and cross-validation tested taste classification accuracy (adjusted for comorbidity, medication use, taste perception, interoception, and brain activation volume). RESULTS: For sucrose versus control solution, classification accuracy differed (F = 2.53, P < 0.041). Post hoc tests indicated higher classification accuracy in healthy comparison compared to women with AN (P < 0.016) or obesity (P < 0.027), and in recovered AN as compared to AN (P < 0.016) or obesity (P < 0.047) groups. Taste stimulation resulted in sparse insula voxel activation across all groups. DISCUSSION: Reduced classification accuracy across stimuli in women with AN or obesity could indicate low brain encoding discrimination of stimulus quality, which could contribute to altered reward activation and eating drive that is not adjusted to nutritional needs. This deficit appears to normalize with recovery from AN, but adjusting food flavor intensity could aid in the treatment of individuals with AN or obesity. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2016; 49:603-612).

The medical complications associated with purging.

OBJECTIVE: Purging behaviors, including self-induced vomiting, laxative abuse, and diuretic abuse, are present across many of the eating disorders. Here we review the major medical complications of these behaviors. METHOD: Although we identified over 100 scholarly articles describing medical complications associated with purging, most papers involved case studies or small, uncontrolled samples. Given the limited evidence base, we conducted a qualitative (rather than systematic) review to identify medical complications that have been attributed to purging behaviors. RESULTS: Medical conditions affecting the teeth, esophagus, gastrointestinal system, kidneys, skin, cardiovascular system, and musculoskeletal system were identified, with self-induced vomiting causing the most medical complications. DISCUSSION: Purging behavior can be associated with severe medical complications across all body systems. Mental health professionals should refer patients with purging behaviors to medical providers for screening and treatment as needed. The medical work-up for individuals with eating disorders should include a comprehensive metabolic panel, complete blood count, and a full body exam including the teeth to prevent severe complications. Medical providers should screen patients for purging behaviors and associated medical complications, even in the absence of an eating disorder diagnosis, to increase the detection of eating disorders. Recognizing the link between purging and medical complications can aid in identifying potential eating disorders, particularly those that often elude detection such as purging disorder.

Speaking of That: Terms to Avoid or Reconsider in the Eating Disorders Field.

Inspired by an article on 50 terms that, in the interest of clarity in scientific reasoning and communication in psychology, psychiatry, and allied fields, "should be avoided or at most be used sparingly and only with explicit caveats,"(1) we propose a list of terms to avoid or think twice about before using when writing for the International Journal of Eating Disorders (IJED). Drawing upon our experience as reviewers or editors for the IJED, we generated an abridged list of such terms. For each term, we explain why it made our list and what alternatives we recommend. We hope that our list will contribute to improved clarity in scientific thinking about eating disorders, and that it will stimulate discussion of terms that may need to be reconsidered in our field's vocabulary to ensure the use of language that is respectful and sensitive to individuals who experience an eating disorder.

Recent advances in neuroimaging to model eating disorder neurobiology.

The eating disorders (EDs) anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED) are severe psychiatric disorders with high mortality. There are many symptoms, such as food restriction, episodic binge eating, purging, or excessive exercise that are either overlapping or lie on opposite ends of a scale or spectrum across those disorders. Identifying how specific ED behaviors are linked to particular neurobiological mechanisms could help better categorize ED subgroups and develop specific treatments. This review provides support from recent brain imaging research that brain structure and function measures can be linked to disorder-specific biological or behavioral variables, which may help distinguish ED subgroups, or find commonalities between them. Brain structure and function may therefore be suitable research targets to further study the relationship between dimensions of behavior and brain function relevant to EDs and beyond the categorical AN, BN, and BED distinctions.